CPD 22: HIV Infection & Diagnosis Continuing Professional Development
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Grimes RM1, Hardwicke RL, Grimes DE, DeGarmo DS. Patients presenting with fever, pharyngitis, and lymphadenopathy are likely to have mononucleosis; however, patients with acute HIV infection may present with similar symptoms. Acute HIV infection should be considered as a differential diagnosis if test results for mononucleosis are negative. This article describes when to order HIV testing and discusses the importance of early intervention for acute HIV infection.
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60 Second Summary Any clinician is faced with a diagnostic challenge when a patient presents with fever, pharyngitis, and lymphadenopathy. Mononucleosis, the most likely of these conditions, can be diagnosed with a positive monospot: the heterophile antibody test; however, there are a number of diagnostic considerations when this test is negative. First, the heterophile test will yield a false negative in 25% of patients who are in the early stages of infectious mononucleosis, and 10% of those with the condition will always have a false negative. Traditionally, viral illnesses were managed by supportive care only; however, recent advances in treatment of acute HIV infection and its sequelae have greatly increased the importance of diagnosing this condition for early treatment. Acute HIV infection occurs almost immediately after a patient is infected with HIV and leads to two major events. Treatment with antiretroviral medications immediately after infection can greatly reduce this high level of circulating virus and can make the patient less infectious. This is extremely important because acute HIV infection is usually the result of recent unsafe sexual practices that are likely to continue after infection. There are important benefits to both the patient and the public’s health if the clinician recognises HIV infection as early as possible. The best guarantee for detecting acute HIV infection is the sensitivity to its possible presence. Given the severity of the symptoms of acute HIV infection, many of these individuals with acute HIV infection are likely to seek clinical care in secure settings– such as primary care practices, EDs, and public health clinics.
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assessment. Follow the 4 previous steps, log and record your findings. Published by HPN, sponsored by MSD. Copies can be downloaded from www.irishpharmacytraining.ie Disclaimer: All material published is copyright, no part of this can be used in any other publication without permission of the publishers and author. MSD has no editorial oversight of the CPD programmes included in these modules.
When to consider acute HIV infection in the differential diagnosis Any clinician is faced with a diagnostic challenge when a patient presents with fever, pharyngitis, and lymphadenopathy. In a very well-researched review article, Hurt and Tammaro list eight possible conditions that may be found in a patient with these symptoms.1 Influenza is another potential diagnosis when these symptoms are present. Mononucleosis, the most likely of these conditions, can be diagnosed with a positive monospot: the heterophile antibody test; however, there are a number of diagnostic considerations when this test is negative. First, the heterophile test will yield a false negative in 25% of patients who are in the early stages of infectious mononucleosis, and 10% of those with the condition will always have a false negative.1 In addition to recognising that the negative test may be false, the clinician would consider the potential of other pathogens causing the symptoms. Suspecting a specific pathogen allows the clinician to determine whether the condition can be treated with specific therapy as opposed to supportive care. For example, strep throat is a relatively common condition that mimics mononucleosis and can be diagnosed with rapid antigen detection testing (RADT). A positive result can be considered diagnostic of streptococcal pharyngitis. Treatment with appropriate antibiotics is curative and can prevent further sequelae, such as rheumatic fever.3
There are a significant number of false-negative results with the RADT as well. Toxoplasmosis is difficult to diagnose but relatively easy to treat with anti-parasitic medications.4 ACUTE HIV INFECTION AND THE IMPORTANCE OF ITS RECOGNITION Traditionally, viral illnesses were managed by supportive care only; however, recent advances in treatment of acute HIV infection and its sequelae have greatly increased the importance of diagnosing this condition for early treatment. Acute HIV infection occurs almost immediately after a patient is infected with HIV and leads to two major events. The first is that the virus attacks and ravages the gastrointestinal (GI) tract associated lymphoid tissue, causing severe depletion of CD4+ cells in the GI tract within weeks of initial infection. Without these cells, there is a constant passage of intestinal microbes into the circulatory system, a process known as bacterial translocation. This, in turn, creates a constant inflammatory response as the immune system seeks to suppress the constant introduction of bacteria.5 Once the GI tract’s response is depleted, its capability can only be partially restored even after extensive treatment with anti-HIV medications. This occurs even if the patient has an undetectable HIV viral load in his or her plasma. Treatment is most effective in preserving the GI tract’s immune system when initiated as soon as possible after infection.6-8
