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HIV Infection & AIDS Andrew R. Zolopa, MD Mitchell H. Katz, MD

``

E s s en t i a l s o f d i a g no s i s

Risk factors: sexual contact with an infected person, parenteral exposure to infected blood by transfusion or needle sharing, perinatal exposure.

Prominent systemic complaints such as sweats, diarrhea, weight loss, and wasting.

Opportunistic infections due to diminished cellular immunity—often life-threatening.

Aggressive cancers, particularly Kaposi sarcoma and extranodal lymphoma.

Neurologic manifestations, including dementia, aseptic meningitis, and neuropathy.

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``General Considerations When AIDS was first recognized in the United States in 1981, cases were identified by finding severe opportunistic infections such as Pneumocystis pneumonia that indicated profound defects in cellular immunity in the absence of other causes of immunodeficiency. When HIV was identified as the cause of the syndrome, it became obvious that severe opportunistic infections and unusual neoplasms were at one end of a spectrum of disease, while healthy seropositive individuals were at the other end.

The Centers for Disease Control and Prevention (CDC) AIDS case definition (Table 31–1) includes opportunistic infections and malignancies that rarely occur in the absence of severe immunodeficiency (eg, Pneumocystis pneumonia, central nervous system lymphoma). It also classifies persons as having AIDS if they have positive HIV serology and certain infections and malignancies that can occur in immunocompetent hosts but that are more common among persons infected with HIV (pulmonary tuberculosis, invasive cervical cancer). Several nonspecific conditions, including dementia and wasting (documented weight loss)—in the presence of a positive HIV serology— are considered AIDS. The definition includes criteria for both definitive and presumptive diagnoses of certain

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infections and malignancies. Finally, persons with positive HIV serology who have ever had a CD4 lymphocyte count below 200 cells/mcL or a CD4 lymphocyte percentage below 14% are considered to have AIDS. Inclusion of persons with low CD4 counts as AIDS cases reflects the recognition that immunodeficiency is the defining characteristic of AIDS. The choice of a cutoff point at 200 cells/mcL is supported by several cohort studies showing that AIDS will develop within 3 years in over 80% of persons with counts below this level in the absence of effective antiretroviral therapy (ART). The 1993 definition was also expanded to include persons with positive HIV serology and pulmonary tuberculosis (see Figure 9–5), recurrent pneumonia, and invasive cervical cancer. The prognosis of persons with HIV/AIDS has dramatically improved due to the introduction of highly active antiretroviral therapy (HAART) in the mid 1990s. One consequence is that fewer persons with HIV ever develop an infection or malignancy or have a low enough CD4 count to classify them as having AIDS, which means that the CDC definition has become a less useful measure of the impact of HIV/AIDS in the United States. Conversely, persons in whom AIDS had been diagnosed based on a serious opportunistic infection, malignancy, or immunodeficiency may now be markedly healthier, with high CD4 counts, due to the use of HAART. Therefore, the Social Security Administration as well as most social service agencies focus on functional assessment for determining eligibility for benefits rather than the simple presence or absence of an AIDS-defined illness.

``Epidemiology The modes of transmission of HIV are similar to those of hepatitis B, in particular with respect to sexual, parenteral, and vertical transmission. Although certain sexual practices (eg, receptive anal intercourse) are significantly riskier than other sexual practices (eg, oral sex), it is difficult to quantify per-contact risks. The reason is that studies of sexual transmission of HIV show that most people at risk for HIV infection engage in a variety of sexual practices and have sex with multiple persons, only some of whom may

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Table 31–1. CDC AIDS case definition for surveillance of adults and adolescents.

Definitive AIDS diagnoses (with or without laboratory evidence of HIV infection) 1. Candidiasis of the esophagus, trachea, bronchi, or lungs.

2. Cryptococcosis, extrapulmonary.

3. Cryptosporidiosis with diarrhea persisting > 1 month.

4. Cytomegalovirus disease of an organ other than liver, spleen, or lymph nodes.

5. Herpes simplex virus infection causing a mucocutaneous ulcer that persists longer than 1 month; or bronchitis, pneumonitis, or esophagitis of any duration.

6. Kaposi sarcoma in a patient < 60 years of age.

7. Lymphoma of the brain (primary) in a patient < 60 years of age.

8. Mycobacterium avium complex or Mycobacterium kansasii disease, disseminated (at a site other than or in addition to lungs, skin, or cervical or hilar lymph nodes).

9. Pneumocystis jiroveci pneumonia.

10. Progressive multifocal leukoencephalopathy.

11. Toxoplasmosis of the brain.

Definitive AIDS diagnoses (with laboratory evidence of HIV infection) 1. Coccidioidomycosis, disseminated (at a site other than or in addition to lungs or cervical or hilar lymph nodes).

2. HIV encephalopathy.

3. Histoplasmosis, disseminated (at a site other than or in addition to lungs or cervical or hilar lymph nodes).

4. Isosporiasis with diarrhea persisting > 1 month.

5. Kaposi sarcoma at any age.

6. Lymphoma of the brain (primary) at any age.

7. Other non-Hodgkin lymphoma of B cell or unknown immunologic phenotype.

8. Any mycobacterial disease caused by mycobacteria other than Mycobacterium tuberculosis, disseminated (at a site other than or in addition to lungs, skin, or cervical or hilar lymph nodes).

9. Disease caused by extrapulmonary M tuberculosis.

10. Salmonella (nontyphoid) septicemia, recurrent.

11. HIV wasting syndrome.

12. CD4 lymphocyte count below 200 cells/mcL or a CD4 lymphocyte percentage below 14%.

13. Pulmonary tuberculosis.

14. Recurrent pneumonia.

15. Invasive cervical cancer.

Presumptive AIDS diagnoses (with laboratory evidence of HIV infection) 1. Candidiasis of esophagus: (a) recent onset of retrosternal pain on swallowing; and (b) oral candidiasis.

2. Cytomegalovirus retinitis. A characteristic appearance on serial ophthalmoscopic examinations.

3. Mycobacteriosis. Specimen from stool or normally sterile body fluids or tissue from a site other than lungs, skin, or cervical or hilar lymph nodes, showing acid-fast bacilli of a species not identified by culture.

4. Kaposi sarcoma. Erythematous or violaceous plaque-like lesion on skin or mucous membrane.

5. Pneumocystis jiroveci pneumonia: (a) a history of dyspnea on exertion or nonproductive cough of recent onset (within the past 3 months); and (b) chest x-ray evidence of diffuse bilateral interstitial infiltrates or gallium scan evidence of diffuse bilateral pulmonary disease; and (c) arterial blood gas analysis showing an arterial oxygen partial pressure of < 70 mm Hg or a low respiratory diffusing capacity of < 80% of predicted values or an increase in the alveolar-arterial oxygen tension gradient; and (d) no evidence of a bacterial pneumonia.

6. Toxoplasmosis of the brain: (a) recent onset of a focal neurologic abnormality consistent with intracranial disease or a reduced level of consciousness; and (b) brain imaging evidence of a lesion having a mass effect or the radiographic appearance of which is enhanced by injection of contrast medium; and (c) serum antibody to toxoplasmosis or successful response to therapy for toxoplasmosis.

7. Recurrent pneumonia: (a) more than one episode in a 1-year period; and (b) acute pneumonia (new symptoms, signs, or radiologic evidence not present earlier) diagnosed on clinical or radiologic grounds by the patient’s physician.

8. Pulmonary tuberculosis: (a) apical or miliary infiltrates and (b) radiographic and clinical response to antituberculous therapy.

HIV Infection & AIDS actually be HIV infected. Thus, it is difficult to determine which practice with which person actually resulted in HIV transmission.

Nonetheless, the best available estimates indicate that the risk of HIV transmission with receptive anal intercourse is between 1:100 and 1:30, with insertive anal intercourse 1:1000, with receptive vaginal intercourse 1:1000, with insertive vaginal intercourse 1:10,000, and with receptive fellatio with ejaculation 1:1000. The per-contact risk of HIV transmission with other behaviors, including receptive fellatio without ejaculation, insertive fellatio, and cunnilingus, is not known.

All per-contact risk estimates assume that the source is HIV infected. If the HIV status of the source is unknown, the risk of transmission is the risk of transmission multiplied by the probability that the source is HIV infected.

This would vary by risk practices, age, and geographic area. A number of cofactors are known to increase the risk of HIV transmission during a given encounter, including the presence of ulcerative or inflammatory sexually transmitted diseases, trauma, menses, and lack of male circumcision.

The risk of acquiring HIV infection from a needlestick with infected blood is approximately 1:300. Factors known to increase the risk of transmission include depth of penetration, hollow bore needles, visible blood on the needle, and advanced stage of disease in the source. The risk of HIV transmission from a mucosal splash with infected blood is unknown but is assumed to be significantly lower.

The risk of acquiring HIV infection from illicit drug use with sharing of needles from an HIV-infected source is estimated to be 1:150. Use of clean needles markedly decreases the chance of HIV transmission but does not eliminate it if other drug paraphernalia are shared (eg, cookers).

When blood transfusion from an HIV-infected donor occurs, the risk of transmission is 95%. Fortunately, since 1985, blood donor screening using the HIV enzyme-linked immunosorbent assay (ELISA) has been universally practiced in the United States. Also, persons who have recently engaged in unsafe behaviors (eg, sex with a person at risk for HIV, injection drug use) are not allowed to donate. This essentially eliminates donations from persons who are HIV infected but have not yet developed antibodies (ie, persons in the “window” period). In recent years, HIV antigen and viral load testing have been added to the screening of blood to further lower the chance of HIV transmission. With these precautions, the chance of HIV transmission with receipt of blood transfusion is about 1:1,000,000.

In the absence of perinatal HIV prophylaxis, between 13% and 40% of children born to HIV-infected mothers contract HIV infection. The risk is higher with vaginal than with cesarean delivery, higher among mothers with high viral loads, and higher among those who breast-feed their children. The risk can be decreased by administering antiretroviral treatment to the mother during pregnancy and to the infant immediately after birth (see below).

HIV has not been shown to be transmitted by respiratory droplet spread, by vectors such as mosquitoes, or by casual nonsexual contact.

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There are an estimated 1,106,400 Americans infected with HIV, about 51,000 new infections each year and an estimated 468,578 persons in the United States living with AIDS. Of those, 76% are men, of whom 60% were exposed through male-to-male sexual contact, 18% were exposed through injection drug use, 11% were exposed through heterosexual contact, and 8% were exposed through maleto-male sexual contact and injection drug use. Women account for 23% of living persons with HIV infection, of whom 66% were infected through heterosexual contact and 32% were exposed through injection drug use. Children account for < 1% of living cases. African Americans have been disproportionately hard hit by the epidemic. The estimated rate of new AIDS cases in the United States per 100,000 adult/adolescent population is 59.2 among African Americans, 20.4 among Latinos, 8.6 among native Americans and native Alaskans, 6.1 among whites, 4.3 among Asians, and 22.3 among Pacific Islanders.

In general, the progression of HIV-related illness is similar in men and women. However, there are some important differences. Women are at risk for gynecologic complications of HIV, including recurrent candidal vaginitis, pelvic inflammatory disease, and cervical dysplasia.

Violence directed against women, pregnancy, and frequent occurrence of drug use and poverty all complicate the treatment of HIV-infected women. Although “safer sex” campaigns dramatically decreased the rates of seroconversions among men who have sex with men (MSM) living in metropolitan areas in the United States by the mid 1980s, relapse to unsafe sexual practices among MSM in several large cities in the United States and in western Europe has been observed. The higher rates of unsafe sex appear to be related to decreased concern about acquiring HIV due to the availability of HAART. Decreased interest in following safer sex recommendations and increasing use of crystal methamphetamine among certain risk groups also appears to be playing a role in the increased unsafe sex rates.

Worldwide there are an estimated 33 million persons infected with HIV, with heterosexual spread being the most common mode of transmission for men and women. In Central and East Africa, in some urban areas, as many as one-third of sexually active adults are infected. The reason for the greater risk for transmission with heterosexual intercourse in Africa and Asia than in the United States may relate to cofactors such as general health status, the presence of genital ulcers, relative lack of male circumcision, the number of sexual partners, and different HIV serotypes.

Centers for Disease Control and Prevention: HIV/AIDS Sur­ veillance Reports. http://www.cdc.gov/hiv/topics/surveillance/ resources/reports/index.htm.

Hall HI et al; HIV Incidence Surveillance Group. Estimation of HIV incidence in the United States. JAMA. 2008 Aug 6;300(5): 520–9. [PMID: 18677024] Public Health Service Task Force recommendations for use of antiretroviral drugs in pregnant HIV-infected women for maternal health and interventions to reduce perinatal HIV-1 transmission in the United States. April 29, 2009 Guideline. http:// aidsinfo. nih.gov/ContentFiles/PerinatalGL.pdf

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``Etiology HIV, like other retroviruses, depends on a unique enzyme, reverse transcriptase (RNA-dependent DNA polymerase), to replicate within host cells. The other major pathogenic human retrovirus, human T cell lymphotropic/leukemia virus (HTLV)-I, is associated with lymphoma, while HIV is not known to be directly oncogenic. The HIV genomes contain genes for three basic structural proteins and at least five other regulatory proteins; gag codes for group antigen proteins, pol codes for polymerase, and env codes for the external envelope protein. The greatest variability in strains of HIV occurs in the viral envelope. Since neutralizing activity is found in antibodies directed against the envelope, this variability presents problems for vaccine development.

In addition to the classic AIDS virus (HIV-1), a group of related viruses, HIV-2, has been isolated in West African patients. HIV-2 has the same genetic organization as HIV-1, but there are significant differences in the envelope glycoproteins. Some infected individuals exhibit AIDS-like illnesses, but the rate of progression in individuals infected with HIV-2 appears to be slower than that of HIV-1 infection. HIV-2 remains relatively rare in the United States but has become more common in Western Europe due to immigration from endemic areas. Cases have been documented in which AIDS-like illnesses have occurred in the absence of HIV infection or other known infectious causes of immunodeficiency.

``Pathogenesis The hallmark of symptomatic HIV infection is immunodeficiency caused by continuing viral replication. The virus can infect all cells expressing the T4 (CD4) antigen, which HIV uses to attach to the cell. Chemokine co-­ receptors (CCR5 or CXCR4, or both) are required for virus entry, and individuals with CCR5 deletions (ie, “delta 32”) are less likely to become infected and, once infected, the disease is more likely to progress slowly.

Once it enters a cell, HIV can replicate and cause cell fusion or death. A latent state is also established, with integration of the HIV genome into the cell’s genome. The cell principally infected is the CD4 (helper-inducer) lymphocyte, which directs many other cells in the immune network. With increasing duration of infection, the number of CD4 lymphocytes falls. Some of the immunologic defects, however, are explained not by quantitative abnormalities of lymphocyte subsets but by qualitative defects in CD4 responsiveness induced by HIV. Other cells in the immune network that are infected by HIV include B lymphocytes and macrophages. The defect in B cells is partly due to disordered CD4 lymphocyte function. These direct and indirect effects can lead to generalized hypergammaglobulinemia and can also depress B cell responses to new antigen challenges. Because of these defects, the immunodeficiency of HIV is mixed. Elements of humoral and cellular immunodeficiency are present, especially in children. Macrophages act as a reservoir for HIV and serve to disseminate it to other organ systems (eg, the central nervous system).

Apart from the immunologic effects of HIV, the virus can also directly cause a variety of neurologic effects.

Neuropathology largely results from the release of cyto­ kines and other neurotoxins by infected macrophages.

Perturbations of excitatory neurotransmitters and calcium flux may contribute to neurologic dysfunction. Direct HIV infection of renal tubular cells and gastrointestinal epithelium may contribute to these organ system manifestations of infection.

``Pathophysiology Clinically, the syndromes caused by HIV infection are usually explicable by one of three known mechanisms: immunodeficiency, autoimmunity, and allergic and hyper-sensitivity reactions.

A. Immunodeficiency Immunodeficiency is a direct result of the effects of HIV upon immune cells. A spectrum of infections and neoplasms is seen, as in other congenital or acquired immunodeficiency states. Two remarkable features of HIV immunodeficiency are the low incidence of certain infections such as listeriosis and aspergillosis and the frequent occurrence of certain neoplasms such as lymphoma or Kaposi sarcoma. This latter complication has been seen primarily in MSM or in bisexual men, and its incidence steadily declined through the first 15 years of the epidemic.

A herpesvirus (KSHV or HHV-8) is the cause of Kaposi sarcoma.

B. Autoimmunity/Allergic and Hypersensitivity Reactions Autoimmunity can occur as a result of disordered cellular immune function or B lymphocyte dysfunction. Examples of both lymphocytic infiltration of organs (eg, lymphocytic interstitial pneumonitis) and autoantibody production (eg, immunologic thrombocytopenia) occur. These phenomena may be the only clinically apparent disease or may coexist with obvious immunodeficiency. Moreover, HIV-infected individuals appear to have higher rates of allergic reactions to unknown allergens as seen with eosinophilic pustular folliculitis (“itchy red bump syndrome”) as well as increased rates of hypersensitivity reactions to medications (for example, the fever and sunburn-like rash seen with trimethoprimsulfamethoxazole reactions).

``Clinical Findings The complications of HIV-related infections and neoplasms affect virtually every organ. The general approach to the HIV-infected person with symptoms is to evaluate the organ systems involved, aiming to diagnose treatable conditions rapidly. As can be seen in Figure 31–1, the CD4 lymphocyte count provides very important prognostic information. Certain infections may occur at any CD4 count, while others rarely occur unless the CD4 lymphocyte count has dropped below a certain level. For example, a patient with a CD4 count of 600 cells/mcL, cough, and

HIV Infection & AIDS

Absolute CD4 lymphocyte count (/mcL)

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Bacterial infections Tuberculosis Herpes simplex Herpes zoster Vaginal candidiasis Hairy leukoplakia Kaposi sarcoma

200 Pneumocystosis Toxoplasmosis Cryptococcosis Coccidioidomycosis Cryptosporidiosis 50

Disseminated MAC infection Histoplasmosis CMV retinitis CNS lymphoma

s Figure 31–1. Relationship of CD4 count to development of opportunistic infections. MAC, Mycobacterium avium complex; CMV, cytomegalovirus; CNS, central nervous system. fever may have a bacterial pneumonia but would be very unlikely to have Pneumocystis pneumonia.

A. Symptoms and Signs Many individuals with HIV infection remain asymptomatic for years even without ART, with a mean time of approximately 10 years between infection and development of AIDS. When symptoms occur, they may be remarkably protean and nonspecific. Since virtually all the findings may be seen with other diseases, a combination of complaints is more suggestive of HIV infection than any one symptom.

