HIV/AIDS Update by Physician's Weekly

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Table of Contents 4

Updated Guidelines for HIV-Opportunistic Infections —John T. Brooks, MD

10 Making the Case for Early Antiretroviral Therapy —Paul E. Sax, MD

14 Overcoming Challenges in HIV Therapy —Eric S. Daar, MD

A message from the editor We at Physician’s Weekly are excited to present you with an eBook dedicated to HIV. In recent months, our publication has featured a variety of news items in this field, focusing on clinical and evidence-based research and guidelines. The content in these articles relies on the expertise of our contributing physician authors. We anticipate that Physician’s Weekly will continue to feature news in this field of medicine in the coming months, and subsequent eBooks will emerge in the future. We hope that you find this information useful in your practice. Please let us know your thoughts by contacting us at editor@physweekly.com. Sincerely,

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Updated

HIV-Oppo

John T. Brooks, MD Leader, HIV Clinical Epidemiology Team Division of HIV/AIDS Prevention Centers for Disease Control and Prevention

October 26, 2009 â&#x20AC;˘ Issue No. 40 Click here to view this article online.

d Guidelines for

ortunistic Infections The CDC, NIH, and the HIV Medicine Association of the Infectious Diseases Society of America have updated guidelines for the prevention and treatment of opportunistic infections.

espite advances in antiretroviral therapy (ART) and opportunistic infection (OI) prophylaxis and treatment, OIs continue to afflict patients infected with HIV and cause considerable morbidity and mortality in the United States. OIs have been defined as infections that are more frequent or severe because of immunosuppression in HIV-infected people. Before the widespread use of combination ART, OIs were the primary cause of morbidity and mortality in this patient group. However, the use of ART has been associated with drastic reductions in the frequency of HIV-associated OIs and mortality. Today, HIV-associated OIs continue to occur, primarily because patients are unaware of their HIV infection; in such cases an OI may be the initial indication

of HIV disease. They also occur among those who are aware of their HIV infection but do not take ART because of psychosocial or economic factors. There is also evidence suggesting that OIs may occur in patients who take ART but fail to attain adequate virologic and immunologic response due to adherence, pharmacokinetics, or unexplained biologic factors.

A Necessary Update The CDC, NIH, and the HIV Medicine Association of the Infectious Diseases Society of America updated guidelines for prevention and treatment of OIs in HIV-infected adults and adolescents (Table 1). The report, published in the March 24, 2009 Morbidity and Mortality Weekly Report and available online at visit www.physweekly.com

Table 1

Major Guideline Changes

• Greater emphasis on the importance of antiretroviral therapy for the prevention and treatment of opportunistic infections (OIs), especially those OIs for which no specific therapy exists. • Information regarding the diagnosis and management of immune reconstitution inflammatory syndromes. • Information regarding the use of interferon-gamma release assays for the diagnosis of latent Mycobac terium tuberculosis (TB) infection. • Updated information concerning drug interactions that affect the use of rifamycin drugs for prevention and treatment of TB. • The addition of a section on hepatitis B virus infection. • The addition of malaria to the list of OIs that might be acquired during international travel. Source: Adapted from: Kaplan JE, et al. MMWR Recomm Rep. 200910;58:1-207.

www.cdc.org/mmwr, places greater emphasis on the role of effective ART to prevent and treat acute OIs (Table 2). It also updates information on 29 opportunistic diseases that are of concern for patients infected with HIV/AIDS.

For each OI discussed in the report, recommendations are provided that address: 1) preventing exposure to opportunistic pathogens, 2) preventing disease, 3) discontinuing primary prophylaxis after immune reconstitution, 4) treating patients with the disease, 5) monitoring for adverse effects, 6) managing treatment failure, 7) preventing disease recurrence, 8) discontinuing secondary prophylaxis after immune reconstitution, and 9) addressing considerations during pregnancy. “Major additions to the guidelines include significantly expanded sections addressing hepatitis B virus infection and tuberculosis,” says Dr. Brooks. “The recommendations in regard to prevention and treatment of hepatitis B infection are in line with antiviral treatment guidelines published by the Department of Health and Human Services.”