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CPD 22: HIV Infection & Diagnosis
The second important event immediately following HIV infection is the extraordinary production of virus that can easily exceed 1,000,000 viral copies/mL in plasma.9,10 Very high levels of HIV also occur in the genital tract.11,12 Therefore, the patient in the early phases of HIV infection is highly infectious and much more likely to sexually transmit the virus to others. Studies suggest that individuals who are experiencing these high rates of viremia are 8 to 26 times more likely to transmit the virus to a sexual partner than at later stages in the infection.13,14 The risk of transmission from an infected male to a female sexual partner during this early period have been estimated at between 7% and 24% depending on the frequency of intercourse.9 The highest rates of transmission seem to occur at the earliest point in infection(up to 2 months after infection) and diminish over time as the body begins to produce HIV-specific antibodies that begin to suppress the virus.14 Treatment with antiretroviral medications immediately after infection can greatly reduce this high level of circulating virus and can make the patient less infectious. This is extremely important because acute HIV infection is usually the result of recent unsafe sexual practices that are likely to continue after infection. Additionally, there is increasing evidence that early treatment with anti-retroviral medications can also have the important long-term benefit by preventing the patient from losing circulating CD4+ cells that are essential to maintaining the integrity of the immune response.15 RECOGNISING ACUTE HIV INFECTION There are important benefits to both the patient and the public’s health if the clinician recognises HIV infection as early as possible. Most HIV-infected persons experience an acute viral syndrome, with symptoms similar to infectious mononucleosis, shortly after becoming infected. The frequency of symptoms has been estimated between 50% and 90%.16 The exact frequency is hard to estimate because identifying HIV infection may occur years after the syndrome has occurred, and the patient may not recall the acute viral event. The acute infection tends to occur within 2 to 3 weeks after transmission and will last 2 to 4 weeks. Acute HIV infection symptoms are often severe enough for the infected patient to seek
Table 1: Potential diagnoses and symptoms associated with mononucleosis-like presentations Condition Signs/symptoms (estimated frequency of occurrence) Adenovirus (1%)
Pharyngitis, conjunctivitis, high fever, enlarged anterior cervical lymph nodes, headache, general malaise, and weakness. Incubation period 5–9 days and typically occurs in 5- to 18-year olds.
Acute HIV infection (<2%)
Fever, fatigue, myalgia, or arthralgia, lymphadenopathy, weight loss/anorexia, pharyngitis, GI symptoms, rash, headache, mucocutaneous ulcers, meningitis-like symptoms.
Toxoplasma gondii (Toxoplasmosis) (3%)
Flu-like symptoms, lymphadenopathy, myalgia that may last for a month or more. History of eating undercooked meat or exposure to contaminated cat feces.
Group A, Beta hemolytic Streptococcus pyogenes (pharyngitis; rheumatic fever) (3%–4%)
Abrupt onset of sore throat, erythema, and possible exudative tonsils and/or pharynx; tender, swollen lymph nodes; infections of the skin, such as impetigo, cellulitis, erysipelas. Peak incidence is winter/spring.
Herpes simplex virus, Type 1 (Herpes labialis) (6%)
Cold sores/ fever blisters; painful ulcerative vesicular lesions of the lips, mouth, and or pharynx.
Cytomegalovirus Fatigue, low-grade fever (lasting days to weeks), (mononucleosis-like illness) (5%–7%) chills/ sweats, myalgia, anorexia, lymphadenitis, pharyngitis, headache. Exanthema subitum (roseola infantum): human herpesvirus 6 (HHV-6) (9%)
Sudden onset of high fever (104° F [40.0° C] or greater) lasting 3–5 days; followed by a maculopapular rash on the trunk, although rash not always present. Malaise, irritability, and tympanic membrane inflammation. Highest among infants 6-12 months of age.
Epstein-Barr virus (infectious mononucleosis) (50%-90%)
Extreme fatigue, low-grade fever and in some cases moderate to-high fever, palatal petechiae, pharyngitis, posterior cervical or auricular adenopathy, hepatosplenomegaly, atypical lymphocytosis.
Influenza (very common depending on the season of the year)
Fever, chills, cough, pharyngitis, rhinorrhea or nasal congestion, myalgia, and headaches. The fever and myalgia can last 3–5 days and the cough and fatigue may last for 2 or more weeks.
treatment either in a primary care or ED setting. The clinician who encounters these patients can, by early identification of the acute infection, intervene before these patients lose their GI-associated lymphoid tissue. They can also have a major impact
on preventing HIV transmission by arranging for early treatment and by counselling patients to avoid unprotected sex. Such tasks are possible when the clinician is aware of the potential for patients presenting with acute HIV infection and by ordering the appropriate diagnostic tests.