Physical examination may be entirely normal. Abnormal findings range from completely nonspecific to highly specific for HIV infection. Those that are specific for HIV infection include hairy leukoplakia of the tongue, disseminated Kaposi sarcoma, and cutaneous bacillary angiomatosis. Generalized lymphadenopathy is common early in infection.

The specific presentations and management of the various complications of HIV infection are discussed under the Complications section below.

B. Laboratory Findings Specific tests for HIV include antibody and antigen detection (Table 31–2). Conventional HIV antibody testing is done by ELISA. Positive specimens are then confirmed by a different method (eg, Western blot). The sensitivity of screening serologic tests is > 99.9%. The

specificity of positive results by two different techniques approaches 100% even in low-risk populations. Falsepositive screening tests may occur as normal biologic variants or in association with recent influenza vaccination or other disease states, such as connective tissue disease. These are usually detected by negative confirmatory tests. Molecular biology techniques (PCR) show a small incidence of individuals (< 1%) who are infected with HIV for up to 36 months without generating an antibody response. However, antibodies that are detectable by screening serologic tests will develop in 95% of persons within 6 weeks after infection.

Rapid HIV antibody tests provide results within 10–20 minutes and can be performed in clinician offices, including by personnel without laboratory training and without a Clinical Laboratory Improvement Amendment (CLIA) approved laboratory. Persons who test positive on a rapid test should be told that they may be HIV-infected or their test may be falsely reactive. Standard testing (ELISA with Western blot confirmation) should be performed to distinguish these two possibilities. Rapid testing is particularly helpful in settings where a result is needed immediately (eg, a woman in labor who has not recently been tested for HIV) or when the patient is unlikely to return for a result.

Nonspecific laboratory findings with HIV infection may include anemia, leukopenia (particularly lymphopenia), and thrombocytopenia in any combination, elevation of the erythrocyte sedimentation rate, polyclonal hypergammaglobulinemia, and hypocholesterolemia. Cutaneous anergy is common.

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Table 31–2. Laboratory findings with HIV infection.

Test

Significance

HIV enzyme-linked immunosorbent assay (ELISA)

Screening test for HIV infection. Of ELISA tests 50% are positive within 22 days after HIV transmission; 95% are positive within 6 weeks after transmission. Sensitivity > 99.9%; to avoid false-positive results, repeatedly reactive results must be confirmed with Western blot.

Western blot

Confirmatory test for HIV. Specificity when combined with ELISA > 99.99%. Indeterminate results with early HIV infection, HIV-2 infection, autoimmune disease, pregnancy, and recent tetanus toxoid administration.

HIV rapid antibody test

Screening test for HIV. Produces results in 10–20 minutes. Can be performed by personnel with limited training. Positive results must be confirmed with standard HIV test (ELISA and Western blot).

Complete blood count

Anemia, neutropenia, and thrombocytopenia common with advanced HIV infection.

Absolute CD4 lymphocyte count

Most widely used predictor of HIV progression. Risk of progression to an AIDS opportunistic infection or malignancy is high with CD4 < 200 cells/mcL in the absence of treatment.

CD4 lymphocyte percentage

Percentage may be more reliable than the CD4 count. Risk of progression to an AIDS opportunistic infection or malignancy is high with percentage < 14% in the absence of treatment.

HIV viral load tests

These tests measure the amount of actively replicating HIV virus. Correlate with disease progression and response to antiretroviral drugs. Best tests available for diagnosis of acute HIV infection (prior to seroconversion); however, caution is warranted when the test result shows low-level viremia (ie, < 500 copies/mL) as this may represent a false-positive test.

Several laboratory markers are available to provide prognostic information and guide therapy decisions (Table 31–2).

The most widely used marker is the absolute CD4 lymphocyte count. As counts decrease, the risk of serious opportunistic infection over the subsequent 3–5 years increases (Figure 31–1).

There are many limitations to using the CD4 count, including diurnal variation, depression with intercurrent illness, and intralaboratory and interlaboratory variability.

Therefore, the trend is more important than a single determination. The frequency of performance of counts depends on the patient’s health status and whether or not they are receiving antiretroviral treatment. Patients not receiving treatment whose CD4 counts are substantially above the threshold for initiation of antiviral therapy (500 cells/mcL) should have counts performed every 6 months. Those who have counts near or below 500 cells/mcL should have counts performed every 3 months. For patients receiving ART, with undetectable viral loads, and CD4 counts > 350 cells/mcL, CD4 counts need only be performed every 3-6 months. In patients who have detectable viral loads, CD4 counts should be performed every 3 months to evaluate the need for a change in therapy or for initiation of P jiroveci prophylactic therapy when the CD4 count drops below 200 cells/mcL, or initiation of M avium prophylaxis when the CD4 count drops below 75-100 cells/mcL. Some studies suggest that the percentage of CD4 lymphocytes is a more reliable indicator of prognosis than the absolute counts because the percentage does not depend on calculating a manual differential. While the CD4 count measures immune dysfunction, it does not provide a measure of how actively HIV is replicating in the body.

HIV viral load tests (discussed below) assess the level of viral replication and provide useful prognostic information that is independent of the information provided by CD4 counts.

``Differential Diagnosis HIV infection may mimic a variety of other medical ­illnesses. Specific differential diagnosis depends on the mode of presentation. In patients presenting with constitutional symptoms such as weight loss and fevers, differential considerations include cancer, chronic infections such as tuberculosis and endocarditis, and endocrinologic diseases such as hyperthyroidism. When pulmonary processes dominate the presentation, acute and chronic lung infections must be considered as well as other causes of diffuse interstitial pulmonary infiltrates. When neurologic disease is the mode of presentation, conditions that cause mental status changes or neuropathy—eg, alcoholism, liver disease, kidney dysfunction, thyroid disease, and vitamin deficiency—should be considered. If a patient presents with headache and a cerebrospinal fluid pleocytosis, other causes of chronic meningitis enter the differential. When diarrhea is a prominent complaint, infectious enterocolitis, antibiotic-associated colitis, inflammatory bowel disease, and malabsorptive symptoms must be considered.

``Complications A. Systemic Complaints Fever, night sweats, and weight loss are common symptoms in HIV-infected patients and may occur without a complicating opportunistic infection. Patients with persistent fever and no localizing symptoms should nonetheless be carefully examined, and evaluated with a chest radiograph (Pneumocystis pneumonia can present without respiratory symptoms), bacterial blood cultures if the fever is > 38.5 °C, serum cryptococcal antigen, and mycobacterial cultures of the blood. Sinus CT scans or sinus radiographs should be considered to evaluate occult sinusitis. If these studies are

HIV Infection & AIDS normal, patients should be observed closely. Antipyretics are useful to prevent dehydration.

1. Weight loss—Weight loss is a particularly distressing complication of long-standing HIV infection. Patients typically have disproportionate loss of muscle mass, with maintenance or less substantial loss of fat stores. The mechanism of HIV-related weight loss is not completely understood but appears to be multifactorial.

A. Presentation—AIDS patients frequently suffer from anorexia, nausea, and vomiting, all of which contribute to weight loss by decreasing caloric intake. In some cases, these symptoms are secondary to a specific infection, such as viral hepatitis. In other cases, however, evaluation of the symptoms yields no specific pathogen, and it is assumed to be due to a primary effect of HIV. Malabsorption also plays a role in decreased caloric intake. Patients may suffer diarrhea from infections with bacterial, viral, or parasitic agents.

Exacerbating the decrease in caloric intake, many AIDS patients have an increased metabolic rate. This increased rate has been shown to exist even among asymptomatic HIV-infected persons, but it accelerates with disease progression and secondary infection. AIDS patients with secondary infections also have decreased protein synthesis, which makes maintaining muscle mass difficult.

B. Management—Several strategies have been developed to slow AIDS wasting. Effective fever control decreases the metabolic rate and may slow the pace of weight loss, as does treating the underlying opportunistic infection. Food supplementation with high-calorie drinks may enable patients with not much appetite to maintain their intake. Selected patients with otherwise good functional status and weight loss due to unrelenting nausea, vomiting, or diarrhea may benefit from total parenteral nutrition (TPN). It should be noted, however, that TPN is more likely to increase fat stores than to reverse the muscle wasting process.

Two pharmacologic approaches for increasing appetite and weight gain are the progestational agent megestrol acetate (80 mg orally four times a day) and the antiemetic agent dronabinol (2.5–5 mg orally three times a day). Side effects from megestrol acetate are rare, but thromboembolic phenomena, edema, nausea, vomiting, and rash have been reported. Euphoria, dizziness, paranoia, and somnolence and even nausea and vomiting have been reported in 3–10% of patients using dronabinol. Dronabinol contains only one of the active ingredients in smoked marijuana, and many patients report better relief of nausea and improvement of appetite with smoking marijuana. Thirteen states allow patients to obtain marijuana for medicinal purposes with a letter of recommendation from their doctor. However, the use and sale of marijuana is still illegal under federal law. The Supreme Court has ruled that physicians cannot be prosecuted for recommending marijuana to their patients (it would be an infringement of freedom of speech). Therefore, while a physician’s recommendation may not completely protect patients, letters decrease the chance that patients will be prosecuted for use of marijuana. Unfortunately, neither megestrol acetate nor dronabinol increases lean body mass.

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Two regimens that have resulted in increases in lean body mass are growth hormone and anabolic steroids.

Growth hormone at a dose of 0.1 mg/kg/d (up to 6 mg) subcutaneously for 12 weeks has resulted in modest increases in lean body mass. Treatment with growth hormone can cost as much as $10,000 per month. Anabolic steroids also increase lean body mass among HIV-infected patients. They seem to work best for patients who are able to do weight training. The most commonly used regimens are testosterone enanthate or testosterone cypionate (100–200 mg intramuscularly every 2–4 weeks). Testosterone transdermal system (apply 5 mg system each evening) and testosterone gel (1%; apply a 5-g packet [50 mg testosterone] to clean, dry skin daily) are also available. The anabolic steroid oxandrolone (20 mg orally in two divided doses) has also been found to increase lean body mass.

2. Nausea—Nausea leading to weight loss is sometimes due to esophageal candidiasis. Patients with oral candidiasis and nausea should be empirically treated with an oral antifungal agent. Patients with weight loss due to nausea of unclear origin may benefit from use of antiemetics prior to meals (prochlorperazine, 10 mg three times daily; metoclopramide, 10 mg three times daily; or ondansetron, 8 mg three times daily). Dronabinol (5 mg three times daily) can also be used to increase appetite. Depression and adrenal insufficiency are two potentially treatable causes of weight loss.

B. Pulmonary Disease 1. Pneumocystis pneumonia—(See also discussions in Chapter 36.) Pneumocystis jiroveci pneumonia is the most common opportunistic infection associated with AIDS. Pneumocystis pneumonia may be difficult to diagnose because the symptoms—fever, cough, and shortness of breath—are nonspecific. Furthermore, the severity of symptoms ranges from fever and no respiratory symptoms through mild cough or dyspnea to frank respiratory distress.

Hypoxemia may be severe, with a Po2 < 60 mm Hg. The cornerstone of diagnosis is the chest radiograph. Diffuse or perihilar infiltrates are most characteristic, but only two-thirds of patients with Pneumocystis pneumonia have this finding. Normal chest radiographs are seen in 5–10% of patients with Pneumocystis pneumonia, while the remainder have atypical infiltrates. Apical infiltrates are commonly seen among patients with Pneumocystis pneumonia who have been receiving aerosolized pentamidine prophylaxis. Large pleural effusions are uncommon with Pneumocystis pneumonia; their presence suggests bacterial pneumonia, other infections such as tuberculosis, or pleural Kaposi sarcoma.

Definitive diagnosis can be obtained in 50–80% of cases

by Wright-Giemsa stain or direct fluorescence antibody (DFA) test of induced sputum. Sputum induction is performed by having patients inhale an aerosolized solution of 3% saline produced by an ultrasonic nebulizer. Patients should not eat for at least 8 hours and should not use toothpaste or mouthwash prior to the procedure since they can interfere with test interpretation. The next step for

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patients with negative sputum examinations in whom Pneumocystis pneumonia is still suspected should be bronchoalveolar lavage. This technique establishes the diagnosis in over 95% of cases.

In patients with symptoms suggestive of Pneumocystis pneumonia but with negative or atypical chest radiographs and negative sputum examinations, other diagnostic tests may provide additional information in deciding whether to proceed to bronchoalveolar lavage.

Elevation of serum lactate dehydrogenase occurs in 95% of cases of Pneumocystis pneumonia, but the specificity of this finding is at best 75%. A serum β-glucan test is more sensitive and specific test for Pneumocystis pneumonia compared with serum lactate dehydrogenase and may avoid more invasive tests when used in the appropriate clinical setting. Either a normal diffusing capacity of carbon monoxide (DLCO) or a high-resolution CT scan of the chest that demonstrates no interstitial lung disease makes the diagnosis of Pneumocystis pneumonia very unlikely. In addition, a CD4 count > 250 cells/mcL within 2 months prior to evaluation of respiratory symptoms makes a diagnosis of Pneumocystis pneumonia unlikely; only 1–5% of cases occur above this CD4 count level (Figure 31–1). This is true even if the patient previously had a CD4 count lower than 200 cells/mcL but has had an increase with ART. Pneumothoraces can be seen in HIV-infected patients with a history of Pneumocystis pneumonia, especially if they have received aerosolized pentamidine treatment.

2. Other infectious pulmonary diseases— A. Presentation—Other infectious causes of pulmonary disease in AIDS patients include bacterial, mycobacterial, and viral pneumonias. Community-acquired pneumonia is the most common cause of pulmonary disease in HIVinfected persons. An increased incidence of pneumococcal pneumonia with septicemia and Haemophilus influenzae pneumonia has been reported. Pseudomonas aeruginosa is an important respiratory pathogen in advanced disease and, more rarely, pneumonia from Rhodococcus equi infection can occur. The incidence of infection with Mycobacterium tuberculosis has markedly increased in metropolitan areas because of HIV infection as well as homelessness.

Tuberculosis occurs in an estimated 4% of persons in the United States who have AIDS. Apical infiltrates and disseminated disease occur more commonly than among immunocompetent persons. Although a purified protein derivative (PPD) test should be performed on all HIVinfected persons in whom a diagnosis of tuberculosis is being considered, the lower the CD4 cell count, the greater the likelihood of anergy. Because “anergy” skin test panels do not accurately classify those patients who are infected with tuberculosis but unreactive to the PPD, they are not recommended.

B. Management—Treatment of HIV-infected persons with active tuberculosis is similar to treatment of HIVuninfected tubercular individuals (see Figure 31–1).

However, rifampin should not be given to patients receiving a boosted protease inhibitor (PI)-regimen. In these

cases, rifabutin may be substituted, but it may require dosing modifications depending on the antiretroviral regimen.

Multidrug-resistant tuberculosis has been a major problem in several metropolitan areas of the developed world, and reports from South Africa of “extremely resistant” tuberculosis in AIDS patients is a growing global concern.

Noncompliance with prescribed antituberculous drugs is a major risk factor. Several of the reported outbreaks appear to implicate nosocomial spread. The emergence of drug resistance makes it essential that antibiotic sensitivities be performed on all positive cultures. Drug therapy should be individualized. Patients with multidrug-resistant M tuberculosis infection should receive at least three drugs to which their organism is sensitive. Atypical mycobacteria can cause pulmonary disease in AIDS patients with or without preexisting lung disease and responds variably to treatment. Making a distinction between M tuberculosis and atypical mycobacteria requires culture of sputum specimens. If culture of the sputum produces acid-fast bacilli, definitive identification may take several weeks using traditional techniques. DNA probes allow for presumptive identification usually within days of a positive culture.

While awaiting definitive diagnosis, clinicians should err on the side of treating patients as if they have M tuberculosis infection. In cases in which the risk of atypical mycobacteria is very high (eg, a person without risk for tuberculosis exposure with a CD4 count under 50 cells/mcL—see Figure 31–1), clinicians may wait for definitive diagnosis if the person is smear-negative for acid-fast bacilli, clinically stable, and not living in a communal setting. Isolation of cytomegalovirus (CMV) from bronchoalveolar lavage fluid occurs commonly in AIDS patients but does not establish a definitive diagnosis. Diagnosis of CMV pneumonia requires biopsy; response to treatment is poor.

Histoplasmosis, coccidioidomycosis, and cryptococcal disease as well as more common respiratory viral infections should also be considered in the differential diagnosis of unexplained pulmonary infiltrates.

3. Noninfectious pulmonary diseases— A. Presentation—Noninfectious causes of lung disease include Kaposi sarcoma, non-Hodgkin lymphoma, and interstitial pneumonitis. In patients with known Kaposi sarcoma, pulmonary involvement complicates the course in approximately one-third of cases. However, pulmonary involvement is rarely the presenting manifestation of Kaposi sarcoma. Non-Hodgkin lymphoma may involve the lung as the sole site of disease but more commonly involves other organs as well, especially the brain, liver, and gastrointestinal tract. Both of these processes may show nodular or diffuse parenchymal involvement, pleural effusions, and mediastinal adenopathy on chest radiographs.

Nonspecific interstitial pneumonitis may mimic Pneumocystis pneumonia. Lymphocytic interstitial pneumonitis seen in lung biopsies has a variable clinical course.

Typically, these patients present with several months of mild cough and dyspnea; chest radiographs show interstitial infiltrates. Many patients with this entity undergo transbronchial biopsies in an attempt to diagnose Pneumocystis

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pneumonia. Instead, the tissue shows interstitial inflammation ranging from an intense lymphocytic infiltration (consistent with lymphoid interstitial pneumonitis) to a mild mononuclear inflammation.

with toxoplasmosis have negative titers. Therefore, negative Toxoplasma titers in an HIV-infected patient with a space-occupying lesion should be a cause for aggressively pursuing an alternative diagnosis.

B. Management—Corticosteroids may be helpful in some cases refractory to ART.

2. Central nervous system lymphoma—Primary nonHodgkin lymphoma is the second most common spaceoccupying lesion in HIV-infected patients. Symptoms are similar to those with toxoplasmosis. While imaging techniques cannot distinguish these two diseases with certainty, lymphoma more often is solitary. Other less common lesions should be suspected if there is preceding bacteremia, positive tuberculin test, fungemia, or injection drug use. These include bacterial abscesses, cryptococcomas, tuberculomas, and Nocardia lesions.

Because techniques for stereotactic brain biopsy have improved, this procedure plays an increasing role in diagnosing cerebral lesions. Biopsy should be strongly considered if lesions are solitary or do not respond to toxoplasmosis treatment, especially if they are easily accessible. Diagnosis of lymphoma is important because many patients benefit from treatment (radiation therapy). Although a positive polymerase chain reaction (PCR) assay of cerebrospinal fluid for Epstein–Barr virus DNA, is consistent with a diagnosis of lymphoma, the sensitive and specificity of the test are not high enough to obviate the need for a brain biopsy.