Taking More Into Consideration For the first time, the guidelines include information on the diagnosis and management of immune reconstitution inflammatory syndrome (IRIS). “IRIS occurs following the initiation of ART,” Dr. Brooks says. “As the immune system begins to recover, it can respond with an overwhelming inflammatory

It’s critical that healthcare providers recognize the signs and symptoms of OIs— particularly newer physicians who may have less experience with these infections—and provide effective prophylaxis and treatment. —John T. Brooks, MD

“Much has changed in the field of HIV/AIDS management since the previous guidelines were published,” says John T. Brooks, MD, who was a co-author of the updated recommendations. “It’s critical that healthcare providers recognize the signs and symptoms of OIs—particularly newer physicians who may have less experience with these infections—and provide effective prophylaxis and treatment.” 6

response to an OI that makes the symptoms of infection worse,” says Dr. Brooks. “Diagnosis of IRIS is clinically challenging. It involves differentiation of progression of a previously quiescent OI or development of a new OI from unrelated organ dysfunction or drug toxicity. Although no consensus has been reached concerning the optimal time to start ART for a recently diagnosed OI, one recently completed

randomized clinical trial suggests that early therapy, within the first 2 weeks, is indicated for an acute OI, with the exception of tuberculosis.” The expert panel also expanded on drug-drug interactions and adverse events associated with HIV medications. Sections in each chapter on considerations in women who are pregnant were also enhanced. It is recommended that ART with OI therapy be initiated immediately for pregnant women who have a diagnosed OI and are not on ART to minimize the risk for perinatal transmission of HIV. According to the guidelines, decisions about immediate versus delayed initiation of ART in pregnancy should include consideration of gestational age, maternal HIV RNA levels and clinical condition, and potential toxicities and interactions between ART and OI drugs.

Recognizing OIs in HIV-Infected Patients Strict adherence to immunization recommendations and a continued focus on ART therapy are pivotal for preventing and managing OIs in patients infected with HIV/AIDS. “OIs continue to threaten the health of many HIV patients,” says Dr. Brooks. “It’s important that the clinical knowledge around these infections be passed on to each new generation of

Management of Acute OIs in Patients Receiving ART

Table 2

• When an opportunistic infection (OI) occurs within 12 weeks of starting antiretroviral therapy (ART), treatment for the OI should be started and ART should be continued. • When an OI occurs despite complete virologic suppression (ie, late OI), therapy for the OI should be initiated and ART should be continued. • If the CD4+ response to ART has been suboptimal, modification of the ART regimen may be considered, although no evidence exists to indicate that changing the ART regimen in this setting will improve the CD4+ response. • When an OI occurs in the setting of virologic failure, OI therapy should be started, antiretroviral resistance testing should be performed, and the ART regimen should be modified, if possible, to achieve better virologic control. Source: Adapted from: Kaplan JE, et al. MMWR Recomm Rep. 200910;58:1-207.

physicians so that the presence of an HIV-associated OI can be better recognized and treated.” John T. Brooks, MD, has indicated to Physician’s Weekly that he has or has had no financial interests to report.

References Kaplan JE, Benson C, Holmes KH, et al. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR Recomm Rep. 2009;10;58:1-207. Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/rr58e324a1.htm Brooks JT, Kaplan JE, Holmes KK, Benson C, Pau A, Masur H. HIV-associated opportunistic infections--going, going, but not gone: the continued need for prevention and treatment guidelines. Clin Infect Dis. 2009;48:609-611. Hermsen ED, Wynn HE, McNabb J. Discontinuation of prophylaxis for HIV-associated opportunistic infections in the era of highly active antiretroviral therapy. Am J Health Syst Pharm. 2004;61:245-256. Masur H, Kaplan JE. New guidelines for the management of HIV-related opportunistic infections. JAMA. 2009;301:2378-2380. Tabarsi P, Tehrani AS, Baghaei P, et al. Early initiation of antiretroviral therapy results in decreased morbidity and mortality among patients with TB and HIV. J Int AIDS Soc. 2009;12:14.

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Making the Case for

Early Antiretroviral T New data demonstrate that early initiation of antiretroviral therapy before CD4 counts fall below pre-specified thresholds can significantly improve survival as compared with deferring therapy.

lthough antiretroviral therapy has helped reduce AIDS complications and deaths among patients with HIV, the optimal time to begin therapy in asymptomatic patients is still uncertain. Current guidelines recommend that treatment begin for asymp tomatic patients when they have CD4 counts of less than 350 cells/mm3. “Although antiretroviral therapy is clearly life-saving for patients with AIDS, there are also side effects to consider,” says Paul E. Sax, MD. “In the late 1990s, many clinicians put asymptomatic HIV patients on treatment early, but the drugs available at that time were much more toxic. As a result, in the early 2000s, clinicians changed their approach, often holding off on using antiretroviral therapy for as long as possible.”