Acute HIV infection, like most acute viral infections, does not present a clear clinical picture to differentiate it from other conditions, nor does the literature on acute HIV infection provide the clinician with a clear picture. The studies of acute HIV infection symptoms have relatively small
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29 Table 2: Frequency and symptoms in acute HIV infection14,17-20
mononucleosis. The rash originates on the trunk but can spread to the limbs, including the palms and soles.
Symptom
Reported frequency
Fever
High
IMPORTANCE OF A PATIENT HISTORY AND DIAGNOSTIC TESTING
Fatigue
High
Myalgia or arthralgia
Medium
Lymphadenopathy
Medium
Weight loss/anorexia
Medium
Pharyngitis
Medium
GI symptoms
Medium
Rash
Medium
Headache
Medium
Mucocutaneous ulcers
Low
Meningitis-like symptoms
Low
samples (usually less than 100 patients). In addition, some of the studies have used patient reports, while others have reported clinician findings. Consequently, while clinicians may report lymphadenopathy, the patient may report soreness; the patient report of a severe headache may be diagnosed as aseptic meningitis, migraine, or other cranial malady14,17-20 (see Frequency and symptoms in acute HIV infection). Acute HIV infection presents like many viral infections: with diffuse symptoms that are more useful in alerting the clinician than in making a diagnosis. Acute HIV infection is usually described as “an acute flu-like illness.” The easiest way to differentiate acute HIV infection from influenza or viral upper respiratory tract infection is that acute HIV infection is not reported to have the respiratory symptoms (runny or stuffy nose) that are characteristic of these conditions. The absence of fever and fatigue increases the likelihood that the patient does not have acute HIV infection. However, if a patient has additional signs and symptoms even though he or she does not have a fever or report fatigue, there is still some likelihood that the patient has acute HIV infection, and it may need to be ruled out.
DIFFERENTIATING ACUTE HIV INFECTION FROM MONONUCLEOSIS Mononucleosis tests are diagnostic when positive but are associated with a significant level of false negatives; therefore, it is imperative to distinguish mononucleosis from acute HIV infection in the patient with a negative test. Patients with mononucleosis are likely to present with the classictriad of fever, pharyngitis, and lymphadenopathy, all of which are frequently found in those with acute HIV infection. However, there are characteristic differences between acute HIV infection and mononucleosis that are helpful in differentiation. Fever in mononucleosis is likely to be less than 100.0° F (37.7° C) and in some cases a moderate to high fever; however, fever in acute HIV infection tends to be much higher, ranging up to 104° F (40.0° C).1,14,15 Infectious mononucleosis is also frequently associated with petechiae of the palate, although this condition is seen less frequently in acute HIV infection. Acute HIV infection is occasionally accompanied with mucocutaneous ulcers in the mouth and the genitals, which do not occur in infectious mononucleosis. A non-pruritic, maculopapular rash can occur in acute HIV infection and not in infectious
Taking a history of recent sexual encounters and/or injection drug use is another method of determining if testing for acute HIV infection is warranted. Acute HIV infection testing should be done if the patient admits to these behaviours. Unfortunately, sexual and drug histories often yield false negatives, as patients are sometimes not truthful because of the stigma associated with these behaviours. THE NEW HIV TEST
or safer sex methods. Previous versions of HIV tests, including the oral swabs or other rapid tests, will not be useful in ruling out HIV infection. If these are all that is available, an HIV viral load test should be obtained. DEALING WITH THE POSITIVE TEST In the event that a patient is found to be HIV infected, they will need to be counselled regarding the importance of abstaining from sex due to the high infectiousness during this phase of the infection. If abstinence is not feasible, the patient should be counselled to use condoms for any sexual encounter. This counselling session is crucial to halting the spread of HIV.
In the past, HIV testing relied on HIV antibodies appearing in the blood as detected by an enzyme-linked immunosorbent assay (ELISA) test. Because of the possibility of false-positive results, the test results were confirmed by a second test, the Western blot assay, which might also give an indeterminate result. Antibody levels sufficiently high enough to be detected by an ELISA often did not appear until after the acute HIV infection had resolved. Therefore, the commonly used test for detecting HIV infection was not likely to be helpful in detecting acute HIV infection at the time of its occurrence.