4. Sinusitis— A. Presentation—Chronic sinusitis can be a frustrating problem for HIV-infected patients even in those on adequate ART. Symptoms include sinus congestion and discharge, headache, and fever. Some patients may have radiographic evidence of sinus disease on sinus CT scan or sinus x-ray in the absence of significant symptoms.

B. Management—Nonsmoking patients with purulent drainage should be treated with amoxicillin (500 mg orally three times a day). Patients who smoke should be treated with amoxicillin-potassium clavulanate (500 mg orally three times a day) to cover H influenzae. Prolonged treatment (3–6 weeks) with an antibiotic and guaifenesin (600 mg orally twice daily) to decrease sinus congestion may be required. For patients not responding to amoxicillin­potassium clavulanate, levofloxacin may be tried (400 mg orally daily). In patients with advanced immunodeficiency, Pseudomonas infections should be suspected, especially if there is not a response to first-line antibiotics. Some patients may require referral to an otolaryngologist for sinus drainage.

C. Central Nervous System Disease Central nervous system disease in HIV-infected patients can be divided into intracerebral space-occupying lesions, encephalopathy, meningitis, and spinal cord processes.

Many of these complications have declined markedly in prevalence in the era of effective ART. Cognitive declines, however, may be more common in HIV patients, even those who are taking fully suppressive ART. 1. Toxoplasmosis—Toxoplasmosis is the most common space-occupying lesion in HIV-infected patients. Headache, focal neurologic deficits, seizures, or altered mental status may be presenting symptoms. The diagnosis is usually made presumptively based on the characteristic appearance of cerebral imaging studies in an individual known to be seropositive for Toxoplasma. Typically, toxoplasmosis appears as multiple contrast-enhancing lesions on CT scan.

Lesions tend to be peripheral, with a predilection for the basal ganglia.

Single lesions are atypical of toxoplasmosis. When a single lesion has been detected by CT scanning, MRI scanning may reveal multiple lesions because of its greater sensitivity. If a patient has a single lesion on MRI and is neurologically stable, clinicians may pursue a 2-week empiric trial of toxoplasmosis therapy. A repeat scan should be performed at 2 weeks. If the lesion has not diminished in size, biopsy of the lesion should be performed. Since many HIV-infected patients will have detectable titers, a positive Toxoplasma serologic test does not confirm the diagnosis. Conversely, < 3% of patients

3. HIV-associated dementia—Patients with HIVassociated dementia typically have difficulty with cognitive tasks (eg, memory, attention), exhibit diminished motor function, and have emotional or behavioral problems.

Patients may first notice a deterioration in their handwriting. The manifestations of dementia may wax and wane, with persons exhibiting periods of lucidity and confusion over the course of a day. The diagnosis of HIVassociated dementia is one of exclusion based on a brain imaging study and on spinal fluid analysis that excludes other pathogens. Neuropsychiatric testing is helpful in distinguishing patients with dementia from those with depression. Many patients improve with effective antiretroviral treatment. Metabolic abnormalities may also cause changes in mental status: hypoglycemia, hyponatremia, hypoxia, and drug overdose are important considerations in this population. Other less common infectious causes of encephalopathy include progressive multifocal leukoencephalopathy (discussed below), CMV, syphilis, and herpes simplex encephalitis.

4. Cryptococcal meningitis—Cryptococcal meningitis typically presents with fever and headache. Less than 20% of patients have meningismus. Diagnosis is based on a positive latex agglutination test that detects cryptococcal antigen (or “CRAG”) or positive culture of spinal fluid for Cryptococcus. Seventy to 90% of patients with cryptococcal meningitis have a positive serum CRAG. Thus, a negative serum CRAG test makes a diagnosis of cryptococcal meningitis unlikely and can be useful in the initial evaluation of a patient with headache, fever, and normal mental status.

HIV meningitis, characterized by lymphocytic pleocytosis of the spinal fluid with negative culture, is common early in HIV infection.

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5. HIV myelopathy—Spinal cord function may also be impaired in HIV-infected individuals. HIV myelopathy presents with leg weakness and incontinence. Spastic paraparesis and sensory ataxia are seen on neurologic examination.

Myelopathy is usually a late manifestation of HIV disease, and most patients will have concomitant HIV encephalopathy. Pathologic evaluation of the spinal cord reveals vacuolation of white matter. Because HIV myelopathy is a diagnosis of exclusion, symptoms suggestive of myelopathy should be evaluated by lumbar puncture to rule out CMV polyradiculopathy (described below) and an MRI or CT scan to exclude epidural lymphoma.

6. Progressive multifocal leukoencephalopathy (PML)—PML is a viral infection of the white matter of the brain seen in patients with very advanced HIV infection.

It typically results in focal neurologic deficits such as aphasia, hemiparesis, and cortical blindness. Imaging studies are strongly suggestive of the diagnosis if they show nonenhancing white matter lesions without mass effect. Extensive lesions may be difficult to differentiate from the changes caused by HIV. Several patients have stabilized or improved after the institution of effective ART or cidofovir, or both.

D. Peripheral Nervous System A. Presentation—Peripheral nervous system syndromes include inflammatory polyneuropathies, sensory neuropathies, and mononeuropathies.

An inflammatory demyelinating polyneuropathy similar to Guillain-Barré syndrome occurs in HIV-infected patients, usually prior to frank immunodeficiency. The syndrome in many cases improves with plasmapheresis, supporting an autoimmune basis of the disease. CMV can cause an ascending polyradiculopathy characterized by lower extremity weakness and a neutrophilic pleocytosis on spinal fluid analysis with a negative bacterial culture. Transverse myelitis can be seen with herpes zoster or CMV. Peripheral neuropathy is common among HIV-infected persons. Patients typically complain of numbness, tingling, and pain in the lower extremities. Symptoms are disproportionate to findings on gross sensory and motor evaluation. Beyond HIV infection itself, the most common cause is prior ART with stavudine or didanosine. Although not used commonly in Western countries, stavudine is still being used in resource-limited settings through national ART programs. Caution should be used when administering these agents to patients with a history of peripheral neuropathy. Unfortunately, drug-induced neuropathy is not always reversed when the offending agent is discontinued. Patients with advanced disease may also develop peripheral neuropathy even if they have never taken ART. Evaluation should rule out other causes of sensory neuropathy such as alcoholism, thyroid disease, vitamin B12 deficiency, and syphilis.

B. Management—Treatment of peripheral neuropathy is aimed at symptomatic relief. Patients should be initially treated with gabapentin (start at 300 mg at bedtime and increase to 300–900 mg orally three times a day).

E. Rheumatologic and Bone Manifestations Arthritis, involving single or multiple joints, with or without effusion, has been commonly noted in HIV-infected patients. Involvement of large joints is most common.

Although the cause of HIV-related arthritis is unknown, most patients will respond to nonsteroidal anti-inflammatory drugs. Patients with a sizable effusion, especially if the joint is warm or erythematous, should have the joint aspirated, followed by culture of the fluid to rule out suppurative arthritis as well as fungal and mycobacterial disease.

Several rheumatologic syndromes, including reactive arthritis, psoriatic arthritis, sicca syndrome, and systemic lupus erythematosus, have been reported in HIV-infected patients (see Chapter 20). However, it is unclear if the prevalence is greater than in the general population. Cases of avascular necrosis of the femoral heads have been reported sporadically, generally in the setting of advanced disease with long-standing infection and in patients receiving long-term ART. The etiology is not clear but is probably multifactorial in nature.

Osteoporosis and osteopenia appear to be more common in HIV infected patients with chronic infection and perhaps associated with long-term use of ART. Vitamin D deficiency appears to be quite common among HIVinfected populations and monitoring vitamin D levels and replacement therapy for detected deficiency is recommended. Bone scans to determine bone density for patients over the age of 50 is also recommended.

F. Myopathy Myopathies are infrequent in the era of effective ART but can be related to either HIV-infection or ART, particularly with use of zidovudine (azidothymidine [AZT]). Proximal muscle weakness is typical, and patients may have varying degrees of muscle tenderness. A muscle biopsy can distinguish HIV myopathy from zidovudine myopathy and should be considered in patients for whom continuation of zidovudine is essential.

G. Retinitis Complaints of visual changes must be evaluated immediately in HIV-infected patients. CMV retinitis, characterized by perivascular hemorrhages and white fluffy exudates, is the most common retinal infection in AIDS patients and can be rapidly progressive. In contrast, cotton wool spots, which are also common in HIV-infected people, are benign, remit spontaneously, and appear as small indistinct white spots without exudation or hemorrhage. This distinction may be difficult at times for the nonspecialist, and patients with visual changes should be seen by an ophthalmologist. Other rare retinal processes include other herpesvirus infections or toxoplasmosis.

H. Oral Lesions A. Presentation—The presence of oral candidiasis or hairy leukoplakia is significant for several reasons. First, these lesions are highly suggestive of HIV infection in patients who have no other obvious cause of immunodeficiency. Second,

HIV Infection & AIDS several studies have indicated that patients with candidiasis have a high rate of progression to AIDS even with statistical adjustment for CD4 count.

Hairy leukoplakia is caused by the Epstein-Barr virus.

The lesion is not usually troubling to patients and sometimes regresses spontaneously. Hairy leukoplakia is commonly seen as a white lesion on the lateral aspect of the tongue. It may be flat or slightly raised, is usually corrugated, and has vertical parallel lines with fine or thick (“hairy”) projections. Oral candidiasis can be bothersome to patients, many of whom report an unpleasant taste or mouth dryness. The two most common forms of oral candidiasis seen are pseudomembranous (removable white plaques) and erythematous (red friable plaques).

B. Management—Treatment is with topical agents such as clotrimazole 10-mg troches (one troche four or five times a day). Patients with candidiasis who do not respond to topical antifungals can be treated with fluconazole (50–100 mg orally once a day for 3–7 days). Angular cheilitis—­ fissures at the sides of the mouth—is usually due to Candida as well and can be treated topically with ketoconazole cream (2%) twice a day.

Gingival disease is common in HIV-infected patients and is thought to be due to an overgrowth of microorganisms. It usually responds to professional dental cleaning and chlorhexidine rinses. A particularly aggressive gingivitis or periodontitis will develop in some HIV-infected patients; these patients should be given antibiotics that cover anaerobic oral flora (eg, metronidazole, 250 mg four times a day for 4 or 5 days) and referred to oral surgeons with experience with these entities.

Aphthous ulcers are painful and may interfere with eating. They can be treated with fluocinonide (0.05% ointment mixed 1:1 with plain Orabase and applied six times a day to the ulcer). For lesions that are difficult to reach, patients should use dexamethasone swishes (0.5 mg in 5 mL elixir three times a day). The pain of the ulcers can be relieved with use of an anesthetic spray (10% lidocaine). Other lesions seen in the mouths of HIV-infected patients include Kaposi sarcoma (usually on the hard palate) and warts.

I. Gastrointestinal Manifestations 1. Candidal esophagitis—(See also discussion in Chapter 15.) Esophageal candidiasis is a common AIDS complication. In a patient with characteristic symptoms, empiric antifungal treatment is begun with fluconazole (200 mg daily for 10–14 days). Further evaluation to identify other causes of esophagitis (herpes simplex, CMV) is reserved for patients who do not improve with antifungal treatment.

2. Hepatic disease— A. Presentation—Autopsy studies have demonstrated that the liver is a frequent site of infections and neoplasms in HIV-infected patients. However, many of these infections are not clinically symptomatic. Clinicians may note elevations of alkaline phosphatase and aminotransferases on routine chemistry panels. Mycobacterial disease, CMV, hepatitis B virus, hepatitis C virus, and lymphoma cause

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liver disease and can present with varying degrees of nausea, vomiting, right upper quadrant abdominal pain, and jaundice. Sulfonamides, imidazole drugs, antituberculous medications, pentamidine, clarithromycin, and didanosine have also been associated with hepatitis. HIVinfected patients with chronic hepatitis may have more rapid progression of liver disease because of the concomitant immunodeficiency or hepatotoxicity of ART. Percutaneous liver biopsy may be helpful in diagnosing liver disease, but some common causes of liver disease (eg, Mycobacterium avium complex, lymphoma) can be determined by less invasive measures (eg, blood culture, biopsy of a more accessible site).

B. Management—With patients living longer as a result of advances in ART, advanced liver disease and hepatic failure due to chronic active hepatitis B and or C are increasing causes of morbidity and mortality. HIV-infected individuals who are coinfected with hepatitis B, should be treated with antiretroviral regimens that include drugs with activity against both viruses (eg, lamivudine [3TC], emtricitabine [FTC], tenofovir [TDF]). Treatment of HIV-infected persons with hepatitis C with peginterferon and ribavirin has been shown to be efficacious, although less so than in HIV-uninfected persons. HIV-infected persons are also more likely to have difficulty tolerating treatment with peginterferon than uninfected persons.

HIV-infected patients with hepatitis C genotype 1 who received telaprevir therapy for 12 weeks had a better response than those who received only peginterferon and ribavirin. Telaprevir is approved in combination with peginterferon and ribavirin for treatment of hepatitis C in HIV-uninfected persons. Patients with advanced fibrosis or cirrhosis due to chronic hepatitis C infection should be considered for treatment with telaprevir, peginterferon, and ribavirin. However, this treatment regimen is difficult for many patients to tolerate, therefore, coinfected patients with less advanced liver disease may benefit from waiting until newer direct-acting agents for hepatitis C treatment become available. Liver transplants have been performed successfully in HIV-infected patients. This strategy is most likely to be successful in persons who have CD4 counts > 100 cells/mcL and nondetectable viral loads.

3. Biliary disease—Cholecystitis presents with manifestations similar to those seen in immunocompetent hosts but is more likely to be acalculous. Sclerosing cholangitis and papillary stenosis have also been reported in HIV-infected patients. Typically, the syndrome presents with severe nausea, vomiting, and right upper quadrant pain. Liver function tests generally show alkaline phosphatase elevations disproportionate to elevation of the aminotransferases. Although dilated ducts can be seen on ultrasound, the diagnosis is made by endoscopic retrograde cholangiopancreato­ graphy, which reveals intraluminal irregularities of the proximal intrahepatic ducts with “pruning” of the terminal ductal branches. Stenosis of the distal common bile duct at the papilla is commonly seen with this syndrome. CMV, Cryptosporidium, and microsporidia are thought to play inciting roles in this syndrome.

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4. Enterocolitis— A. Presentation—Enterocolitis is a common problem in HIV-infected individuals. Organisms known to cause enterocolitis include bacteria (Campylobacter, Salmonella, Shigella), viruses (CMV, adenovirus), and protozoans (Cryptosporidium, Entamoeba histolytica, Giardia, Isospora, microsporidia). HIV itself may cause enterocolitis. Several of the organisms causing enterocolitis in HIV-infected individuals also cause diarrhea in immunocompetent persons. However, HIV-infected patients tend to have more severe and more chronic symptoms, including high fevers and severe abdominal pain that can mimic acute abdominal catastrophes. Bacteremia and concomitant biliary involvement are also more common with enterocolitis in HIVinfected patients. Relapses of enterocolitis following adequate therapy have been reported with both Salmonella and Shigella infections.

Because of the wide range of agents known to cause enterocolitis, a stool culture and multiple stool examinations for ova and parasites (including modified acidfast staining for Cryptosporidium) should be performed.

Those patients who have Cryptosporidium in one stool with improvement in symptoms in < 1 month should not be considered to have AIDS, as Cryptosporidium is a cause of self-limited diarrhea in HIV-negative persons. More commonly, HIV-infected patients with Cryptosporidium infection have persistent enterocolitis with profuse watery diarrhea.

B. Management—To date, no consistently effective treatments have been developed for Cryptosporidium infection. The most effective treatment of cryptosporidiosis is to improve immune function through the use of effective antiretroviral treatment. The diarrhea can be treated symptomatically with diphenoxylate with atropine (one or two tablets orally three or four times a day).

Those who do not respond may be given paregoric with bismuth (5–10 mL orally three or four times a day).

Octreotide in escalating doses (starting at 0.05 mg subcutaneously every 8 hours for 48 hours) has been found to ameliorate symptoms in approximately 40% of patients with cryptosporidia or idiopathic HIV-associated diarrhea.

Patients with a negative stool examination and persistent symptoms should be evaluated with colonoscopy and biopsy. Patients whose symptoms last longer than 1 month with no identified cause of diarrhea are considered to have a presumptive diagnosis of AIDS enteropathy. Patients may respond to institution of effective antiretroviral treatment.

Upper endoscopy with small bowel biopsy is not recommended as a routine part of the evaluation.

5. Other disorders—Two other important gastrointestinal abnormalities in HIV-infected patients are gastropathy and malabsorption. It has been documented that some HIV-infected patients do not produce normal levels of stomach acid and therefore are unable to absorb drugs that require an acid medium. This decreased acid production may explain, in part, the susceptibility of HIVinfected patients to Campylobacter, Salmonella, and

Shigella, all of which are sensitive to acid concentration.

There is no evidence that Helicobacter pylori is more common in HIV-infected persons.

A malabsorption syndrome occurs commonly in AIDS patients. It can be due to infection of the small bowel with M avium complex, Cryptosporidium, or microsporidia.

J. Endocrinologic Manifestations Hypogonadism is probably the most common endocrinologic abnormality in HIV-infected men. The adrenal gland is also a commonly afflicted endocrine gland in patients with AIDS. Abnormalities demonstrated on autopsy include infection (especially with CMV and M avium complex), infiltration with Kaposi sarcoma, and injury from hemorrhage and presumed autoimmunity. The prevalence of clinically significant adrenal insufficiency is low. Patients with suggestive symptoms should undergo a cosyntropin stimulation test.

Although frank deficiency of cortisol is rare, an isolated defect in mineralocorticoid metabolism may lead to saltwasting and hyperkalemia. Such patients should be treated with fludrocortisone (0.1–0.2 mg daily).

AIDS patients appear to have abnormalities of thyroid function tests different from those of patients with other chronic diseases. AIDS patients have been shown to have high levels of triiodothyronine (T3), thyroxine (T4), and thyroid-binding globulin and low levels of reverse triiodothyronine (rT3). The causes and clinical significance of these abnormalities are unknown.

K. Skin Manifestations The skin manifestations that commonly develop in HIVinfected patients can be grouped into viral, bacterial, fungal, neoplastic, and nonspecific dermatitides.