Paul E. Sax, MD Clinical Director, HIV Program Division of Infectious Diseases Brigham and Women’s Hospital Associate Professor of Medicine Harvard Medical School

New Data Emerging Until recently, there has been a lack of data regarding timing of the initiation of antiretroviral therapy. Several studies have compared patients with similar CD4 counts who either initiated or deferred antiretroviral therapy, but they did not have the statistical power and methods to examine outcome differences. In 2006, a subgroup analysis of the Strategies for Management of Antiretroviral Therapy (SMART) trial found that deferring antiretroviral therapy until CD4 counts fell below 250 cells/mm3 increased the risk of progression to AIDS or death when compared with initiating therapy when CD4 counts were higher than 350 cells/mm3. “The SMART trial was primarily designed to determine the effects of continuous versus intermittent therapy, but in some ways, it also investigated the issue of early-versus-deferred therapy,” says Dr. Sax. “Findings from this trial and other data in the last 5 years have shown that early antiretroviral treatment can lead to better responses to therapy and preserve immune function.” In the April 30, 2009 New England Journal of Medicine, researchers in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD)

May 18, 2009 â&#x20AC;˘ Issue No. 19 Click here to view this article online.

Therapy

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The NA-ACCORD study provides some of the strongest data suggesting that early treatment is better. — Paul E. Sax, MD examined 17,517 asymptomatic HIV-infected patients in the United States and Canada from 1996 to 2005. None of the patients had undergone previous antiretroviral therapy. Participants were stratified into two groups, those with counts ranging between 351 cells/mm3 and 500 cells/mm3 and those with counts higher than 500 cells/mm3, at the initiation of antiretroviral therapy. The relative risk of death was assessed for patients who initiated therapy early—when the CD4 count was above each of the two thresholds of interest—and for patients who deferred therapy until the CD4 count fell below the thresholds. In the first NA-ACCORD analysis, researchers observed a 69% increase in the risk of death when patients with CD4 counts between 351 cells/mm3 and 500 cells/mm3 deferred therapy (Table 1). The second analysis, which analyzed patients who initiated therapy when their CD4 counts were higher than 500 cells/ mm3, revealed a 94% increased risk of death for the deferred-therapy group. Older age, a history of injection-drug use, and the presence of hepatitis C virus infection were also identified independent risk factors for death in patients with HIV (Table 2). “The NAACCORD study provides some of the strongest data suggesting that early treatment is better,” Dr. Sax says.

Important Implications Despite the positive findings from NA-ACCORD, Dr. Sax warns that more data are needed. “We must be cautious when interpreting observational data despite efforts to control for confounders,” he says. “The NAACCORD data do not provide definitive proof that we should be starting antiretroviral therapy in all patients with HIV infection. More data from randomized, prospective clinical trials are required.” At least three such studies are either ongoing or planned; meanwhile, the supportive evidence for the benefits of earlier therapy continues to increase. Dr. Sax says that if an asymptomatic patient with HIV and a CD4 count of more than 500 cells/mm3 wished to start antiretroviral therapy 5 years ago, “most expe12

rienced clinicians could have made an excellent case as to why treatment should be deferred. Today, if a similar patient was eager to start, clinicians should be ready and willing to prescribe therapy, so long as it’s understood that ongoing careful monitoring for side effects is critical for a treatment that could last decades.” The benefits of initiating antiretroviral therapy earlier after HIV infection must still be weighed against the potential adverse effects of treatment, says Dr. Sax. “Newer antiretroviral therapies are more potent, have fewer side effects, and can be taken less frequently than

Table 1

Highlighting Key Findings

In the April 1, 2009 online edition of the New England Journal of Medicine, researchers conducted two parallel analyses of asymptomatic patients with HIV infection to determine the effect of early versus deferred antiretroviral therapy for HIV on survival: Findings From the First Analysis: (CD4+ counts were 351 cells/mm3–500 cells/mm3) • Of the 8,362 patients assessed, 2,084 (25%) initiated therapy at a CD4+ count of 351 cells/mm3 to 500 cells/ mm3 and 6,278 (75%) deferred therapy. • A 69% increase in the risk of death was observed in patients in the deferred-therapy group as compared with that of the early-therapy group (after adjustment for calendar year, cohort of patients, and demographic and clinical characteristics). Findings From the Second Analysis: (CD4+ counts were >500 cells/mm3) • Of the 9,155 patients assessed, 2,220 (24%) initiated therapy at a CD4+ count of more than 500 cells/mm3 and 6,935 (76%) deferred therapy. • A 94% increase in the risk of death was observed in patients in the deferred-therapy group. *Note: The early-therapy group consisted of patients who initiated therapy when the CD4+ count was above each of the two thresholds of interest. The deferredtherapy group consisted of patients who deferred therapy until the CD4+ count fell below these thresholds. Source: Adapted from: Kitahata MM, et al; for the NA-ACCORD Investigators. N Eng J Med. 2009.360. [Epub ahead of print 2009 Apr 1].