The patient also needs to be referred for immediate treatment to preserve the GI-associated lymphoid tissue. In addition, HIV treatment is a lifelong process, and it is necessary to develop a long-term relationship.
However, there is a new, fourthgeneration test for HIV infection that detects HIV infection within 15 to 25 days of infection. This is usually around the time that a patient with acute HIV infection will be seeking care.21,22 Therefore, it is possible to diagnose HIV infection simultaneously with acute HIV infection.
A number of studies in Europe and in the United States suggest that acute HIV infection appears in 1% to 2% of patients appearing with mononucleosis-like symptoms in primary care.24-26 Acute HIV infection may not be diagnosed, as was reported in a North Carolina study of 32 adults diagnosed with acute HIV infection during voluntary HIV testing, and 24 of the adult participants reported that they had symptoms associated with acute HIV infection. Of these, 20 sought medical care for the symptoms, but only 3 were tested for HIV.27
When evaluating a patient for acute HIV infection, one can use the CDC’s new HIV diagnostic algorithm for HIV-1/HIV-2 antigen and antibody combination immunoassay.21 Because the test detects P24 antigen (a major core protein of HIV) that appears before antibodies appear, it is able to detect HIV infection several days earlier than with previous tests. This fourth-generation test also gives a definitive result of either infected or not infected. To definitively rule out infection, patients should be asked to return in a week or two to have a viral load test that will determine whether the virus is present. This should be accompanied with counselling regarding no sex
IMPLICATIONS FOR PRACTICE The best guarantee for detecting acute HIV infection is the sensitivity to its possible presence. Given the severity of the symptoms of acute HIV infection, many of these individuals with acute HIV infection are likely to seek clinical care in secure settings–such as primary care practices, EDs, and public health clinics.
Acute HIV infection is not a highprobability diagnosis, but it is a very important one. Patients who are detected early have much better outcomes and fewer HIVrelated diseases. Once treated, individuals have a decreased likelihood of transmission of the virus. Studies have shown that as much as 50% of all HIV transmissions occur during early HIV infection.6,28 Early detection and treatment can be crucial to control the HIV epidemic.
Continuous Professional Development Modules are sponsored by MSD MSD has no editorial oversight of the CPD programmes included in these modules.
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CPD 22: HIV Infection & Diagnosis
REFERENCES 1. Hurt C, Tammaro D. Diagnostic evaluation of mononucleosis-like illnesses. Am J Med. 2007;120(10):911. e1-911.e8. 2. Centres for Disease Control and Prevention. Influenza symptoms and the role of laboratory diagnostics. www. cdc.gov/fl u/professionals/diagnosis/ labrolesprocedures.htm. Last updated: October 16, 2014. 3. Shulman ST, Bisno AL, Clegg HW, et al. Clinical Practice Guideline for the Diagnosis and Management of Group A Streptococcal Pharyngitis: 2012 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2012;55(10):e86–102. 4. Centres for Disease Control and Prevention. Parasites—Toxoplasmosis (Toxoplasma infection) www.cdc.gov/ parasites/toxoplasmosis/treatment. html. Last reviewed: January 10, 2013. 5. Marchetti G, Tincati C, Silvestri G. Microbial translocation in the pathogenesis of HIV infection and AIDS. Clin Microbiol Rev. 2013;26(1):2-18. 6. Chun TW, Nickle DC, Justement JS, et al. Persistence of HIV in gutassociated lymphoid tissue despite long-term antiretroviral therapy. J Infect Dis. 2008;197(5):714-720. 7. Ananworanich J, Schuetz A, Vandergeeten C, et al. Impact of multitargeted antiretroviral treatment on gut T cell depletion and HIV reservoir seeding during acute HIV infection. PLoS One. 2012;7(3):e33948. 8. Schuetz A, Phuang-Ngern Y, Rerknimitr R, et al. Early ART Initiation Prevents Disruption of the Mucosal Barrier and Subsequent T-Cell Activation. 21st Conference
on Retroviruses and Opportunistic Infections (CROI 2014). Boston, March 3-6. Abstract 77. 9. Pilcher CD, Tien HC, Eron JJ, et al. for the Quest Study and the DukeUNCEmory Acute HIV Consortium. Brief but effi cient: acute HIV infection and the sexual transmission of HIV. J Infect Dis. 2004;189(10):1785-1792. 10. Pilcher CD, Price MA, Hoffman IF, et al. Frequent detection of acute primary HIV infection in men in Malawi. AIDS. 2004;18(3):517-524. 11. Morrison CS, Demers K, Kwok C, et al. Plasma and cervical viral loads among Ugandan and Zimbabwean women during acute and early HIV-1 infection. AIDS. 2010;24(4):573-582. 12. Pilcher CD, Joaki G, Hoffman IF, et al. Amplifi ed transmission of HIV-1: comparison of HIV-1 concentrations in semen and blood during acute and chronic infection. AIDS. 2007;21(13):1723-1730. 13. Wawer MJ, Gray RH, Sewankambo NK, et al. Rates of HIV-1 transmission per coital act, by stage of HIV-1 infection, in Rakai, Uganda. J Infect Dis. 2005;191(9):1403-1409. 14. Hollingsworth TD, Anderson RM, Fraser C. HIV-1 transmission, by stage of infection. J Infect Dis. 2008;198(5):687-693. 15. Le T, Wright EJ, Smith DM, et al. Enhanced CD4+ T-cell recovery with earlier HIV-1 antiretroviral therapy. N Engl J Med. 2013;368(3):218-230. 16. Richey LE, Halperin J. Acute human immunodefi ciency virus infection. Am J Med Sci. 2013;345(2):136-142. 17. Yerly S, Hirschel B. Diagnosing acute HIV infection. Expert Rev Anti Infect Ther. 2012;10(1):31-41.