1. Viral dermatitides— A. Herpes simplex infections—These infections occur more frequently, tend to be more severe, and are more likely to disseminate in AIDS patients than in immunocompetent persons. Because of the risk of progressive local disease, all herpes simplex attacks should be treated with acyclovir (400 mg orally three times a day until healed, usually 7 days), famciclovir (500 mg orally twice daily until healed), or valacyclovir (500 mg orally twice daily until healed). To avoid the complications of attacks, many clinicians recommend suppressive therapy for HIVinfected patients with a history of recurrent herpes.

Options for suppressive therapy include acyclovir (400 mg orally twice daily), famciclovir (250 mg orally twice daily), and valacyclovir (500 mg orally daily). A randomized trial of women infected with both herpes simplex and HIV showed that suppressive therapy with valacyclovir at a dose of 500 mg orally twice daily decreased genital and plasma HIV-1 RNA levels, suggesting the possibility that suppressive treatment may reduce HIV transmission.

However, a recent large randomized clinical trial failed to show a reduction in HIV transmission with suppressive acyclovir therapy.

HIV Infection & AIDS B. Herpes zoster—This is a common manifestation of HIV infection. As with herpes simplex infections, patients with zoster should be treated with acyclovir to prevent dissemination (800 mg orally four or five times per day for 7 days).

Alternatively, famciclovir (500 mg orally three times a day) or valacyclovir (500 mg three times a day) may be used. Vesicular lesions should be cultured if there is any question about their origin, since herpes simplex responds to much lower doses of acyclovir. Disseminated zoster and cases with ocular involvement should be treated with intravenous (10 mg/kg every 8 hours for 7–10 days) rather than oral acyclovir.

C. Molluscum contagiosum—This infection is caused by a pox virus is seen in HIV-infected patients, as in other immunocompromised patients. The characteristic umbilicated fleshy papular lesions have a propensity for spreading widely over the patient’s face and neck and should be treated with topical liquid nitrogen.

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3. Fungal rashes— A. Rashes due to dermatophytes and Candida—The majority of fungal rashes afflicting AIDS patients are due to dermatophytes and Candida. These are particularly common in the inguinal region but may occur anywhere on the body.

Fungal rashes generally respond well to topical clotrimazole (1% twice a day) or ketoconazole (2% twice a day).

B. Seborrheic dermatitis—This is more common in HIV-infected patients. Scrapings of seborrhea have revealed Malassezia furfur (Pityrosporum ovale), implying that the seborrhea is caused by this fungus. Consistent with the isolation of this fungus is the clinical finding that seborrhea responds well to topical clotrimazole (1% cream) as well as hydrocortisone (1% cream).

4. Neoplastic dermatitides—See Chapter 6 and the Kaposi sarcoma section below.

2. Bacterial dermatitides—

5. Nonspecific dermatitides—

A. Staphylococcal infection—Staphylococcus is the most common bacterial cause of skin disease in HIVinfected patients; it usually presents as folliculitis, superficial abscesses (furuncles), or bullous impetigo. Because dissemination with sepsis has been reported, attempts should be made to treat these lesions aggressively.

Folliculitis is initially treated with topical clindamycin or mupirocin, and patients may benefit from regular washing with an antibacterial soap such as chlorhexidine.

Intranasal mupirocin has been used successfully for staphylococcal decolonization in other settings. In HIVinfected patients with recurrent staphylococcal infections, weekly intranasal mupirocin should be considered in addition to topical care and systemic antibiotics. Abscesses often require incision and drainage. Patients may need antistaphylococcal antibiotics as well. Due to high frequency of methicillin-resistant Staphylococcus aureus (MRSA) skin infections in HIV-infected populations, lesions should be cultured prior to initiating empiric antistaphylococcal therapy. Although there is limited experience treating MRSA with oral antibiotics, current recommendations for empiric treatment are trimethoprimsulfamethoxazole (one double-strength tablet orally twice daily) with or without clindamycin (500 mg orally three times daily) or doxycycline (100 mg orally twice daily) with close follow-up.

A. Xerosis—This condition presents in HIV-infected patients with severe pruritus. The patient may have no rash, or nonspecific excoriations from scratching. Treatment is with emollients (eg, absorption base cream) and antipruritic lotions (eg, camphor 9.5% and menthol 0.5%).

B. Bacillary angiomatosis—This is a well-described entity in HIV-infected patients. It is caused by two closely related organisms: Bartonella henselae and Bartonella ­quintana. The epidemiology of these infections suggests zoonotic transmission from fleas of infected domestic cats.

The most common manifestation is raised, reddish, highly vascular skin lesions that can mimic the lesions of Kaposi sarcoma. Fever is a common manifestation of this infection; involvement of bone, lymph nodes, and liver has also been reported. The infection responds to doxycycline, 100 mg orally twice daily, or erythromycin, 250 mg orally four times daily. Therapy is continued for at least 14 days, and patients who are seriously ill with visceral involvement may require months of therapy.

B. Psoriasis—Psoriasis can be very severe in HIV-infected patients. Phototherapy and etretinate (0.25–9.75 mg/kg/d orally in divided doses) may be used for recalcitrant cases in consultation with a dermatologist.

L. HIV-Related Malignancies Four cancers are currently included in the CDC classification of AIDS: Kaposi sarcoma, non-Hodgkin lymphoma, primary lymphoma of the brain, and invasive cervical carcinoma. Epidemiologic studies have shown that between 1973 and 1987 among single men in San Francisco, the risk of Kaposi sarcoma increased more than 5000-fold and the risk of non-Hodgkin lymphoma more than tenfold. The increase in incidence of malignancies is probably a function of impaired cell-mediated immunity.

1. Kaposi sarcoma— A. Presentation—Lesions may appear anywhere; careful examination of the eyelids, conjunctiva, pinnae, palate, and toe webs is mandatory to locate potentially occult lesions.

In light-skinned individuals, Kaposi lesions usually appear as purplish, nonblanching lesions that can be papular or nodular. In dark-skinned individuals, the lesions may appear more brown. In the mouth, lesions are most often palatal papules, though exophytic lesions of the tongue and gingivae may also be seen. Kaposi lesions may be confused with other vascular lesions such as angiomas and pyogenic granulomas. Visceral disease (eg, gastrointestinal, pulmonary) will develop in about 40% of patients with dermatologic Kaposi sarcoma. Kaposi sarcoma lesions can occur shortly after initiating ART, especially in patients starting ART who have advanced immunodeficiency. In this situation, Kaposi sarcoma is likely to be an immune reconstitution reaction (see below).

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B. Management—Rapidly progressive dermatologic or visceral disease is best treated with systemic chemotherapy.

Liposomally encapsulated doxorubicin given intravenously every 3 weeks has a response rate of approximately 70%. α-Interferon (10 million units subcutaneously three times a week) also has activity against Kaposi sarcoma. However, symptoms such as malaise and anorexia limit the utility of this therapy. Patients with milder forms of Kaposi sarcoma do not require specific treatment as the lesions usually improve and can completely resolve with ART. However, it should be noted that the lesions may flare when ART is first initiated—probably as a result of an immune reconstitution process (see Inflammatory reactions below).

2. Non-Hodgkin lymphoma— A. Presentation—Non-Hodgkin lymphoma in HIVinfected persons tends to be very aggressive. The malignancies are usually of B cell origin and characterized as diffuse large-cell tumors. Over 70% of the malignancies are extranodal.

B. Management—The prognosis of patients with systemic non-Hodgkin lymphoma depends primarily on the degree of immunodeficiency at the time of diagnosis.

Patients with high CD4 counts do markedly better than those diagnosed at a late stage of illness. Patients with primary central nervous system lymphoma are treated with radiation. Response to treatment is good, but prior to the availability of HAART, most patients died within a few months after diagnosis due to their underlying disease.

Systemic disease is treated with chemotherapy. Common regimens are CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) and modified M-BACOD (methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone). Granulocyte colony-­stimulating factor (G-CSF; filgrastim) is used to maintain white blood counts with this latter regimen.

Intrathecal chemotherapy is administered to prevent or treat meningeal involvement.

3. Hodgkin disease—Although Hodgkin disease is not included as part of the CDC definition of AIDS, studies have found that HIV infection is associated with a fivefold increase in the incidence of Hodgkin disease. HIV-infected persons with Hodgkin disease are more likely to have mixed cellularity and lymphocyte depletion subtypes of Hodgkin disease and to seek medical attention at an advanced stage of disease.

4. Anal dysplasia and squamous cell carcinoma— These lesions have been strongly correlated with previous infection by human papillomavirus (HPV) and have been noted in HIV-infected men and women. Although many of the infected MSM report a history of anal warts or have visible warts, a significant percentage have silent papillomavirus infection. Cytologic (using Papanicolaou smears) and papillomavirus DNA studies can easily be performed on specimens obtained by anal swab. Because of the risk of progression from dysplasia to cancer in immunocompromised patients, some experts suggest that annual anal swabs for cytologic examination should be done in all

HIV-infected persons. An anal Papanicolaou smear is performed by rotating a moistened Dacron swab about 2 cm into the anal canal. The swab is immediately inserted into a cytology bottle. However, there is no evidence that screening for anal cancer with Papanicolaou smears decreases the incidence of invasive cancer.

HPV also appears to play a causative role in cervical dysplasia and neoplasia. The incidence and clinical course of cervical disease in HIV-infected women are discussed below.

M. Gynecologic Manifestations Vaginal candidiasis, cervical dysplasia and neoplasia, and pelvic inflammatory disease are more common in HIVinfected women than in uninfected women. These manifestations also tend to be more severe when they occur in association with HIV infection. Therefore, HIV-infected women need frequent gynecologic care. Vaginal candidiasis may be treated with topical agents (see Chapter 36). However, HIV-infected women with recurrent or severe vaginal candidiasis may need systemic therapy.

The incidence of cervical dysplasia in HIV-infected women is 40%. Because of this finding, HIV-infected women should have Papanicolaou smears every 6 months (as opposed to the Agency for Healthcare Research and Quality [AHRQ] Guideline recommendation for every 12 months).

Some clinicians recommend routine colposcopy or cervicography because cervical intraepithelial neoplasia has occurred in women with negative Papanicolaou smears.

Cone biopsy is indicated in cases of serious cervical dysplasia. For 1 year following treatment of an abnormal Papanicolaou smear, women should have repeat smears every 3 to 4 months.

Cervical neoplasia appears to be more aggressive among HIV-infected women. Most HIV-infected women with cervical cancer die of that disease rather than of AIDS. Because of its frequency and severity, cervical neoplasia was added to the CDC definition of AIDS in 1993.

While pelvic inflammatory disease appears to be more common in HIV-infected women, the bacteriology of this condition appears to be the same as among HIV-uninfected women. At present, HIV-infected women with pelvic inflammatory disease should be treated with the same regimens as uninfected women (see Chapter 18). However, inpatient therapy is generally recommended.

N. Coronary Artery Disease HIV-infected persons are at higher risk for coronary artery disease than age- and sex-matched controls. Part of this increase in coronary artery disease is due to changes in lipids caused by antiretroviral agents (see Treatment section on Antiretroviral Therapy below), especially stavudine and several of the PIs. However, some of the risk appears to be due to HIV infection, independent of its therapy. It is important that clinicians pay close attention to this issue because the first presentation of coronary artery disease in HIV-infected persons may be sudden death. HIV-infected patients with symptoms of coronary artery disease such as chest pain or dyspnea should be rapidly evaluated.

Clinicians should aggressively treat conditions that result

HIV Infection & AIDS in increased risk of heart disease, especially smoking, hypertension, hyperlipidemia, obesity, diabetes mellitus, and sedentary lifestyle.

O. Inflammatory Reactions (Immune Reconstitution Syndromes) With initiation of HAART, some patients experience inflammatory reactions that appear to be associated with immune reconstitution as indicated by a rapid increase in CD4 count. These inflammatory reactions may present with generalized signs of fevers, sweats, and malaise with or without more localized manifestations that usually represent unusual presentations of opportunistic infections. For example, vitreitis has developed in patients with CMV retinitis after they have been treated with HAART. M avium can present as focal even suppurative lymphadenitis or granulomatous masses in patients receiving HAART. Tuberculosis may paradoxically worsen with new or evolving pulmonary infiltrates and lymphadenopathy.

PML and cryptococcal meningitis may also behave atypically. Clinicians should be alert to these syndromes, which are most often seen in patients who have initiated ART in the setting of advanced disease and who show rapid increases in CD4 counts with treatment. The diagnosis of IRIS is one of exclusion and can be made only after recurrence or new opportunistic infection has been ruled out as the cause of the clinical deterioration.

Management of IRIS is conservative and supportive with use of corticosteroids only for severe reactions. Most authorities recommend that ART be continued unless the reaction is life-threatening.

``Prevention A. Primary Prevention Until vaccination is a reality, prevention of HIV infection will depend on effective precautions regarding sexual practices and injection drug use, use of perinatal HIV prophylaxis, screening of blood products, and infection control practices in the health care setting. Primary care clinicians should routinely obtain a sexual history and provide risk factor assessment of their patients. Because approximately one-fifth of the HIV-infected persons in the United States do not know they are infected, the CDC recommends all adults be tested for HIV as a routine part of medical care. Clinicians should review the risk factors for HIV infection with the patient and discuss safer sex and safer needle use as well as the meaning of a positive test. Although the CDC recommends “opt-out” testing in medical settings, some states require specific written consent. For persons whose test results are positive, referrals for partner-notification services, social services, mental health services, and HIV-prevention services should be provided. Prevention interventions focused on the importance of HIV-infected persons not putting others at risk have been successful. For patients whose test results are negative, clinicians should review safer sex and needle use practices, including counseling not to exchange bodily fluids unless they are in a long-term

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mutually monogamous relationship with someone who has tested HIV antibody-negative and has not engaged in unsafe sex, injection drug use, or other HIV risk behaviors for at least 6 months prior to or at any time since the negative test.

Only latex condoms should be used, along with a watersoluble lubricant. Although nonoxynol-9, a spermicide, kills HIV, it is contraindicated because in some patients it may cause genital ulcers that could facilitate HIV transmission.

Patients should be counseled that condoms are not 100% effective. They should be made familiar with the use of condoms, including, specifically, the advice that condoms must be used every time, that space should be left at the tip of the condom as a receptacle for semen, that intercourse with a condom should not be attempted if the penis is only partially erect, that men should hold on to the base of the condom when withdrawing the penis to prevent slippage, and that condoms should not be reused. Although anal intercourse remains the sexual practice at highest risk for transmitting HIV, seroconversions have been documented with vaginal and oral intercourse as well. Therefore, condoms should be used when engaging in these activities. Women as well as men should understand how to use condoms so as to be sure that their partners are using them correctly. Several recent randomized trials in Africa demonstrated that male circumcision significantly reduced HIV incidence in men, but there are a number of barriers to performing widespread circumcisions among men in Africa.

Two major studies have demonstrated the proof of concept that HIV transmission can be reduced by drugs that are used to treat HIV infection. In a study from South Africa, women who used a tenofovir-containing vaginal gel reduced their risk of HIV infection by 39% and those who followed the recommended application schedule (use before and after intercourse) had a more than 50% reduction in risk of infection. In a randomized placebocontrolled study of MSM across several different countries, researchers showed that risk of HIV transmission was reduced by 44% in those men receiving daily tenofovir/ emtricitabine fixed-dose combination; in those who were over 90% adherent, the risk was reduced more 70%.

Although transmission was not universally prevented in either of these studies, they demonstrate that “biological methods” could serve as a useful adjunct to current behavioral approaches in preventing HIV transmission.

In addition, having persons with HIV take effective ART appears to reduce the chance that they can transmit HIV to their partners. An international study showed that among serodiscordant couples, early ART almost completely eliminated the risk of HIV transmission to the uninfected partner. Although HIV-negative persons in stable long-term partnerships with HIV-infected persons represent only one group of at risk persons, theoretically increasing the use of ART among the population of HIVinfected persons could decrease community wide transmission of HIV. Persons using injection drugs should be cautioned never to exchange needles or other drug paraphernalia.

When sterile needles are not available, bleach does appear to inactivate HIV and should be used to clean needles.

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Current efforts to screen blood and blood products have lowered the risk of HIV transmission with transfusion of a unit of blood to 1:1,000,000.

In health care settings, universal body fluid precautions should be used, including use of gloves when handling body fluids and the addition of gown, mask, and goggles for procedures that may result in splash or droplet spread, and use of specially designed needles with sheath devices to decrease the risk of needle sticks. Because transmission of tuberculosis may occur in health care settings, all patients with cough should be encouraged to wear masks. Hospitalized HIVinfected patients with cough should be placed in respiratory isolation until tuberculosis can be excluded by chest radiograph and sputum smear examination.

Primate model data have suggested that development of a protective vaccine may be possible, but clinical trials in humans have been disappointing. Only one vaccine trial has shown any degree of efficacy. In this randomized, doubleblind, placebo-controlled trial, a recombinant canarypox vector vaccine plus two booster injections of a recombinant gp120 vaccine was moderately efficacious (26–31%) in reducing the risk of HIV among a primarily heterosexual population in Thailand. Current vaccine development efforts are aimed at identifying broadly neutralizing antibodies to the highly conserved regions of the HIV envelope.

B. Secondary Prevention In the era prior to the development of highly effective antiretroviral treatment, cohort studies of individuals with documented dates of seroconversion demonstrate that AIDS develops within 10 years in approximately 50% of untreated seropositive persons. With currently available treatment, progression of disease has been markedly decreased. In addition to antiretroviral treatment, prophylactic regimens can prevent opportunistic infections and improve survival. Prophylaxis and early intervention prevent several infectious diseases, including tuberculosis and syphilis, which are transmissible to others. Recommenda­ tions for screening tests, vaccinations, and prophylaxis are listed in Table 31–3.

1. Tuberculosis—Because of the increased occurrence of tuberculosis among HIV-infected patients, all such individuals should undergo PPD testing. Although anergy is common among AIDS patients, the likelihood of a falsenegative result is much lower when the test is done early in infection. Those with positive tests (defined for HIVinfected patients as > 5 mm of induration) need a chest radiograph. Patients with an infiltrate in any location, especially if accompanied by mediastinal adenopathy, should have sputum sent for acid-fast staining. Patients with a positive PPD but negative evaluations for active disease should receive isoniazid (300 mg orally daily) with pyridoxine (50 mg orally daily) for 9 months to a year. A blood test (QuantiFERON Gold test) can also be used to assess prior tuberculosis exposure. Blood samples are mixed with synthetic antigens representing M tuberculosis.

Patients infected with M tuberculosis produce interferongamma in response to contact with the antigens. Unlike the PPD, the patient does not have to return for a second

Table 31–3. Health care maintenance of HIV-infected individuals.