previous drug regimens. However, the potential side effects of long-term antiretroviral therapy are still unknown. Advancing our understanding of the role of HIV infection in inflammation and immune activation may support the practice of earlier treatment for HIV. Furthermore, patients who go on antiretroviral therapy early are less likely to transmit the virus to others. From a personal and public health perspective, this

Table 2

is important because getting patients on therapy earlier may help slow the HIV epidemic.” Paul E. Sax, MD, has disclosed to Physician’s Weekly that he has served as an advisor or consultant to, and has received grants for educational activities from Abbott Laboratories, Bristol-Myers Squibb, Gilead Sciences, Tibotec, and Pfizer. He has also received grants for clinical research and educational activities and served as an advisor or consultant to Merck and GlaxoSmithKline.

Risk of Death Associated With Deferral of Antiretroviral Therapy* 351–500 CD4+ Count

More Than 500 CD4+ Count

Relative Risk

Deferral of antiretroviral therapy

1.69

1.94

Female sex

1.21

1.85

1.68

1.83

1.13

0.93

Deferral of antiretroviral therapy

1.63

1.85

Female sex

1.47

1.35

1.89

1.81

Baseline CD4+ count (per 100 cells/mm )

0.74

0.97

Baseline HIV RNA level (per log10 copies/mL)

1.11

1.13

Variable Without inclusion of HIV RNA data

Older age (per 10-yr increment) Baseline CD4+ count (per 100 cells/mm ) 3

With inclusion of HIV RNA data

Older age (per 10-yr increment) 3

* According to CD4+ count at baseline, with adjustment for HIV RNA level, age, and sex. The CD4+ count was measured in cells per cubic millimeter. Results were calculated with the use of Cox regression analyses with inverse probability-of-censoring weights.

Source: Adapted from: Kitahata MM, et al; for the NA-ACCORD Investigators. N Eng J Med. 2009.360.

References Kitahata MM, Gange SJ, Abraham AG, et al; for the NA-ACCORD Investigators. Effect of early versus deferred antiretroviral therapy for HIV on survival. N Eng J Med. 2009.360. Available at: http://content.nejm.org/cgi/content/full/NEJMoa0807252v1 Sax PE, Baden LR. When to start antiretroviral therapy—ready when you are? N Eng J Med. 2009.360. Available at: http://content.nejm.org/cgi/content/full/NEJMe0902713v1 The Strategies for Management of Antiretroviral Therapy (SMART) Study Group. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med. 2006;355:2283-2296. Hughes MD, Ribaudo HR. The search for data on when to start treatment for HIV infection. J Infect Dis. 2008;197:1084-1086. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents — January 29, 2008. Rockville, MD: AIDSinfo, 2008. Available at: www.aidsinfo.nih.gov/Guidelines/Default.aspx?MenuItem=Guidelines Kaplan JE, Hanson DL, Cohn DL, et al. When to begin highly active antiretroviral therapy? Evidence supporting initiation of therapy at CD4+ lymphocyte counts <350 cells/microL. Clin Infect Dis. 2003;37:951-958. Phillips AN, Lepri AC, Lampe F, Johnson M, Sabin CA. When should antiretroviral therapy be started for HIV infection? Interpreting the evidence from observational studies. AIDS. 2003;17:1863-1869. Hammer SM, Eron JJ Jr, Reiss P, et al. Antiretroviral treatment of adult HIV infection: 2008 recommendations of the International AIDS Society-USA panel. JAMA. 2008;300:555-570.