18. Vanhems P, Dassa C, Lambert J, et al. Comprehensive classifi cation of symptoms and signs reported among 218 patients with acute HIV-1 infection. J Acquir Immune Defi c Syndr. 1999;21(2):99-106. 19. Chu C, Selwyn PA. Diagnosis and initial management of acute HIV infection. Am Fam Physician. 2010;81(10):1239-1244. 20. Hightow-Weidman LB, Golin CE, Green K, Shaw EN, MacDonald PD, Leone PA. Identifying people with acute HIV infection: demographic features, risk factors, and use of health care among individuals with AHI in North Carolina. AIDS Behav. 2009;13(6):10751083. 21. Branson BM, Owen SM, Wesolowski LG, et al. Laboratory testing for the diagnosis of HIV infection: updated recommendations. 2014. http://stacks. cdc.gov/view/cdc/23447. 22. Eller LE, Manak M, Shutt A, et al. Evaluation of the Proposed US CDC Algorithm for Detection of Acute HIV Infection in Serial Samples. Conference on Retroviruses and Opportunistic Infections. Mar 3-6, 2014. San Francisco Abstract 619. 23. Centers for Disease Control and Prevention. HIV in the United States: at a glance. www.cdc.gov/hiv/statistics/ basics/ataglance.html. Last updated: December 3, 2013. 24. Hsu DT, Ruf M, O’Shea S, Costelloe S, Peck J, Tong CY. Diagnosing HIV infection in patients presenting with glandular fever-like illness in primary care: are we missing primary HIV infection? HIV Med. 2013;14(1):60-63.
tested for mononucleosis. N Engl J Med. 1999;360(12):969. 26. Pincus JM, Crosby SS, Losina E, King ER, LaBelle C, Freedberg KA. Acute human immunodefi ciency virus infection in patients presenting to an urban urgent care center. Clin Infect Dis. 2003;37(12):1699-1704. 27. Hightow-Weidman LB, Golin CE, Green K, Shaw EN, MacDonald PD, Leone PA. Identifying people with acute HIV infection: demographic features, risk factors, and use of health care among individuals with AHI in North Carolina. AIDS Behav. 2009;13(6):10751083. 28. Brenner BG, Roger M, Routy JP, et al. High rates of forward transmission events after acute/early HIV-1 infection. J Infect Dis. 2007;195(7):951-959. Richard M. Grimes is an adjunct professor, The University of Texas Health Science Center at Houston Medical School, Department of Internal Medicine and Baylor UT Houston Center for AIDS Research. Robin L. Hardwicke is an associate professor, The University of Texas Health Science Center at Houston Medical School, Department of Internal Medicine. Deanna E. Grimes is a professor, The University of Texas Health Science Center at Houston, School of Nursing, Department of Nursing Systems and Baylor UT Houston Center for AIDS Research. D. Sean DeGarmo is an instructor, The University of Texas Health Science Center at Houston, School of Nursing, Department of Family Health. The authors have disclosed that they have no financial relationships related to this article.
25. Rosenberg ES, Caliendo AM, Walker BD. Acute HIV infection among patients
Continuous Professional Development Modules are sponsored by MSD MSD has no editorial oversight of the CPD programmes included in these modules.