For all HIV-infected individuals: CD4 counts every 3–6 months Viral load tests every 3–6 months and 1 month following a change in therapy Cholesterol and triglycerides at baseline, 6–12 months after starting antiretroviral therapy, and annually for everyone over 40 years of age PPD INH for those with positive PPD and normal chest radiograph RPR or VDRL Toxoplasma IgG serology Hepatitis serologies: hepatitis A antibody, hepatitis B surface antigen, hepatitis B surface antibody, hepatitis B core antibody, hepatitis C antibody Pneumococcal vaccine Inactivated influenza vaccine in season Hepatitis A vaccine for those without immunity to hepatitis A. Hepatitis B vaccine for those who are hepatitis B surface antigen and antibody negative. (Use 40 mcg formulation at 0, 1, and 6 months; repeat if no immunity 1 month after three-shot series.)

Combined tetanus, diphtheria, pertussis vaccine Human papillomavirus vaccine for HIV-infected women age 26 years or less.

Haemophilus influenzae type b vaccination Bone mineral density monitoring for women and men over 50 years of age Papanicolaou smears every 6 months for women Consider anal swabs for cytologic evaluation For HIV-infected individuals with CD4 < 200 cells/mcL: Pneumocystis jiroveci prophylaxis (see Prophylaxis of Opportunistic Infections section under Treatment and Table 31–4) For HIV-infected individuals with CD4 < 75 cells/mcL: Mycobacterium avium complex prophylaxis (see Prophylaxis of Opportunistic Infections section under Treatment) For HIV-infected individuals with CD4 < 50 cells/mcL: Consider CMV prophylaxis PPD, purified protein derivative; INH, isoniazid; RPR, rapid plasma reagin; VDRL, Venereal Disease Research Laboratories; IgG, immunoglobulin G.

visit. The test is less likely to result in false-positive results than a PPD. Unfortunately, HIV-infected persons may not produce sufficient interferon-gamma, in which case the test may be falsely negative.

2. Syphilis—Because of recent increases in the number of cases of syphilis among MSM, including those who are HIV infected, all such men should be screened for syphilis by rapid plasma reagin (RPR) or Venereal Disease Research Laboratories (VDRL) test every 6 months.

Increases of syphilis cases among HIV-infected persons are of particular concern because these individuals are at increased risk for reactivation of syphilis and progression to tertiary syphilis despite standard treatment. Because the only widely available tests for syphilis are serologic and because HIV-infected individuals are known to have

HIV Infection & AIDS disordered antibody production, there is concern about the interpretation of these titers. This concern has been fueled by a report of an HIV-infected patient with secondary syphilis and negative syphilis serologic testing.

Furthermore, HIV-infected individuals may lose fluorescent treponemal antibody absorption (FTA-ABS) reactivity after treatment for syphilis, particularly if they have low CD4 counts. Thus, in this population, a nonreactive treponemal test does not rule out a past history of syphilis. In addition, persistence of treponemes in the spinal fluid after one dose of benzathine penicillin has been demonstrated in HIV-infected patients with primary and secondary syphilis. Therefore, the CDC has recommended an aggressive diagnostic approach to HIVinfected patients with reactive RPR or VDRL tests of > 1 year or unknown duration. All such patients should have a lumbar puncture with cerebrospinal fluid cell count and cerebrospinal fluid VDRL. Those with a normal cerebrospinal fluid evaluation are treated as having late latent syphilis (benzathine penicillin G, 2.4 million units intramuscularly weekly for 3 weeks) with follow-up titers. Those with a pleocytosis or a positive cerebrospinal fluid-VDRL test are treated as having neurosyphilis (aqueous penicillin G, 2–4 million units intravenously every 4 hours, or procaine penicillin G, 2.4 million units intramuscularly daily, with probenecid, 500 mg four times daily, for 10 days). Some clinicians take a less aggressive approach to patients who have low titers (< 1:8), a history of having been treated for syphilis, and a normal neurologic examination. Close follow-up of titers is mandatory if such a course is taken. For a more detailed discussion of this topic, see Chapter 34.

3. Immunizations—HIV-infected individuals should receive the pneumococcal vaccine and the inactivated influenza vaccine. Patients without immunity to hepatitis A should be vaccinated against it. Patients without evidence of hepatitis B surface antigen or surface antibody should receive hepatitis B vaccination, using the 40 mcg formulation; the higher dose is to increase the chance of developing protective immunity. If the patient does not have immunity 1 month after the three-shot series, then the series should be repeated. HIV-infected persons should also receive the standard inactivated vaccines such as tetanus and diphtheria boosters that would be given to uninfected persons. Live vaccines, such as yellow fever vaccine, should be avoided. Measles vaccination, while a live virus vaccine, appears relatively safe when administered to HIV-infected individuals and should be given if the patient has never had measles or been adequately vaccinated. Herpes zoster vaccine is contraindicated in HIV-infected persons with evidence of immune suppression.

4. Other measures—A randomized study found that multivitamin supplementation decreased HIV disease progression and mortality in HIV-infected women in Africa.

However, supplementation is unlikely to be as effective in well-nourished populations.

HIV-infected individuals should be counseled with regard to safe sex. Because of the risk of transmission, they should be warned to use condoms with sexual intercourse,

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including oral intercourse. Partners of HIV-infected women should use latex barriers such as dental dams (available at dental supply stores) to prevent direct oral contact with vaginal secretions. Substance abuse treatment should be recommended for persons who are using recreational drugs. They should be warned to avoid consuming raw meat or eggs to avoid infections with Toxoplasma, Campylobacter, and Salmonella. HIV-infected patients should wash their hands thoroughly after cleaning cat litter or should forgo this household chore to avoid possible exposure to toxoplasmosis. To reduce the likelihood of infection with Bartonella species, patients should avoid activities that might result in cat scratches or bites. Although the data are not conclusive, many clinicians recommend that HIV-infected persons—especially those with low CD4 counts—drink bottled water instead of tap water to prevent cryptosporidia infection.

Because of the emotional impact of HIV infection and subsequent illness, many patients will benefit from supportive counseling.

C. HIV Risk for Health Care Professionals Epidemiologic studies show that needle sticks occur commonly among health care professionals, especially among surgeons performing invasive procedures, inexperienced hospital house staff, and medical students. Efforts to reduce needle sticks should focus on avoiding recapping needles and use of safety needles whenever doing invasive procedures under controlled circumstances. The risk of HIV transmission from a needle stick with blood from an HIV-infected patient is about 1:300. The risk is higher with deep punctures, large inocula, and source patients with high viral loads. The risk from mucous membrane contact is too low to quantitate.

Health care professionals who sustain needle sticks should be counseled and offered HIV testing as soon as possible. HIV testing is done to establish a negative baseline for worker’s compensation claims in case there is a subsequent conversion. Follow-up testing is usually performed at 6 weeks, 3 months, and 6 months.

A case-control study by the CDC indicates that administration of zidovudine following a needle stick decreases the rate of HIV seroconversion by 79%. Therefore, providers should be offered therapy with Combivir (zidovudine 300 mg plus lamivudine 150 mg orally twice daily).

Therapy should be started as soon as possible after exposure and continued for 4 weeks. Providers who have exposures to persons who are likely to have antiretroviral drug resistance (eg, persons receiving therapy who have detectable viral loads) should have their therapy individualized, using at least two drugs to which the source is unlikely to be resistant. Some clinicians recommend triple combination regimens, including a PI for all occupational exposures, because of uncertainty about drug resistance. Others save these more aggressive regimens for the higher-risk exposures listed above. Because reports have noted hepatotoxicity due to nevirapine in this setting, this agent should be avoided. Unfortunately, there have been documented cases of seroconversion following potential parenteral exposure to HIV despite prompt use of zidovudine

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­ rophylaxis. Counseling of the provider should include p “safer sex” guidelines.

D. Postexposure Prophylaxis for Sexual and Drug Use Exposures to HIV Following publication of a case-control study indicating that ART decreased the odds of seroconversion among health care workers who had occupational exposure, some experts have recommended offering ART following potential exposure to HIV through sexual activity or drug use.

Although there are no efficacy data to support this practice, there are similarities between the immune response following transcutaneous and transmucosal exposures. The goal of postexposure prophylaxis is to reduce or prevent local viral replication prior to dissemination such that the infection can be aborted.

The choice of antiretroviral agents and the duration of treatment are the same as those for exposures that occur through the occupational route (see above). In contrast to those with occupational exposures, some individuals may present very late after exposure. Because the likelihood of success declines with length of time from HIV exposure, it is not recommended that treatment be offered after 72 hours.

In addition, because the psychosocial issues involved with postexposure prophylaxis for sexual and drug use exposures are complex, it should be offered only in the context of prevention counseling. Counseling should focus on how to prevent future exposures. Clinicians needing more information on postexposure prophylaxis for occupational or nonoccupational exposures should contact the National Clinician’s Post-exposure Hotline (1-888-448-4911; http:// www.nccc.ucsf.edu/about_nccc/pepline/).

E. Preventing Perinatal Transmission of HIV A multicenter trial showed that when zidovudine is administered to women during pregnancy, labor, and delivery and to their newborns, the rate of HIV transmission is decreased by two-thirds. An observational trial demonstrated that zidovudine treatment is almost as effective when begun during labor or when administered only to the infant, as long as treatment is begun within 48 hours after birth. Nonetheless, treatment begun by at least the second trimester is still recommended. Many women are currently being offered combination antiretroviral treatment to further lower the risk of transmission. The availability of treatment makes it essential that all women who are pregnant or considering pregnancy be offered HIV counseling and testing. Many obstetricians recommend combination antiretroviral treatment, especially if zidovudine resistance is suspected. HIV-infected women receiving ART in whom pregnancy is recognized during the first trimester should be counseled about the benefits and potential risks to the fetus of treatment during the first trimester. Because healthy mothers make healthy babies, continuation of therapy should be strongly considered. Because about half of fetal infections in non–breast-feeding women occur shortly before or during the birth process, ART should be administered whenever a woman initiates perinatal care even if she did not begin therapy in the second trimester. Breast-feeding is

thought to increase the rate of transmission by 10–20% and should be avoided.

Abdool Karim Q et al; CAPRISA 004 Trial Group. Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women. Science. 2010 Sep 3;329(5996):1168–74. [PMID: 20643915] Branson BM et al; Centers for Disease Control and Prevention (CDC). Revised recommendations for HIV testing of adults, adolescents, and pregnant women in health-care settings.

MMWR Recomm Rep. 2006 Sep 22;55(RR-14):1–17. [PMID: 16988643] Cohen MS et al; HPTN 052 Study Team. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med. 2011 Aug 11;365(6):493–505. [PMID: 21767103] Grant RM et al; iPrEx Study Team. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med. 2010 Dec 30;363(27):2587–99. [PMID: 21091279] Johnston MI et al. HIV vaccine development—improving on natural immunity. N Engl J Med. 2011 Sep 8;365(10):873–5.

[PMID: 21899447] Landovitz RJ et al. Clinical practice. Postexposure prophylax­is for HIV infection. N Engl J Med. 2009 Oct 29;361(18): 1768–75. [PMID: 19864675] Mahajan AP et al. Consistency of state statutes with the Centers for Disease Control and Prevention HIV testing recommendations for health care settings. Ann Intern Med. 2009 Feb 17;150(4):263–9. [PMID: 19221378] Sax PE et al; AIDS Clinical Trians Group Study A5164 Team.

Blood (1→3)-beta-D-glucan as a diagnostic test for HIV Pneumocystis jirovecii pneumonia. Clin Infect Dis. 2011 Jul 15;53(2):197–202. [PMID: 21690628]

``Treatment Treatment for HIV infection can be broadly divided into the following categories: (1) prophylaxis for opportunistic infections, malignancies, and other complications of HIV infection; (2) treatment of opportunistic infections, malignancies, and other complications of HIV infection; and (3) treatment of the HIV infection itself with combination ART. Treatment regimens for HIV infection are constantly changing. Clinicians may obtain up-to-date information on new and experimental treatments by calling the AIDS Clinical Trials Information Service (ACTIS), 800-TRIALS-A (English and Spanish), and the National AIDS Hot Line, 800-342-AIDS (English), 800-344-SIDA (Spanish), and 800-AIDS-TTY (hearing-impaired).

A. Prophylactic Treatment of Complications of HIV Infection In general, decisions about prophylaxis of opportunistic infections are based on the CD4 count, other evidence of severe immunosuppression (eg, oral candidiasis), and a history of having had the infection in the past. In the era prior to HAART, patients who started taking prophylactic regimens were maintained on them indefinitely.

However, studies have shown that in patients with robust improvements in immune function—as measured by increases in CD4 counts above the levels that are used to initiate treatment—prophylactic regimens can safely be discontinued.

HIV Infection & AIDS Because individuals with advanced HIV infection are susceptible to a number of opportunistic pathogens, the use of agents with activity against more than one pathogen is preferable. It has been shown, for example, that trimethoprim-sulfamethoxazole confers some protection against toxoplasmosis in individuals receiving this drug for Pneumocystis prophylaxis.

1. Prophylaxis against Pneumocystis pneumonia— Patients with CD4 counts below 200 cells/mcL, a CD4 lymphocyte percentage below 14%, or weight loss or oral candidiasis should be offered primary prophylaxis for Pneumocystis pneumonia. Patients with a history of Pneumocystis pneumonia should receive secondary prophylaxis until they have had a durable virologic response to HAART for at least 3–6 months and maintain a CD4 count of > 250 cells/mcL. Regimens for Pneumocystis prophylaxis are given in Table 31–4.

2. Prophylaxis against M avium complex ­infection—Patients whose CD4 counts fall to below 75–100 cells/mcL should be given prophylaxis against M avium complex infection. Clarithromycin (500 mg orally twice daily) and azithromycin (1200 mg orally weekly) have both been shown to decrease the incidence of disseminated M avium complex infection by approximately 75%, with a low rate of breakthrough of resistant disease.

The azithromycin regimen is generally preferred based on high compliance and low cost. Adding rifabutin increases the toxicity of the regimen but does not significantly increase its efficacy and is therefore not recommended.

Prophylaxis against M avium complex infection may be discontinued in patients whose CD4 counts rise above 100 cells/mcL in response to HAART and whose plasma viral load has been optimally suppressed to < 50–75 ­copies/mL. 3. Prophylaxis against M tuberculosis infection— Isoniazid, 300 mg orally daily, plus pyridoxine, 50 mg orally daily, for 9–12 months should be given to all HIVinfected patients with positive PPD reactions (defined as > 5 mm of induration for HIV-infected patients).

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4. Prophylaxis against toxoplasmosis—Toxoplasmosis prophylaxis is desirable in patients with a positive IgG toxoplasma serology and CD4 counts below 100 cells/mcL. Trimethoprim-sulfamethoxazole (one double-strength tablet daily) offers good protection against toxoplasmosis, as does a combination of pyrimethamine, 25 mg orally once a week, plus dapsone, 50 mg orally daily, plus leucovorin, 25 mg orally once a week. A glucose-6-phosphate dehydrogenase (G6PD) level should be checked prior to dapsone therapy, and a methemoglobin level should be checked at 1 month.

5. Prophylaxis against CMV infection—Oral ganciclovir (1000 mg three times daily with food) is approved for CMV prophylaxis among HIV-infected persons with advanced disease (eg, CD4 counts below 50 cells/mcL). However, because the drug causes neutropenia, it is not widely used.

Clini­cians should consider performing serum CMV IgG antibody testing prior to starting ganciclovir. Persons who are CMV IgG-negative are not at risk for development of CMV disease, although it is important that such patients receive only CMV-negative blood if they require transfusion.

Because over 99% of MSM are positive for CMV IgG, it is appropriate to reserve such testing for heterosexuals with HIV. 6. Prophylaxis against cryptococcosis, candidiasis, and endemic fungal diseases—One trial showed a decreased incidence of cryptococcal disease with prophylaxis using fluconazole, 200 mg orally daily, but the treated group had no benefit in terms of mortality. Fluconazole (200 mg orally once a week) was found to prevent oral and vaginal candidiasis in women with CD4 counts below 300 cells/mcL. In areas of the world where histoplasmosis and coccidioidomycosis are endemic and are frequent complications of HIV infection, prophylactic use of fluconazole or itraconazole may prove to be useful strategies. However, the problem of identifying individuals at highest risk makes appropriate targeting of prophylaxis difficult.

B. Treatment of Complications of HIV Infection Treatment of common AIDS-related complications is detailed above and in Table 31–5. In the era prior to the use

Table 31–4. Pneumocystis jiroveci prophylaxis in order of preference.

Drug

Dose

Side Effects

Limitations

Trimethoprimsulfamethoxazole

One double-strength tablet three times a week to one tablet daily

Rash, neutropenia, hepatitis, Stevens-Johnson syndrome

Hypersensitivity reaction is common but, if mild, it may be possible to treat through.

Dapsone

50–100 mg orally daily or 100 mg two or three times per week

Anemia, nausea, methemoglobinemia, hemolytic anemia

Less effective than above. Glucose-6-phosphate dehydrogenase (G6PD) level should be checked prior to therapy. Check methemoglobin level at 1 month.

Atovaquone

1500 mg orally daily with a meal

Rash, diarrhea, nausea

Less effective than suspension trimethoprimsulfamethoxazole; equal efficacy to dapsone, but more expensive.

Aerosolized pentamidine

300 mg monthly

Bronchospasm (pretreat with bronchodilators); rare reports of pancreatitis

Apical Pneumocystis jiroveci pneumonia, extrapulmonary P jiroveci infections, pneumothorax.

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Table 31–5. Treatment of AIDS-related opportunistic infections and malignancies.1 Infection or Malignancy Pneumocystis jiroveci infection2

Treatment

Complications

Trimethoprim-sulfamethoxazole, 15 mg/kg/d (based on trimethoprim component) orally or intravenously for 14–21 days.

Nausea, neutropenia, anemia, hepatitis, drug rash, Stevens-Johnson syndrome.

Pentamidine, 3–4 mg/kg/d intravenously for 14–21 days.

Hypotension, hypoglycemia, anemia, neutropenia, pancreatitis, hepatitis.

Trimethoprim, 15 mg/kg/d orally, with dapsone, 100 mg/d orally, for 14–21 days.3

Nausea, rash, hemolytic anemia in G6PD3deficient patients. Methemoglobinemia (weekly levels should be < 10% of total hemoglobin).

Primaquine, 15–30 mg/d orally, and clindamycin, 600 mg every 8 hours orally, for 14–21 days.

Hemolytic anemia in G6PD-deficient patients.

Methemoglobinemia, neutropenia, colitis.

Atovaquone, 750 mg orally three times daily for 14–21 days.

Rash, elevated aminotransferases, anemia, neutropenia.

Trimetrexate, 45 mg/m2 intravenously for 21 days (given with leucovorin calcium) if intolerant of all other regimens.

Leukopenia, rash, mucositis.