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Overcoming Challenges in HIV Therapy Tolerability & Virologic Failure Eric S. Daar, MD Chief, Division of HIV Medicine Los Angeles Biomedical Research Institute at Harbor-UCLA Professor of Medicine David Geffen School of Medicine at UCLA

Although the tolerability of antiretroviral drugs varies from person to person, currently available HIV treatment regimens are generally easy to take and well tolerated. Clinicians have historically made efforts to address tolerability, but were left with the decision to either have their patients deal with these drug side effects or not be treated. Fortunately, newer treatment options have minimized the effect of tolerability concerns.

ver the last few years, HIV treatment regimens have continued to improve and the number of options and the level of overall antiviral activity of these options is higher than ever. The likelihood of patients achieving undetectable levels of HIV and preventing the emergence of drug-resistant virus is also at an all-time high. Based on clinical trial data and clinical experience, the current expectation is that approximately 80% of patients starting therapy for the first time will achieve undetectable levels of HIV within a few months of initiating treatment and will likely sustain viral suppression over many years.

Although no single regimen will be tolerable by every patient, clinicians who work closely with their patients are more likely than ever to find an effective regimen with minimal side effects. When one regimen is intolerable, clinicians can now offer several different options without the potential for the development of multidrug-resistant virus. It should be noted that when tolerability issues become severe, virologic failure may result. Clinicians need to assess the reason behind the virologic failure so that appropriate treatment adjustments can be made.

Unprecedented advances in HIV have occurred over the past year, including the development of new drugs and the emergence of new data for managing treatment-experienced patients. Several new medications that were developed for treatment-experienced patients with multidrug-resistant virus have become available; theyâ&#x20AC;&#x2122;re providing new treatment options for patients with highly drug resistant virus and/or intolerance to previously available agents.

Patients with tolerability issues often wonâ&#x20AC;&#x2122;t take their HIV medications as directed because the side effects are too great a burden. In addition, they may miss doses for a variety of other reasons, such as having an important meeting at work or attending a social function. In other scenarios, underlying psychiatric social problems or drug abuse can reduce adherence to medications. Regardless of the circumstances, the key for clinicians is to talk openly with patients be-

December 22, 2008 • Issue No. 48 Click here to view this article online.

fore and during treatment. It’s critical to find out about the patient’s personal situation and circumstances before therapy is initiated. Patients also need to understand that available treatment options may help them overcome some of their life obstacles.

to treatment regimens if necessary. A greater emphasis should also be made to have patients understand the goals of therapy. We’re aiming to provide them with therapies that they’ll completely tolerate on a regular basis to achieve undetectable levels of virus.

Newer treatment options have minimized the effect of tolerability concerns. Individualize Approaches Clinicians should strive to identify patients at risk for tolerability issues or poor adherence before initiating therapy in order to reduce the risk of patients developing multidrug-resistant virus while on therapy. This requires having a regular dialogue with patients; they should be informed about the efficacy of therapy and cautioned that no one regimen is perfect for everyone. It’s critical to get “buy in” from patients; they need to believe that their provider will listen to them, work with them, and make changes

To achieve long-term success, establishing individualized approaches and carefully balancing tolerability with efficacy and the potential for drug resistance are paramount. Eric S. Daar, MD has indicated to Physician’s Weekly that he has received grants and/or research support from Abbott, Boehringer Ingelheim, Gilead, GlaxoSmithKline, and Merck. He has also disclosed that he has served on the speaker’s bureau for and/or served as a consultant to Abbott, Boehringer Ingelheim, Gilead, GlaxoSmithKline, Merck, Bristol-Myers Squibb, Pfizer, Tibotec,Pathway Diagnostics, Oncolysis and Monogram.

References To access “Improving the Management of HIV Disease. Current Challenges in HIV Disease: A Case-Based Advanced CME Course on HIV Management,” go to www.iasusa.org/cme/2006-fnewyork/syllabus/syllabus.pdf Centers for Disease Control and Prevention. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Available at: http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf Hammer SM, Eron JJ Jr, Reiss P, et al; International AIDS Society-USA. Antiretroviral treatment of adult HIV infection: 2008 recommendations of the International AIDS Society-USA panel. JAMA. 2008;300:555-570. Struble K, Murray J, Cheng B, Gegeny T, Miller V, Gulick R. Antiretroviral therapies for treatment experienced patients: current status and research challenges. AIDS. 2005;19:747-756. Hicks CB, Cahn P, Cooper DA, et al. Durable efficacy of tipranavir-ritonavir in combination with an optimised background regimen of antiretroviral drugs for treatment-experienced HIV-1-infected patients at 48 weeks in the Randomized Evaluation of Strategic Intervention in multi-drug reSistant patients with Tipranavir (RESIST) studies: an analysis of combined data from two randomised open-label trials. Lancet. 2006;368:466-475. Lagnese M, Daar ES. Antiretroviral regimens for treatment-experienced patients with HIV-1 infection. Expert Opin Pharmacother. 2008;9:687-700.

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