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Antiretroviral Treatment of Adult HIV Infection2012 Recommendations of the International Antiviral Society-USA Panel
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Download the PDF here
JAMA. July 25 2012
Melanie A. Thompson, MD; Judith A. Aberg, MD; Jennifer F. Hoy, MBBS, FRACP; Amalio Telenti, MD, PhD; Constance Benson, MD; Pedro Cahn, MD, PhD; Joseph J. Eron, MD; Huldrych F. Gunthard, MD; Scott M. Hammer, MD; Peter Reiss, MD, PhD; Douglas D. Richman, MD; Giuliano Rizzardini, MD; David L. Thomas, MD; Donna M. Jacobsen, BS; Paul A. Volberding, MD
"recent evidence increasingly supports earlier initiation of ART"
ABSTRACT
Context New trial data and drug regimens that have become available in the last 2 years warrant an update to guidelines for antiretroviral therapy (ART) in human immunodeficiency virus (HIV)-infected adults in resource-rich settings.
Objective To provide current recommendations for the treatment of adult HIV infection with ART and use of laboratory-monitoring tools. Guidelines include when to start therapy and with what drugs, monitoring for response and toxic effects, special considerations in therapy, and managing antiretroviral failure.
Data Sources, Study Selection, and Data Extraction Data that had been published or presented in abstract form at scientific conferences in the past 2 years were systematically searched and reviewed by an International Antiviral Society-USA panel. The panel reviewed available evidence and formed recommendations by full panel consensus.
Data Synthesis Treatment is recommended for all adults with HIV infection; the strength of the recommendation and the quality of the evidence increase with decreasing CD4 cell count and the presence of certain concurrent conditions. Recommended initial regimens include 2 nucleoside reverse transcriptase inhibitors (tenofovir/emtricitabine or abacavir/lamivudine) plus a nonnucleoside reverse transcriptase inhibitor (efavirenz), a ritonavir-boosted protease inhibitor (atazanavir or darunavir), or an integrase strand transfer inhibitor (raltegravir). Alternatives in each class are recommended for patients with or at risk of certain concurrent conditions. CD4 cell count and HIV-1 RNA level should be monitored, as should engagement in care, ART adherence, HIV drug resistance, and quality-of-care indicators. Reasons for regimen switching include virologic, immunologic, or clinical failure and drug toxicity or intolerance. Confirmed treatment failure should be addressed promptly and multiple factors considered.
When HIV is allowed to replicate uninhibited by ART, resultant immune activation and inflammation are associated not only with immune destruction and opportunistic infections but also increased rates of cardiovascular, renal, hepatic, and neurologic diseases; malignancies; and other serious non-AIDS diseases. Evidence from clinical trials, observational cohorts, and pathogenesis studies all point toward the health benefits of earlier ART. Potent and tolerable treatment regimens now make durable viral suppression possible for most persons throughout the course of HIV infection.
Conclusion New recommendations for HIV patient care include offering ART to all patients regardless of CD4 cell count, changes in therapeutic options, and modifications in the timing and choice of ART in the setting of opportunistic illnesses such as cryptococcal disease and tuberculosis.
Since the first antiretroviral drug was approved 25 years ago, improvements in the potency, tolerability, simplicity, and availability of antiretroviral therapy (ART) have resulted in dramatically reduced numbers of opportunistic diseases and deaths where ART is accessible.1 New data show that viral suppression due to ART results in decreased human immunodeficiency virus (HIV) transmission on individual2 and population levels1 and that, when used consistently by HIV-uninfected persons, ART also may provide protection against HIV infection.3 - 5 Together, these developments have translated into newly articulated visions of the "beginning of the end of AIDS."6 This revision of the International Antiviral (formerly AIDS) Society-USA (IAS-USA) guidelines reflects new data informing consideration of when to initiate ART, new options for initial and subsequent therapy, ART management in the setting of special conditions, and new approaches to monitoring treatment success and quality. Discussion of the emerging area of antiretroviral preexposure prophylaxis for high-risk HIV-seronegative persons is included.
Nucleos(t)ide Reverse Transcriptase Inhibitors
Three 2-drug NRTI FDCs are currently available. In some cases, these FDCs are coformulated with another potent drug, adding to the overall regimen convenience.