Clarithromycin, 500 mg orally twice daily with ethambutol, 15 mg/kg/d orally (maximum, 1 g). May also add:

Clarithromycin: hepatitis, nausea, diarrhea; ethambutol: hepatitis, optic neuritis.

Rifabutin, 300 mg orally daily.

Rash, hepatitis, uveitis.

Toxoplasmosis

Pyrimethamine, 100–200 mg orally as loading dose, followed by 50–75 mg/d, combined with sulfadiazine, 4–6 g orally daily in four divided doses, and folinic acid, 10 mg orally daily for 4–8 weeks; then pyrimethamine, 25–50 mg/d, with clindamycin, 2–2.7 g/d in three or four divided doses, and folinic acid, 5 mg/d, until clinical and radiographic resolution is achieved.

Leukopenia, rash.

Lymphoma

Combination chemotherapy (eg, modified CHOP, M-BACOD, with or without G-CSF or GM-CSF). Central nervous system disease: radiation treatment with dexamethasone for edema.

Nausea, vomiting, anemia, leukopenia, cardiac toxicity (with doxorubicin).

Cryptococcal meningitis

Amphotericin B, 0.6 mg/kg/d intravenously, with or without flucytosine, 100 mg/kg/d orally in four divided doses for 2 weeks, followed by:

Fever, anemia, hypokalemia, azotemia.

Fluconazole, 400 mg orally daily for 6 weeks, then 200 mg orally daily.

Hepatitis.

Valganciclovir, 900 mg orally twice a day for 21 days with food (induction), followed by 900 mg daily with food (maintenance).

Neutropenia, anemia, thrombocytopenia.

Ganciclovir, 10 mg/kg/d intravenously in two divided doses for 10 days, followed by 6 mg/kg 5 days a week indefinitely. (Decrease dose for kidney disease.) May use ganciclovir as maintenance therapy (1 g orally with fatty foods three times a day).

Neutropenia (especially when used concurrently with zidovudine), anemia, thrombocytopenia.

Foscarnet, 60 mg/kg intravenously every 8 hours for 10–14 days (induction), followed by 90 mg/kg once daily. (Adjust for changes in kidney function.)

Nausea, hypokalemia, hypocalcemia, hyperphosphatemia, azotemia.

Esophageal candidiasis or recurrent vaginal candidiasis

Fluconazole, 100–200 mg orally daily for 10–14 days.

Hepatitis, development of imidazole resistance.

Herpes simplex infection

Acyclovir, 400 mg orally three times daily until healed; or acyclovir, 5 mg/kg intravenously every 8 hours for severe cases.

Resistant herpes simplex with chronic therapy.

Famciclovir, 500 mg orally twice daily until healed.

Nausea.

Valacyclovir, 500 mg orally twice daily until healed.

Nausea.

Foscarnet, 40 mg/kg intravenously every 8 hours, for acyclovirresistant cases. (Adjust for changes in kidney function.)

See above.

Mycobacterium avium complex infection

Cytomegalovirus infection

(continued )

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Table 31–5. Treatment of AIDS-related opportunistic infections and malignancies.1 (continued) Infection or Malignancy

Treatment

Complications

Acyclovir, 800 mg orally four or five times daily for 7 days.

Intravenous therapy at 10 mg/kg every 8 hours for ocular involvement, disseminated disease.

See above.

Famciclovir, 500 mg orally three times daily for 7 days.

Nausea.

Valacyclovir, 500 mg orally three times daily for 7 days.

Nausea.

Foscarnet, 40 mg/kg intravenously every 8 hours for acyclovirresistant cases. (Adjust for changes in kidney function.)

See above.

Limited cutaneous disease

Observation, intralesional vinblastine.

Inflammation, pain at site of injection.

Extensive or aggressive cutaneous disease

Systemic chemotherapy (eg, liposomal doxorubicin). Interferon-α (for patients with CD4 > 200 cells/mcL and no constitutional symptoms). Radiation (amelioration of edema).

Bone marrow suppression, peripheral neuritis, flulike syndrome.

Visceral disease (eg, pulmonary)

Combination chemotherapy (eg, daunorubicin, bleomycin, vinblastine).

Bone marrow suppression, cardiac toxicity, fever.

Herpes zoster

Kaposi sarcoma

1

For treatment of M tuberculosis infection, see Chapter 9.

For moderate to severe P jiroveci infection (oxygen saturation < 90%), corticosteroids should be given with specific treatment. The dose of prednisone is 40 mg orally twice daily for 5 days, then 40 mg daily for 5 days, and then 20 mg daily until therapy is complete.

3 When considering use of dapsone, check glucose-6-phosphate dehydrogenase (G6PD) level in black patients and those of Mediterranean origin.

CHOP, cyclophosphamide, doxorubicin (hydroxydaunomycin), vincristine (Oncovin), and prednisone; G-CSF, granulocyte-colony stimulating factor (filgrastim); GM-CSF, granulocyte-macrophage colony-stimulating factor (sargramostim); modified M-BACOD, methotrexate, bleomycin, doxorubicin (Adriamycin), cyclophosphamide, vincristine (Oncovin), and dexamethasone.

2

of HAART, patients required lifelong treatment for many infections, including CMV retinitis, toxoplasmosis, and cryptococcal meningitis. However, among patients who have a good response to HAART, maintenance therapy for some opportunistic infections can be terminated.

For example, in consultation with an ophthalmologist, maintenance treatment for CMV infection can be discontinued when persons receiving HAART have durable suppression of viral load (ie, < 50 copies/mL) and a CD4 count > 100–150 cells/mcL. Similar results have been observed in patients with M avium complex bacteremia. Prophylaxis for P pneumonia is also commonly discontinued in patients who have achieved and maintained a CD4 > 200 cells/mcL with good virologic control.

Treating patients with repeated episodes of the same opportunistic infection can pose difficult therapeutic challenges. For example, patients with second or third episodes of P pneumonia may have developed allergic reactions to standard treatments with a prior episode.

Fortunately, there are several alternatives available for the treatment of Pneumocystis infection. Trimethoprim with dapsone and primaquine with clindamycin are two combinations that often are tolerated in patients with a prior allergic reaction to trimethoprim-sulfamethoxazole and intravenous pentamidine. On the positive side, patients in whom second episodes of P pneumonia

develop while taking prophylaxis tend to have milder courses.

Well-established alternative regimens now also exist for most AIDS-related opportunistic infections: amphotericin B or fluconazole for cryptococcal meningitis; ganciclovir, cidofovir, or foscarnet for CMV infection; and sulfadiazine or clindamycin with pyrimethamine for toxoplasmosis.

Adjunctive Treatments—Although conceptually it would seem that corticosteroids should be avoided in HIVinfected patients, corticosteroid therapy has been shown to improve the course of patients with moderate to severe Pneumocystis jiroveci pneumonia (oxygen saturation < 90%, Po2 < 65 mm Hg) when administered within 72 hours after diagnosis. The mechanism of action is presumed to be a decrease in alveolar inflammation.

Corticosteroids have also been used to treat immune reconstitution and inflammatory syndromes (IRIS) that can sometimes complicate the early treatment course when ART is initiated in patients with advanced AIDS (see section Inflammatory reactions [immune reconstitution syndromes]).

Epoetin alfa (erythropoietin) is approved for use in HIVinfected patients with anemia, including those with anemia secondary to zidovudine use. It has been shown to decrease the need for blood transfusions. The drug is expensive, and

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therefore an erythropoietin level < 500 mU/mL should be demonstrated before starting therapy. The starting dose of epoetin alfa is 8000 units subcutaneously three times a week.

The target hematocrit is 35–40%. The dose may be increased by 12,000 units every 4–6 weeks as needed to a maximum dose of 48,000 units per week. Hypertension is the most common side effect.

Human G-CSF (filgrastim) and granulocyte-macrophage colony-stimulating factor (GM-CSF [sargramostim]) have been shown to increase the neutrophil counts of HIVinfected patients. Because of the high cost of this therapy, the dosage should be closely monitored and minimized, aiming for a neutrophil count of 1000/mcL. When the drug is used for indications other than cytotoxic chemotherapy, one or two doses at 5 mcg/kg per week are usually sufficient.

C. Antiretroviral Therapy The availability of agents that in combination suppress HIV replication (Table 31–6) has had a profound impact on the natural history of HIV infection. Indeed, with the advent of antiretroviral treatment, the life expectancy of HIV-infected persons approaches that of uninfected persons when treatment is initiated early in the course of the disease.

The greater potency and the improved side effect profile have led to recommendations to start treatment earlier in the course of HIV disease. Treatment should be initiated for all symptomatic patients, and for asymptomatic persons who (1) have CD4 cell counts below 500 cells/mcL, (2) have rapidly dropping CD4 counts (> 100 cells/mcL/yr) or very high viral loads (> 100,000/mcL), (3) have active infection with hepatitis B or C (rapid HIV replication is thought to hasten progression of hepatitis B and C), (4) have risk factors for cardiac disease (ongoing HIV replication may increase the risk of cardiac disease), (5) have HIVrelated renal impairment, (6) pregnancy, or (7) have risk factors for non–AIDS-related cancers (rapid HIV replication may increase such cancers). Current guidelines suggest that patients who have none of the above conditions but are at high risk for transmitting HIV to another person should be considered for ART. However, for patients with difficulty adhering to therapy, deferring ART until the patient is willing to commit to therapy may be a better strategy. In addition, because 5–20% of patients in developed countries who are treatment-naïve have a virus that is resistant to some drugs, resistance testing is recommended for all patients prior to initiating ART. Once a decision to initiate therapy has been made, several important principles should guide therapy. First, because drug resistance to antiretroviral agents develops in HIV-infected patients, a primary goal of therapy should be complete suppression of viral replication as measured by the serum viral load. Therapy that achieves a plasma viral load of < 40 or < 50 copies/mL (depending on the test used) has been shown to provide a durable response to the therapy. To achieve this and maintain virologic control over time, combination therapy with at least 3 drugs from at least two different classes is necessary, and partially suppressive combinations such as dual nucleoside therapy

should be avoided. Similarly, if toxicity develops, it is preferable to either interrupt the entire regimen or change the offending drug rather than reduce individual doses.

Two randomized trials compared early initiation of ART (within 2 weeks of starting treatment for an opportunistic infection or tuberculosis) with ART that was deferred until after treatment of the opportunistic infection was completed (6 weeks after its start); results demonstrated that early initiation reduced death or AIDS progression by 50%. The reduced progression rates were related to more rapid improvements in CD4 counts in patients with advanced immunodeficiency. Furthermore, IRIS and other adverse events were no more frequent in the early ART arm. Based on these results, most treatment guidelines recommend that ART be initiated as early as is clinically feasible for patients with an acute AIDS-related opportunistic infection. For hospitalized patients, this recommendation requires close coordination between inpatient and outpatient physicians to ensure that treatment is continued once patients are discharged.

The current standard is to use at least three agents simultaneously from at least two different classes. Because the number of drugs is finite, it is important to avoid drug resistance, which occurs when patients take medications in the setting of ongoing viral replication. Therefore, the best method for avoiding resistance is for the patient to be compliant with an efficacious regimen. Adherence can be promoted through the use of simple regimens (one pill a day combination regimens, and for those patients with more complicated regimens, medication boxes with compartments [eg, Medisets]). Many patients benefit from adherence counseling and some need daily supervision of therapy. Given these options treatment should not be withheld solely on the basis of a patient’s circumstances (eg, active drug use or housing status) alone. Often, a trial intervention such as offering Pneumocystis pneumonia prophylaxis may be helpful in determining the likelihood of adherence to a more complex antiretroviral regimen.

Monitoring of ART has two goals. Laboratory evaluation for toxicity depends on the specific drugs in the combination but generally should be done approximately every 3-4 months once a patient is on a stable regimen. Patients who are intolerant of their initial regimen (eg, patients who cannot tolerate the neurologic side effects of efavirenz) should be changed to an alternative drug or regimen. The second aspect of monitoring is to regularly measure objective markers of efficacy. The CD4 cell count and HIV viral load should be repeated 1–2 months after the initiation or change of antiretroviral regimen and every 4-6 months thereafter in clinically stable patients (those with higher CD4 counts can have testing every 6 months).

In a patient who is adherent to an effective regimen, viral loads should be undetectable within 12–24 weeks. For patients in whom viral loads are not suppressed or who have viral rebound after suppression, the major question facing the clinician is whether the patient is nonadherent or has resistance to the regimen, or both. The issue is complicated because many patients report being more compliant than they really are, not because they wish to be untruthful but because they wish to tell the clinician what

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Table 31–6. Antiretroviral therapy.

Drug

Dose

Common Side Effects

Special Monitoring1

Cost2

Cost/Month

Nucleoside reverse transcriptase inhibitors Abacavir (Ziagen)

300 mg orally twice daily

Rash, fever—if occur, rechallenge may be fatal

No special monitoring

$11.17/300 mg

$670.20

Didanosine (ddI) (Videx)

400 mg orally daily (entericcoated capsule) for persons ≥ 60 kg

Peripheral neuropathy, pancreatitis, dry mouth, hepatitis

Bimonthly neurologic questionnaire for neuropathy, K+, amylase, bilirubin, triglycerides

$12.30/400 mg

$368.72

Emtricitabine (Emtriva)

200 mg orally once daily

Skin discoloration palms/soles (mild)

No special monitoring

$16.81/200 mg

$504.30

Lamivudine (3TC) (Epivir)

150 mg orally twice daily

Rash, peripheral neuropathy

No special monitoring

$7.16/150 mg

$429.60

Stavudine (d4T) (Zerit)

40 mg orally twice daily for persons ≥ 60 kg

Peripheral neuropathy, hepatitis, pancreatitis

Monthly neurologic questionnaire for neuropathy, amylase

$6.85/40 mg

$410.70

Zalcitabine (ddC) (Hivid)

0.375–0.75 mg orally three times daily

Peripheral neuropathy, aphthous ulcers, hepatitis

Monthly neurologic questionnaire for neuropathy

Not available in the US

Not available in the US

Zidovudine (AZT) (Retrovir)

600 mg orally daily in two divided doses

Anemia, neutropenia, nausea, malaise, headache, insomnia, myopathy

No special monitoring

$6.09/300 mg

$365.09

Gastrointestinal distress

Creatinine every 3-4 months, urine analysis every 6-12 months

$29.11/300 mg

$873.28

Nucleotide reverse transcriptase inhibitors Tenofovir (Viread)

300 mg orally once daily

Protease inhibitors (PIs) Fosamprenavir (Lexiva)

Gastrointestinal, rash For PI-experienced patients: 700 mg orally twice daily and 100 mg of ritonavir orally twice daily.

For PI-naïve patients: above or 1400 mg orally twice daily or 1400 mg orally once daily and 200 mg of ritonavir orally once daily

No special monitoring

$15.79/700 mg

$947.12–$1894.24 (plus cost of ritonavir for lower dose)

Indinavir (Crixivan)

800 mg orally three times daily

Renal calculi

Bilirubin level

$3.05/400 mg

$548.12

Lopinavir/ ritonavir (Kaletra)

400 mg/100 mg orally twice daily

Diarrhea

No special monitoring

$7.26/200 mg (lopinavir)

$871.36

Nelfinavir (Viracept)

750 mg orally three times daily or 1250 mg twice daily

Diarrhea

No special monitoring

$3.06/250 mg $7.66/625 mg

$826.20 $919.43

Ritonavir (Norvir)

600 mg orally twice daily or in lower doses (eg, 100 mg orally once or twice daily) for boosting other PIs

Gastrointestinal distress, peripheral paresthesias

No special monitoring

$10.29/100 mg

$3703.20 ($617.20 in lower doses)

(continued )

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Table 31–6. Antiretroviral therapy. (continued) Dose

Common Side Effects

Special Monitoring1

Saquinavir hard gel (Invirase)

1000 mg orally twice daily with 100 mg ritonavir orally twice daily

Gastrointestinal distress

No special monitoring

$9.07/500 mg

$1088.84 (plus cost of ritonavir)

Atazanavir (Reyataz)

400 mg orally once daily or 300 mg atazanavir with 100 mg ritonavir daily.

Hyperbilirubinemia

Bilirubin level

$19.60/200 mg

$1176.23 (plus cost of ritonavir)

Darunavir/ ritonavir (Prezista/ Norvir)

For PI-experienced patients: 600 mg of darunavir and 100 mg of ritonavir orally twice daily.

Rash

No special monitoring

$20.50/600 mg (darunavir) $10.29/100 mg (ritonavir) __________ $20.50/400 mg (darunavir)

$1847.40 (for combination)

No special monitoring

$11.13/250 mg (tipranavir) $10.29/100 mg (ritonavir)

$2569.54 (for combination)

Drug

_______________ For PI-naïve patients: 800 mg of darunavir and 100 mg of ritonavir orally daily.

Tipranavir/ ritonavir (Aptivus/ Norvir)

500 mg of tipranavir and 200 mg of ritonavir orally twice daily

Gastrointestinal, rash

Cost2

Cost/Month

_________ $1538.80 (for combination)

Nonnucleoside reverse transcriptase inhibitors (NNRTIs) Delavirdine (Rescriptor)

400 mg orally three times daily

Rash

No special monitoring

$2.12/200 mg

$381.89

Efavirenz (Sustiva)

600 mg orally daily

Neurologic disturbances, rash

No special monitoring

$22.98/600 mg

$689.52

Etravirine (Intelence)

200 mg orally twice daily

Rash, peripheral neuropathy

No special monitoring

$8.15/100 mg

$978.64

Nevirapine (Viramune)

200 mg orally daily for 2 weeks, then 200 mg orally twice daily

Rash

No special monitoring

$12.05/200 mg

$723.08

Rilpivirine (Edurant)

25 mg daily

Depression, rash

No special monitoring

$26.81/25 mg

$804.38

Enfuvirtide (Fuzeon)

90 mg subcutaneously twice daily

Injection site pain and allergic reaction

No special monitoring

$54.15/90 mg

$3248.72

Maraviroc (Selzentry)

150–300 mg orally daily

Cough, fever, rash

No special monitoring

$20.00/150 mg or 300 mg

$1199.83

400 mg orally twice daily

Diarrhea, nausea, headache

No special monitoring

$19.52/400 mg

$1171.30

Entry inhibitors

Integrase inhibitor Raltegravir (Isentress)

1 Standard monitoring is complete blood count (CBC) and differential, serum aminotransferases every 3–4 months, and cholesterol (total, LDL, HDL), and triglycerides 6 months after starting ART and annually among those over age 40 years.

Average wholesale price (AWP, for AB-rated generic when available) for quantity listed. Source: Red Book Online, 2012, Thomson Reuters (Healthcare Inc.). AWP may not accurately represent the actual pharmacy cost because wide contractual variations exist among institutions.

he or she wants to hear. Patients who are having trouble adhering to their treatment should receive counseling on how to better comply to their treatment. In patients who are adherent or who have missed enough doses to make resistance possible, resistance testing should be performed.

Based on the results of resistance testing, and assessment of the patient’s ability to comply with complicated regimens or to tolerate predictable side effects, the clinician should

prescribe a combination of three medications to which there is no or only minimal resistance. Some patients whose counts rise dramatically on ART and who are fully suppressed (ie, plasma viral load < 50 copies/mL) may be successfully transitioned from a high potency regimen to a lower potency regimen with fewer side effects; however, this “induction-maintenance” strategy is still being evaluated in clinical trials. Stopping therapy in patients with

HIV Infection & AIDS high CD4 counts will generally result in patients reverting to their pretreatment nadir CD4 count in a matter of months and is therefore not recommended.

Although the ideal combination of drugs has not yet been defined for all possible clinical situations, possible choices can be better understood after a review of the available agents. These drugs can be grouped into five major categories: nucleoside and nucleotide reverse transcriptase inhibitors (NRTI); PI; nonnucleoside reverse transcriptase inhibitors (NNRTI); entry inhibitors, which include a fusion inhibitor and CCR5 antagonists; and integrase inhibitors. Once ART has been initiated in a patient, it is not advisable to stop the therapy unless there is a compelling reason (eg, toxicity, poor adherence, etc). So-called “drug holidays” or “structured treatment interruptions” have been shown to increase risk of AIDS-related complications, increase CD4 declines, and increase morbidity from non–AIDS-related complications (eg, myocardial infarctions and liver failure) and are not recommended.

1. Nucleoside and nucleotide reverse transcriptase inhibitors—There are currently seven nucleoside or nucleotide agents approved for use. The choice of which agent to use depends primarily on the patient’s prior treatment experience, results of resistance testing, drug side effects, other underlying conditions, and convenience of formulation. However, most clinicians use fixed-dose combinations of either tenofovir/emtricitabine (TDF/FTC) or abacavir/lamivudine (ABC/3TC), both of which can be given once a day. Zidovudine/lamivudine (AZT/3TC) is usually reserved for second- or third-line regimens because of toxicity and dosing schedule. Recent studies have raised some concerns about the efficacy of ABC/3TC in patients with high viral loads (eg, > 100,000 copies/mL) as well as concerns about increase risks of myocardial infarction with abacavir. Therefore, TDF/FTC is the preferred fixed-dose combination as part of initial treatment regimens.

Of the available agents, zidovudine is the most likely to cause anemia. Zidovudine and didanosine are the most likely to cause neutropenia. Stavudine is the most likely to cause lipoatrophy (loss of fat in the face, extremities, and buttocks) followed by zidovudine. Zalcitabine and didanosine are the most likely to cause peripheral neuropathy. Lamivudine, emtricitabine, and tenofovir have activity against hepatitis B. Didanosine, lamivudine, emtricitabine, and tenofovir can be administered daily. Information specific to each drug is given below, and recommendations on how to combine them appear in the Constructing ­regimens section below.

A. Zidovudine—Zidovudine was the first approved antiviral drug for HIV infection and remains an important agent. It is administered at a dose of 300 mg orally twice daily. A combination of zidovudine 300 mg and lamivudine 150 mg (Combivir) allows more convenient dosing of medication for individuals taking both of these agents.

Side effects seen with zidovudine are listed in Table 31–6.

Approximately 40% of patients experience subjective side effects that usually remit within 6 weeks. The common doselimiting side effects are anemia and neutropenia, which require ongoing laboratory monitoring. Long-term use has been associated with lipoatrophy.

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B. Didanosine—The most convenient formulation of didanosine (ddI) is the enteric-coated capsule. For adults weighing at least 60 kg, the dose is one 400-mg entericcoated capsule orally daily; for those 30–59 kg, the dose is one 250-mg enteric-coated capsule orally daily. Didanosine should be taken on an empty stomach.

Didanosine has been associated with pancreatitis. The incidence of pancreatitis with didanosine is 5–10%—of fatal pancreatitis, < 0.4%. Patients with a history of pancreatitis, as well as those taking other medications associated with pancreatitis (including trimethoprim-sulfamethoxazole and intravenous pentamidine) are at higher risk for this complication. Other common side effects with didanosine include a dose-related, reversible, painful peripheral neuropathy, which occurs in about 15% of patients, and dry mouth. Fulminant hepatic failure and electrolyte abnormalities, including hypokalemia, hypocalcemia, and hypomagnesemia, have been reported in patients taking didanosine. Because of the side-effect profile, didanosine is rarely used today.

C. Stavudine—Stavudine (d4T) has shown good activity as an antiretroviral drug. The dose is 40 mg orally twice daily for individuals weighing 60 kg or more. However, because of its side effects including lipoatrophy, lipodystrophy (see below), peripheral neuropathy and, rarely, lactic acidosis and hepatitis, this drug should no longer be used except when there is no alternative. Patients taking stavudine should be routinely changed to abacavir or tenofovir, both of which are less likely to cause lipoatrophy.

D. Lamivudine—Lamivudine (3TC) is a safe and welltolerated agent. The dosage is 150 mg orally twice daily or 300 mg orally once a day. The dose should be reduced with chronic kidney disease. There are no significant side effects with lamivudine, and it has activity also against hepatitis B. E. Emtricitabine—Emtricitabine is a nucleoside analog that is dosed at 200 mg orally. It was developed primarily as a once a day alternative to lamivudine. However, lamivudine can be dosed daily, eliminating the special indication for emtricitabine. As is true of lamivudine, emtricitabine has activity against hepatitis B and its dosage should be reduced in patients with chronic kidney disease.

F. Abacavir—A daily dose of 300 mg orally twice daily results in potent antiretroviral activity. Prior to initiation of abacavir, patients should undergo testing for HLA typing. Those with the B*5701 allele should not be treated with abacavir because the likelihood of a hypersensitivity reaction developing is high; the reaction is characterized by a flu-like syndrome with rash and fever that worsens with successive doses. Unfortunately, the absence of this allele does not guarantee that the patient will avoid the hypersensitivity reaction. Individuals in whom the hypersensitivity reaction develops should not be rechallenged with this agent because subsequent hypersensitivity reactions can be fatal. Abacavir has also been shown to be associated with an increased risk of myocardial infarction in some cohort studies. This increased risk is generally seen in patients who have underlying risks of cardiovascular disease. Consequently, abacavir should be avoided in such

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patients if effective alternative nucleoside or nucleotide analog agents exist.

Abacavir is formulated with zidovudine and lamivudine in a single pill (Trizivir, one tablet orally twice daily).

Trizivir is not recommended as solo treatment for HIV because it is not as efficacious as combining two nucleoside/ nucleotide analogs with a PI/ritonavir or an NNRTI; its use as a sole regimen should be reserved only for patients who cannot tolerate a more complicated regimen. Abacavir is also available as a fixed dose combination pill with lamivudine for use as a once daily pill (Epzicom).

G. Zalcitabine—Zalcitabine (ddC) was one of the least effective antiretroviral agents and is no longer being manufactured.

H. Tenofovir—Tenofovir is the only licensed nucleotide analog. It is given as a single daily oral dose of 300 mg and is generally well tolerated. Tenofovir is available in a fixed dose combination pill with emtricitabine (Truvada) for daily dosing and is the only recommended fixed-dose combination for initial regimens. A once-a-day single fixed-dose combination pill that contains efavirenz, emtricitabine, and tenofovir (Atripla) is also available. Tenofovir is active against hepatitis B, including isolates that have resistance to lamivudine.

2. Protease inhibitors—Ten PIs—indinavir, nelfinavir, ritonavir, saquinavir, amprenavir, fosamprenavir, lopinavir (in combination with ritonavir), atazanavir, darunavir, and tipranavir are available. PIs have been shown to potently suppress HIV replication and are administered as part of a combination regimen.

All the PIs—to differing degrees—are metabolized by the cytochrome P450 system, and each can inhibit and induce various P450 isoenzymes. Therefore, drug interactions are common and difficult to predict. Clinicians should consult the product inserts before prescribing PIs with other medications. Drugs such as rifampin that are known to induce the P450 system should be avoided.

The fact that the PIs are dependent on metabolism through the cytochrome P450 system has led to the use of ritonavir to boost the drug levels of saquinavir, lopinavir, indinavir, atazanavir, tipranavir, darunavir and amprenavir, allowing use of lower doses and simpler dosing schedules of these PIs. In fact, current guidelines recommend that all PI-containing regimens use ritonavir boosting if possible. The only PIs that can be safely used without ritonavir boosting are nelfinavir and atazanavir.

When choosing which PI to use, prior patient experience, resistance patterns, side effects, and ease of administration are the major considerations. The first three PIs to be developed—indinavir, saquinavir, and ritonavir (as single agents)—are now rarely used because of the superiority of the second generation of PIs. Amprenavir has been almost entirely replaced by its prodrug, fosamprenavir.

Unfortunately, all PIs, with the exception of unboosted atazanavir have been linked to a constellation of metabolic abnormalities, including elevated cholesterol levels, elevated triglyceride levels, insulin resistance, diabetes mellitus, and changes in body fat composition (eg, buffalo hump, abdominal obesity). The lipid abnormalities and body habitus changes are referred to as lipodystrophy. Although

l­ipodystrophy is commonly associated with PIs, it has been seen also in HIV-infected persons who have never been treated with these agents. In particular, the lipoatrophy effects seen in patients receiving ART appears to be more related to the nucleoside toxicity and in particular to the thymidine analogs (stavudine and zidovudine).

Of the different manifestations of lipodystrophy, the dyslipidemias that occur are of particular concern because of the likelihood that increased levels of cholesterol and triglycerides will result in increased prevalence of heart disease. All patients taking PIs or NRTIs should have fasting serum cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyceride levels performed every 3–6 months.

Clinicians should calculate the Framingham 10-year coronary heart disease risk (see Chapter 28) and consider initiating dietary or drug therapy (or both) to achieve target LDL levels depending on the individual’s risk factors.

Patients who are unable to meet their LDL goal based solely on dietary interventions should be given pravastatin (20 mg daily orally) or atorvastatin (10 mg daily orally). Lovastatin and simvastatin should be avoided because of their interactions with PIs. Fish oil (3000 mg daily) combined with exercise and dietary counseling has been found to decrease triglycerides levels by 25%. Patients with persistently elevated fasting serum triglyceride levels of 500 mg/dL or more who do not respond to dietary intervention should be treated with gemfibrozil (600 mg twice daily prior to the morning and evening meals).

A. Indinavir—The standard dose of indinavir is 800 mg orally three times a day, although it is usually dosed twice daily in combination with ritonavir. Nausea and headache are common complaints with this drug. Indinavir crystals are present in the urine in approximately 40% of patients; this results in clinically apparent nephrolithiasis in about 15% of patients receiving indinavir. Lower urinary tract symptoms and acute kidney injury also have been reported.

Patients taking this drug should be instructed to drink at least 48 ounces of fluid a day to ensure adequate hydration in an attempt to limit these complications. Mild indirect hyperbilirubinemia is also commonly observed in patients taking indinavir but is not an indication for discontinuation of the drug.

B. Saquinavir—Saquinavir is formulated only as a hardgel capsule (Invirase). It should only be used with ritonavir (1000 mg of hard-gel saquinavir with 100 mg of ritonavir orally twice daily). The soft-gel capsule (Fortovase) has been removed from the market in the United States. The most common side effects with saquinavir are diarrhea, nausea, dyspepsia, and abdominal pain.

C. Ritonavir—Use of this potent PI at full dose (600 mg orally twice daily) has been limited by its inhibition of the cytochrome P450 pathway causing a large number of drug–drug interactions and by its frequent side effects of fatigue, nausea, and paresthesias. However, it is widely used in lower dose (eg, 100 mg daily to 100 mg twice daily) as a booster of other PIs. D. Nelfinavir—Nelfinavir is the only PI for which ritonavir boosting is not recommended. Unboosted nelfinavir is

HIV Infection & AIDS generally not as potent as a boosted PI regimen (eg, lopinavir plus ritonavir). The dose of nelfinavir is 1250 mg orally twice daily. Diarrhea is a side effect in 25% of patients taking nelfinavir, but this symptom may be controlled with over-the-counter antidiarrheal agents in most patients.

E. Amprenavir—Amprenavir has efficacy and side effects similar to those of other PIs. Common side effects are nausea, vomiting, diarrhea, rash, and perioral paresthesia. The dose is 1200 mg orally twice daily. The concentration of amprenavir decreases when coadministered with ethinyl estradiol; therefore, amprenavir should be used with circumspection in the treatment of transgender persons requiring high-dose estrogen.

F. Fosamprenavir—Fosamprenavir is a prodrug of amprenavir. Its major advantage over using amprenavir is a much lower pill burden. For PI-naïve patients, it can be dosed at 1400 mg orally twice daily (four capsules a day) or at 1400 mg orally daily (two capsules) with ritonavir 200 mg orally daily (two capsules) or at 700 mg orally with ritonavir 100 mg orally twice daily. Patients previously treated with PIs should receive 700 mg orally with ritonavir 100 mg orally twice daily. Side effects are similar to those with amprenavir—most commonly gastrointestinal distress and hyperlipidemia. As with amprenavir, the concentration of fosamprenavir decreases when coadministered with ethinyl estradiol; therefore, fosamprenavir should be used with circumspection in the treatment of transgender persons requiring high-dose estrogen.

G. Lopinavir/r—Lopinavir/r is lopinavir (200 mg) coformulated with a low dose of ritonavir (50 mg) to maximize the bioavailability of lopinavir. It has been shown to be more effective than nelfinavir when used in combination with stavudine and lamivudine. The usual dose is 400 mg lopinavir with 100 mg of ritonavir (two tablets) orally twice daily with food. When given along with efavirenz or nevirapine, a higher dose (600 mg/150 mg—three tablets) is usually prescribed. The most common side effect is diarrhea, and lipid abnormalities are frequent. Because of these side effects, lopinavir/r has fallen off the list of drugs recommended as part of firstline treatment regimens.

H. Atazanavir—Atazanavir can be dosed as 400 mg (two 200-mg capsules) only daily with food or it can be dosed as 300 mg in combination with 100 mg of ritonavir once daily with food. When used without ritonavir, it has only minimal or no impact on cholesterol and triglyceride levels. The most common side effect is mild hyperbilirubinemia that resolves with discontinuation of the drug. Nephrolithiasis has also been reported with this PI. Both tenofovir and efavirenz lower the serum concentration of atazanavir.

Therefore, when either of these two drugs is used with atazanavir, it should be boosted by administering ritonavir.

Proton pump inhibitors are contraindicated in patients taking atazanavir because atazanavir requires an acidic pH to remain in solution.

I. Tipranavir—Tipranavir is the only nonpeptidic PI currently approved by the US Food and Drug

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Administration (FDA). Because of its unique structure, it is active against some strains of HIV that are resistant to other PIs. It is dosed with ritonavir (two 250 mg capsules of tipranavir with two 100 mg capsules of ritonavir orally twice daily with food). The most common side effects are nausea, vomiting, diarrhea, fatigue, and headache.

Tipranavir/ritonavir has been also associated with liver damage and should be used very cautiously in patients with underlying liver disease. Reports of intracranial hemorrhage in patients taking tipranavir-containing regimens have raised additional safety concerns about this potent PI. Because it is a sulfa-containing drug, its use should be closely monitored in patients with sulfa allergy.

J. Darunavir—Darunavir has impressive antiviral activity in the setting of significant PI resistance and in treatmentnaïve patients. Darunavir has been added to the list of recommended PIs for initial treatment of HIV at a daily dose of 800 mg with 100 mg of ritonavir. For patients with prior PI treatment experience or PI resistance, darunavir should be dosed at 600 mg orally twice daily, with ritonavir, 100 mg orally twice daily. Once daily dosing can be used in treatment-experienced patients who do not have darunavir-related resistance mutations. Darunavir has a safety profile similar to other PIs, such as lopinavir/ritonavir but is generally better tolerated. Like tipranavir, darunavir is a sulfa-containing drug, and its use should be closely monitored in patients with sulfa allergy.

3. Nonnucleoside reverse transcriptase inhibitors— NNRTIs inhibit reverse transcriptase at a site different from that of the nucleoside and nucleotide agents described above. All five NNRTIs have shown antiviral activity as measured by HIV viral load and CD4 responses. The major advantage of the NNRTIs is that three of them (efavirenz, rilpivirine, and nevirapine) have potencies comparable to that of PIs, at least for patients with viral loads under 100,000 copies/mL—with lower pill burden and fewer side effects. In particular, they do not appear to cause lipodystrophy; patients with cholesterol and triglyceride elevations who are switched from a PI to an NNRTI may have improvement in their lipids. The resistance patterns of the NNRTIs are distinct from those of the PIs, so their use still leaves open the option for future PI use.

The NNRTIs can be used with PIs in patients who are difficult to suppress on simpler regimens or when it is difficult to identify at least two nucleoside/nucleotide agents to which the patient is not resistant. Because these agents may cause alterations in the clearance of PIs, dose modifications may be necessary when these two classes of medications are administered concomitantly. There is a high degree of cross-resistance between the “first generation” NNRTIs, such that resistance to one drug in this class uniformly predicts resistance to other drugs. However, etravirine appears to have consistent antiviral activity in patients with prior exposure and resistance to nevirapine, efavirenz, or delavirdine. In particular, the K103N mutation does not appear to have an impact on etravirine (or rilpivirine). There is no therapeutic reason for using more than one NNRTI at the same time.

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A. Efavirenz—The major advantages of efavirenz is that it can be given once daily in a single dose (600 mg orally), and it is available in a once-daily fixed-dose combination with tenofovir and emtricitabine in a single pill (Atripla).

The combination is probably the best first choice for treatment-naïve patients without resistance to this­ regimen. The side effects are neurologic, with patients reporting symptoms ranging from lack of concentration and strange dreams to delusions and mania. Although the neurologic side effects of efavirenz subside over time, usually within a month, there are some patients who cannot tolerate these neurologic effects. Administration of efavirenz with food, especially fatty food, may increase its serum levels and consequent neurotoxicity. Due to teratogenicity, efavirenz should be avoided in women who wish to conceive or are already pregnant.

B. Rilpivirine—This drug, dosed at 25 mg once daily, is approved for persons initiating ART, and is equal in efficacy to efavirenz in patients with HIV viral loads below 100,000 copies/mL. Those with higher viral loads should be treated with efavirenz or a PI. As is true of efavirenz, rilpivirine is available in a once-daily fixed dose combination with tenofovir and emtricitabine (Complera) to be taken with a fatty meal. Rilpivirine has fewer neurologic side effects than efavirenz, making it a good choice as a first regimen, or an alternative regimen in patients who cannot tolerate the neurologic side effects of efavirenz.