Recommended. Tenofovir disoproxil fumarate and emtricitabine are available in a once-daily FDC with no food restrictions. Tenofovir is well tolerated but has been associated with kidney injury, which appears to increase in incidence with long-term administration and concurrent PI/r use.16 ,55 - 56 Renal function should be assessed before use and monitored over time,57 dosing adjusted according to the package insert in the case of renal impairment (estimated glomerular filtration rate [eGFR] <50 mL/min), and tenofovir discontinued when eGFR is below 30 mL/min. Tenofovir causes a decrease in bone mineral density in the spine and hip,58 - 59 the long-term progression of which currently remains ill defined. Emtricitabine is similar to lamivudine in mechanism of action, potency, toxicity, and patterns of resistance.
An abacavir and lamivudine FDC offers once-daily administration, no food restriction, and minimal subjective toxicity. Screening for HLA-B*5701 markedly reduces the risk of potentially life-threatening hypersensitivity reaction to abacavir.7 In some studies60 - 61 but not in others,62 - 65 abacavir has been associated with a higher risk of acute myocardial infarction.
Initial regimens containing abacavir/lamivudine had lower rates of viral suppression in persons with baseline HIV-1 RNA levels above 100 000 copies/mL than regimens containing tenofovir/emtricitabine.7 However, in a second randomized trial, this difference was not observed.66 Lamivudine is extremely well tolerated.
WHEN TO START
All adults with HIV infection should be offered ART regardless of CD4 cell count, based on recent observational cohort data that all patients may benefit from ART and data from a randomized controlled trial showing that ART reduces the likelihood of HIV transmission while providing clinical benefit to treated individuals.2 When prescribing ART, the following should be considered: (1) a patient must be ready and willing to adhere to ART, and adherence education and support should be offered9 ; (2) the benefit of ART is unknown in elite controllers (HIV-1 RNA below the level of quantification without ART) and long-term nonprogressors (those with stable CD4 cell counts >500/μL and HIV-1 RNA <1000 copies/mL while not taking ART); (3) the benefit of ART in asymptomatic acute HIV infection is not as well studied as in symptomatic acute HIV infection; and (4) there is no CD4 cell count threshold at which starting therapy is contraindicated, but the strength of the recommendation and the quality of the evidence supporting initiation of therapy increase as the CD4 cell count decreases and when certain concurrent conditions are present (Box 1).
Box 1. Recommendations for When to Initiate Antiretroviral Therapy (ART)a
· Patient readiness for treatment should be considered when deciding to initiate ART. Clinicians should engage supportive services as needed to assist with ART education and to address barriers to adherence (AIII).
· ART is recommended and should be offered regardless of CD4 cell count (AIa-CIII). The strength of the recommendation increases as CD4 cell count decreases and in the presence of certain conditions, with the following ratings:
For CD4 cell count of 500/μL and below: AIa
For CD4 cell count above 500/μL: BIII
Ratings for specific conditions are as follows:
Pregnancy: AIa
Chronic hepatitis B virus (HBV) coinfection: AIIab
Hepatitis C virus (HCV) coinfection: CIII (however, coinfection with CD4 cell count >500/μL may delay ART until after completion of HCV treatment)
Age older than 60 years: BIIa
Human immunodeficiency virus (HIV)-associated nephropathy: AIIa
· ART is recommended and should be offered to persons during the acute phase of primary HIV infection, regardless of symptoms (BIII).b
· ART should be started as soon as possible, preferably within the first 2 weeks of diagnosis, in patients with opportunistic infections (AIa). The optimal timing for patients with cryptococcal meningitis is less certain, but initiating ART early during cryptococcal treatment may be associated with higher mortality; therefore, ART initiation in these patients should be managed in consultation with experts (BIII).
· ART is recommended in all HIV-infected persons with tuberculosis (TB) and should be started within 2 weeks of TB treatment when the CD4 cell count is below 50/μL and by 8 to 12 weeks for those with higher CD4 cell counts (A1a). The optimal timing for patients with TB meningitis is less certain, but ART should be started within the first 2 to 8 weeks of diagnosis and managed in consultation with experts (BIII).
aRatings of the strength of the recommendations and quality of evidence are described in the eBox.
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