C. Nevirapine—The target dose of nevirapine is 200 mg orally twice daily, but it is initiated at a dose of 200 mg once a day to decrease the incidence of rash, which is as high as 40% when full doses are begun immediately. If rash develops while the patient is taking 200 mg a day, liver enzymes should be checked and the dose should not be increased until the rash resolves. Patients with mild rash and no evidence of hepatotoxicity can continue to be treated with nevirapine. Nevirapine should not be used in treatmentnaïve women with high CD4 counts (> 250/mcL). Because of potential fatal hepatotoxicity, nevirapine should only be used in patients who cannot tolerate efavirenz. An extended-release formulation of nevirapine (Viramune XR) allows for once-daily dosing (400 mg daily). In clinical trials, nevirapine XR was not inferior when compared with standard nevirapine (both forms of nevirapine were combined with tenofovir/emtricitabine). This XR formulation potentially provides another once daily NNRTI regimen for first-line ART, although there has yet to be a direct comparison to any of the currently preferred first-line ART regimens (see below).

D. Delavirdine—Of the available NNRTIs, delavirdine is used the least largely because of its less convenient dosing and pill burden compared with the other available NNRTIs. Unlike nevirapine and efavirenz, delavirdine inhibits P450 cytochromes rather than inducing these enzymes. This means that delavirdine can act like ritonavir and boost other antiretrovirals, although delavirdine is not as potent as ritonavir in this capacity. The dosage is 400 mg orally three times a day. The major side effect is rash.

E. Etravirine—Etravirine is an NNRTI approved for the treatment of patients with prior NNRTI intolerance or resistance. Etravirine has been shown to be effective even when some degree of NNRTI-resistance is present, making it a true “second generation” drug in this class. Etravirine dosage is one 200-mg tablet twice daily. It should be used with a PI and a nucleoside/nucleotide analog and not just with two nucleoside/nucleotide analogs. The most common side effects are nausea and rash; rarely, the rash can be severe (toxic epidermal necrolysis). Patients with signs of severe rash or hypersensitivity reactions should immediately discontinue the drug. Prior rash due to treatment with one of the other NNRTIs does not make rash more likely with etravirine. Etravirine should not be taken by people with severe liver disease or administered with tipranavir/ ritonavir, fosamprenavir/ritonavir, atazanavir/ritonavir, full-dose ritonavir, or PIs without low-dose ritonavir.

4. Entry inhibitors A. Enfuvirtide—Enfuvirtide (Fuzeon) is known as a fusion inhibitor; it blocks the entry of HIV into cells by blocking the fusion of the HIV envelope to the cell membrane. The addition of enfuvirtide to an optimized antiretroviral regimen improved CD4 counts and lowered viral loads in heavily pretreated patients with multidrug-­ resistant HIV. Unfortunately, resistance develops rapidly in patients receiving nonsuppressive treatment. The dose is 90 mg by subcutaneous injection twice daily; unfortunately, painful injection site reactions develop in most patients, which makes long-term use problematic.

B. Maraviroc—Maraviroc is a CCR5 co-receptor antagonist. Drugs in this class prevent the virus from entering uninfected cells by blocking the CCR5 co-receptor.

Unfortunately, this class of entry inhibitors is only active against “CCR5-tropic virus.” This form of the HIV-1 virus tends to predominate early in infection, while socalled “dual/mixed tropic virus” (which utilizes either R5 or CXCR4 co-receptors) emerges later as infection progresses. Approximately 50–60% of previously treated HIV-infected patients have circulating CCR5-tropic HIV. The drug has been shown to be effective in HIV-infected persons with ongoing viral replication despite being heavily treated and who have CCR5-tropic virus. Tropism testing should be performed before beginning the medication. The dose of maraviroc is 150–300 mg orally twice daily, based on the other drugs the patient is taking at the time. Common side effects are cough, fever, rash, musculoskeletal problems, abdominal pain, and dizziness; however, maraviroc is generally well tolerated with limited impact on serum lipids.

5. Integrase inhibitors A. Raltegravir—Raltegravir is an HIV integrase inhibitor. Integrase inhibitors slow HIV replication by blocking the HIV integrase enzyme needed for the virus to multiply.

Raltegravir was impressively effective (when combined with other active drugs) in the treatment of HIV-infected patients with documented resistance to at least one drug in each of the three main classes of antiretroviral medications

HIV Infection & AIDS (nucleoside analogs, PIs, NNRTIs). Clinical trials of integrase inhibitors reveal a consistent pattern of more rapid decline in viral load compared with more standard PI/r or NNRTI-based regimens. The clinical significance of this observation is unclear. Despite the impressive antiviral potency of this new class of antiretroviral drugs, high-level resistance to integrase inhibitors emerges quickly in the setting of virologic failure (much like with the NNRTIs).

Therefore, it is critical that raltegravir be used in combination with other active antiretroviral agents.

Studies in treatment-naïve patients have demonstrated that raltegravir in combination with tenofovir/ emtricitabine is as effective as the current first-line choice of efavirenz/tenofovir/emtricitabine for daily treatment and has fewer side effects. Furthermore, the CD4 response appeared better in patients treated with the raltegravir combination. Raltegravir is approved by the FDA for treatment-naïve patients. The dose of raltegravir is 400 mg orally twice daily. Common side effects are diarrhea, nausea, and headache.

B. Elvitegravir—Elvitegravir is another integrase inhibitor that is in late stage development. The dose is 125 mg once daily, given with ritonavir (100 mg) for boosting.

Elvitegravir showed impressive short-term virologic responses in phase 2 studies and is expected to be approved in 2012.

6. Constructing regimens—There is now little debate about the necessity for combining drugs to achieve longterm suppression of HIV and its associated clinical benefit. Only combinations of three or more drugs have been able to decrease HIV viral load by 2–3 logs and allow long-term suppression of HIV RNA to below the threshold of detection.

Current evidence supports the use of Truvada (tenofovir and emtricitabine) as the “nucleoside/nucleotide backbone” combined with efavirenz as the initial regimen. This regimen has been shown to be more effective and better tolerated than Combivir (zidovudine and lamivudine) and Epzicom (abacavir/lamivudine). It has the advantages of once daily dosing and is available as a single pill (Atripla and Complera). Because 8–10% of newly infected persons in some urban areas of the United States have NNRTI resistance, resistance testing should be performed before initiating efavirenz in this population. The following medications may also be combined with daily fixed-dose tenofovir/emtricitabine as first-line regimens: darunavir/ritonavir (800 mg/100 mg daily), atazanavir/ritonavir (300 mg/100 mg daily), or raltegravir (400 mg twice daily). Regimens that include only nucleoside and nucleotide analogs without nonnucleoside agents or PIs are clinically inferior and should only be used for patients that cannot adhere to a more complicated regimen.

The most important determinant of treatment efficacy is adherence to the regimen. Therefore, it is vitally important that the regimen chosen be one to which the patient can easily adhere. In general, patients are more compliant with medication regimens that are once or twice a day only, do

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not require special timing with regard to meals, can be taken at the same time as other medications, do not require refrigeration or special preparation, and do not have bothersome side effects. Toxicities should ideally be nonoverlapping. An individual’s relative contraindications to a given drug or drugs should be considered. The regimen should not include agents that are either virologically antagonistic or incompatible in terms of drug–drug interactions. For example, etravirine should not be used with boosted tipranavir because of drug-drug interactions. Compatible dosing schedules— prescribing medications that can be taken at the same time—improve adherence to treatment. Finally, highly complex therapeutic regimens should be reserved for individuals who are capable of adhering to the rigorous demands of taking multiple medications and having this therapy closely monitored. Conversely, simplified regimens that deliver the lowest number of pills given at the longest possible dosing intervals are desirable for patients who have difficulty taking multiple medications.

Possible ways of incorporating nonnucleoside agents and PIs into combinations are displayed in Figure 31–2.

A number of points about the “nucleoside/nucleotide backbone” of regimens have become clearer. The combination of stavudine plus didanosine should be avoided, since there is increased risk of toxicities, in particular in pregnant women because of the increased risk of lactic acidosis, which can be fatal. Moreover, the nucleoside pair of zidovudine and stavudine should be avoided because of increased toxicity and the potential for antagonism that results from intracellular competition for phosphorylation. Finally, the combination of didanosine with tenofovir should be avoided due to observed declines in CD4 counts.

In designing second-line regimens for patients with resistance to initial therapy, the goal is to identify three drugs from at least two different classes to which the virus is not resistant. This can be quite complicated because of the problem of cross-resistance between drugs within a class. For example, the resistance patterns of lopinavir/ ritonavir and indinavir are overlapping, and patients with virus resistant to these agents are unlikely to respond to nelfinavir or saquinavir even though they have never received treatment with these agents. Similarly, the resistance patterns of nevirapine and efavirenz are overlapping.

With several new classes of drugs and new generations of existing drug classes now available, the ability to provide fully suppressive regimens even to patients with extensive treatment experience and drug resistance has become more realistic. The goal of therapy, therefore, should be to fully suppress viral loads to < 50 copies/mL even for highly treatment-experienced patients.

In addition to taking a careful history of what antiretroviral agents a patient has taken and for how long, genotypic and phenotypic resistance testing can provide useful information in designing second-line regimens.

Whatever regimen is chosen, patients should be coached in ways to improve adherence. For certain populations (eg, unstably housed individuals), specially tailored programs that include drug dispensing are needed.

Rarely, it is impossible to construct a tolerable regimen that fully suppresses HIV. In such cases, clinicians and

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Symptomatic HIV disease or asymptomatic HIV disease and CD4 < 500/mcL or asymptomatic disease and other factors (see text) Other preferred initial regimens Perform resistance testing and begin a three drug regimen. If no resistance to emtricitabine/tenofovir/efavirenz, begin this regimen. If resistance, choose one of the other preferred initial regimens (listed to the right).

Intolerance to regimen

Viral load detectable after 12–24 weeks of treatment or viral rebound after suppression.

Change to alternative drug or regimen

Assess adherence. If not adherent, initiate adherence counseling. If adherent, or if prolonged period of partial or nonadherence.

Truvada Atazanavir Ritonavir

Truvada Darunavir Ritonavir

Truvada Raltegravir

Perform resistance testing and change to a regimen with three drugs from at least two different classes to which the patient is not resistant Nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs) Zidovudine Didanosine Zalcitabine Stavudine Lamivudine Emtricitabine Abacavir Tenofovir

Nonnucleoside reverse transcriptase inhibitors (NNRTIs) Nevirapine Delavirdine Efavirenz Etravirine

Protease inhibitors (Pls) Saquinavir Ritonavir Indinavir Nelfinavir Amprenavir Fosamprenavir Lopinavir/r Atazanavir Tipranavir Darunavir

Entry inhibitors Enfuvirtide Maraviroc Integrase inhibitor Raltegravir Fixed-dose combinations Combivir (zidovudine/lamivudine) Truvada (emtricitabine/tenofovir) Epzicom (lamivudine/abacavir) Trizivir (zidovudine/lamivudine/abacavir) Atripla (emtricitabine/tenofovir/efavirenz)

s Figure 31–2. Approach to initial and subsequent antiretroviral therapy.

patients should consider their goals. Patients maintained on effective antiretroviral agents often benefit from these regimens (eg, higher CD4 counts, fewer opportunistic infections) even if their virus is detectable. In some cases, patients may request a drug holiday during which they are taken off all medications. Patients often immediately feel better because of the absence of drug side effects. Unfortunately, structured treatment interruptions generally result in viral rebound and rapid CD4 decline. Compared with patients who continue their regimens without interruption, those who interrupt their treatment fare poorly, with increased morbidity and mortality from both HIV-related and non– HIV-related causes.

7. The challenge of drug resistance—HIV-1 drug resistance limits the ability to fully control HIV replication and is a leading cause for antiretroviral regimen failure.

Resistance has been documented for all currently available antiretrovirals including the newer classes of fusion inhibitor, CCR5 inhibitors, and integrase inhibitors. The problem of drug resistance is widespread in HIV-infected patients undergoing treatment in countries where ART is widely available. However, recent reports suggest that the degree of high level resistance is declining in the past few years, which is likely related to better tolerated, easier to use, and more

efficacious antiretroviral agents. Patients who have taken various antiretroviral regimens and who now have resistant HIV-1 represent a major challenge for the treating clinician.

Resistance is now also documented in patients who are ART-naive, but who have been infected with a drug resistant strain—“primary resistance.” Cohort studies of antiretroviral treatment–naive patients entering care in North America and Western Europe show that roughly 10–12% (and as high as 25%) of recently infected individuals have been infected with a drug-resistant strain of HIV-1.

Current expert guidelines recommend resistance testing as part of standard baseline testing in all patients.

Resistance testing is also recommended for patients who are on an antiretroviral regimen and have suboptimal viral suppression (ie, viral loads > 1000 copies/mL). Both genotypic and phenotypic tests are commercially available and in randomized controlled studies their use has been shown to result in improved short-term virologic outcomes compared to making treatment choices without resistance testing. Furthermore, multiple retrospective studies have conclusively demonstrated that resistance tests provide prognostic information about virologic response to newly initiated therapy that cannot be gleaned from standard clinical information (ie, treatment history, examination, CD4 count, and viral load tests).

HIV Infection & AIDS Because of the complexity of resistance tests, many clinicians require expert interpretation of results. In the case of genotypic assays, results may show that the mutations that are selected for during ART are drug-specific or contribute to broad cross-resistance to multiple drugs within a therapeutic class. An example of a drug-specific mutation for the reverse transcriptase inhibitors would be the M184V mutation that is selected for by lamivudine or emtricitabine therapy—this mutation causes resistance only to those two drugs. Conversely, the thymidine analog mutations (“TAMs”) of M41L, D67N, K70R, L210W, T215Y/F, and T219Q/K/E are selected for by either zidovudine or stavudine therapy, but cause resistance to all the drugs in the class and often extend to the nucleotide inhibitor tenofovir when three or more of these TAMs are present. Further complicating the interpretation of genotypic tests is the fact that some mutations that cause resistance to one drug can actually make the virus that contains this mutation more sensitive to another drug. The M184V mutation, for example, is associated with increased sensitivity to zidovudine, stavudine, and tenofovir. The most common mutations associated with drug resistance and cross-resistance patterns for NRTIs, NNRTIs, PIs, and integrase inhibitors can be found at http://hivdb.stanford. edu. Phenotypic tests also require interpretation in that the distinction between a resistant virus and sensitive one is not fully defined for all available drugs.

Both methods of resistance testing are limited by the fact that they may measure resistance in only some of the viral strains present in an individual. Resistance results may also be misleading if a patient is not taking antiretroviral medications at the time of testing. Thus, resistance results must be viewed cumulatively—ie, if resistance is reported to an agent on one test, it should be presumed to be present thereafter even if subsequent tests do not give the same result.

Despite the prevalence of resistance in patients who have not responded to multiple prior treatment regimens and given the availability of new class drugs and new ­generation drugs, virtually all patients—no matter how much resistance is present—can be treated with a combination of ART that should be fully suppressive.

``Course & Prognosis With improvements in therapy, patients are living longer after the diagnosis of AIDS. A population-based study conducted in Denmark found that HIV-infected persons at age 25 years without hepatitis C had a life expectancy of 39 additional years. Unfortunately, not all HIV-infected persons have access to treatment. Studies consistently show less access to treatment for blacks, the homeless, and injection drug users. In addition to access to treatment, sustaining lower mortality will require developing new treatments for patients in whom resistance to existing agents develops.

For patients whose disease progresses even though they are receiving appropriate treatment, meticulous palliative care must be provided (see Chapter 5), with attention to pain control, spiritual needs, and family (biologic and chosen) dynamics.

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``When to Refer • Clinicians with limited experience in HIV/AIDS should refer HIV-infected patients to specialists with experience, given the increasing number and complexity of treatment regimens available.

• Extra efforts should be made to obtain specialty consultation for those patients with detectable viral loads on ART; those intolerant of standard medications; those in need of systemic chemotherapy; and those with complicated opportunistic infections, particularly when invasive procedures or experimental therapies are needed.

``When to Admit Patients with opportunistic infections who are acutely ill (eg, who are febrile, who have had rapid change of mental status, or who are in respiratory distress) or who require intravenous medications.

Bhaskaran K et al. Changes in the risk of death after HIV seroconversion compared with mortality in the general population.

JAMA. 2008 Jul 2;300(1):51–9. [PMID: 18594040] Cohen CJ et al; THRIVE Study Group. Rilpivirine versus efavirenz with two background nucleoside or nucleotide reverse transcriptase inhibitors in treatment-naïve adults infected with HIV-1 (Thrive): a phase 3, randomized, non-inferiority trial.

Lancet. 2011 Jul 16;378(9787):229–37. [PMID: 21763935] Lennox JL et al; STARTMRK investigators. Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial. Lancet. 2009 Sep 5;374(9692):796–806. [PMID: 19647866] Molina JM et al; ECHO Study Group. Rilpivirine versus efavirenz with tenofovir and emtricitabine in treatment-naïve adults infected with HIV-1 (ECHO): a phase 3 randomized double-blind active-controlled trial. Lancet. 2011 July 16; 378 (9787):238–46. [PMID: 21763936] Palella FJ Jr et al; HOPS (HIV Outpatient Study) Investigators.

The association of HIV susceptibility testing with survival among HIV-infected patients receiving antiretroviral therapy: a cohort study. Ann Intern Med. 2009 Jul 21;151(2):73–84.

[PMID: 19620160] Sax PE et al; AIDS Clinical Trials Group Study A5202 Team.

Abacavir-lamivudine versus tenofovir-emtricitabine for initial HIV-1 therapy. N Engl J Med. 2009 Dec 3;361(23):2230–40.

[PMID: 19952143] Thompson MA et al; International AIDS SocietyUSA. Antiretroviral treatment of adult HIV infection: 2010 recommendations of the International AIDS Society-USA panel. JAMA. 2010 Jul 21;304(3):321–33. [PMID: 20639566] US Food and Drug Administration. FDA Drug Safety Communication: interactions between certain HIV or hepatitis C drugs and cholesterol-lowering statin drugs can increase the risk of muscle injury. http://www.fda.gov/Drugs/ DrugSafety/ucm293877.htm Wittkop L et al. Effect of transmitted drug resistance on virological and immunological response to initial combination antiretroviral therapy for HIV (EuroCoord-CHAIN joint project): a European multicohort study. Lancet Infect Dis. 2011 May;11(5):363–71. [PMID: 21354861] Zolopa A et al. Early antiretroviral therapy reduces AIDS progression/death in individuals with acute opportunistic infections: a multicenter randomized strategy trial. PLoS One. 2009;4(5):e5575. [PMID: 19440326]