Antiretroviral Therapy Guidelines for Adults and Adolescents
The widespread use of highly active antiretroviral therapy in the mid to late 1990s spurred a dramatic decline in AIDS-related mortality. Two major sets of guidelines have widely influenced antiretroviral therapy prescribing practices: the United States Health and Human Services (HHS) Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents and the recommendations of the International Antiviral Society (IAS)-USA panel for the treatment of adult HIV infection.[,] The following discussion will focus primarily on the 2016 HHS antiretroviral therapy guidelines, with a particular emphasis on when to initiate antiretroviral therapy. Since 2012, the HHS antiretroviral therapy guidelines have recommended initiating antiretroviral therapy in all HIV-infected adults, both to reduce the risk of disease progression and to prevent transmission of HIV (Figure 1). The strength of the recommendation to initiate antiretroviral therapy had varied based on CD4 cell count. However, given the compelling data from two randomized trials (START and TEMPRANO) the HHS panel now has assigned an A! recommendation for all patients, regardless of CD4 cell count.[,,] Similarly, the IAS-USA panel recommends initiating antiretroviral therapy for all HIV-infected adults with detectable viremia, regardless of CD4 cell count with and AI rating.
Rationale For and Against Earlier Initiation of Antiretroviral Therapy
In recent years, the HHS panel has progressively recommended a more aggressive approach regarding the initiation of antiretroviral therapy. The rationale for earlier initiating of therapy is based on multiple factors, including data showing a clinical and survival benefit of earlier therapy, improvements in antiretroviral therapy (regimens that are more convenient, better tolerated, less toxic, and more effective), increasing data showing HIV causes significant non-AIDS morbidity and mortality, and the growing realization that antiretroviral therapy can play a significant role in preventing sexual transmission of HIV.[,] Multiple observational trials and one randomized trial have shown that HIV-infected persons who take antiretroviral therapy markedly reduce their risk of transmitting HIV to their heterosexual discordant partners (when compared with persons not taking antiretroviral therapy). Arguments against earlier initiation of antiretroviral therapy include cost, potential development of drug toxicity from long-term use, and potential development of antiretroviral resistance. Comprehensive guidelines outline the rationale and potential benefit for earlier initiation for antiretroviral treatment of HIV, including reducing HIV-associated morbidity and mortality, decreasing non-AIDS related complications, reducing HIV-associated inflammation, and decreasing sexual transmission of HIV.
Natural History Data
Recommendations that first suggested possible benefit from initiating antiretroviral therapy in asymptomatic patients who have a CD4 count greater 200 cells/mm3 arose from natural history data in the Multicenter AIDS Cohort Study (MACS), a study performed prior to the use of highly effective antiretroviral therapy (Figure 2).[,] The MACS found that patients with a CD4 count between 201 to 350 cells/mm3 have 3-year risk for progression to AIDS of 38.5%, compared with a 14.3% risk among patients with a CD4 count greater than 350 cells/mm3.[,] Among those persons with a CD4 count between 201 to 350 cells/mm3 the 3-year risk of progressing to AIDS varied significantly based on the RT-PCR plasma HIV RNA level (6.9% with HIV RNA 7,001 to 20,000 copies/ml, 36.4% for 20,001 to 55,000 copies/ml, and 64.4% with greater than 55,000 copies/ml). In addition, a recent evaluation of data from persons in the MACS with low HIV RNA levels found that among 40 individuals with a CD4 count between 201 to 350 cells/mm3 and an HIV RNA less than 10,000 copies/ml none progressed to AIDS by 3 years, whereas 11% of the 28 persons with an HIV RNA level of 10,000 to 20,000 copies/mL progressed to AIDS by 3 years. These natural history data, however, do not address the effect of antiretroviral therapy on survival.
Randomized Controlled Trials
Multiple randomized controlled trials have shown antiretroviral therapy improves survival and delays disease progression in patients who have a CD4 count less than 200 cells/mm3.[,,] In addition, several randomized controlled trials, when taken together, provide support for the recommendation to initiate antiretroviral therapy not only in patients with a CD4 count greater than 200 cells/mm3, but in those with CD4 counts greater than 500 cells/mm3. [,,,]
- CIPRA-HT-001: In the CIPRA HT-001 clinical trial conducted in Haiti, investigators randomized participants to start antiretroviral therapy at a CD4 count of 200 to 350 cells/mm3, or to defer treatment until either their CD4 count decreased to less than 200 cells/mm3 or they developed an AIDS-defining condition. In an interim analysis of the study, participants who began antiretroviral therapy with CD4 counts of 200 to 350 cells/mm3 had a lower mortality rate (P = 0.001) and lower incidence of tuberculosis (P = 0.013) than participants who deferred therapy.
- SMART Trial: In the multi-national SMART trial, investigators randomized more than 5,400 participants with CD4 counts greater than 350 cells/mm3 to receive continuous antiretroviral therapy or to interrupt treatment until the CD4 count decreased to less than 250 cell/mm3. A subgroup analysis, which involved the 249 treatment naive participants at enrollment, found a trend of lower risk of serious AIDS- and non-AIDS-related events in the group who initiated therapy immediately when compared with those who deferred therapy until the CD4 count decreased to less than 250 cells/mm3 (P = 0.06).
- START Trial: In this multinational trial that included patients from Africa, Europe and the Americas, 4685 patients with CD4 counts greater than 500 cells/mm3 were randomly assigned to initiate antiretroviral therapy immediately or to defer therapy until CD4 declined to less than 350 cells/mm3. The primary endpoint was any AIDS-related event, serious non-AIDS-related event or death from any cause. These events occurred, over a mean follow-up of 3 years, in 1.8% of patients in the immediate therapy arm versus 4.1% of those in the deferred arm with a hazard ratio of 0.43 (95% confidence interval 0.30 to 0.62, P<0.001). The three most common events were cardiovascular disease, non-AIDS-defining cancers and tuberculosis. Notably, 68% of these events occurred in patients with CD4 counts greater than 500 cells/mm3.
- TEMPRANO Trial: This was a multicenter randomized trial with a 2 x 2 factorial design of HIV-infected patients from the Ivory Coast who had CD4 counts less than 800 cells/mm3 and no indication yet for starting antiretroviral therapy (ART) according to WHO guidelines at that time (CD4 count less than 350 cells/mm3 or clinical criteria). Investigators randomly assigned 2056 patients to one of 4 arms: deferred ART (per WHO), deferred ART with 6-month isoniazid preventive therapy (IPT), early ART, and early ART with IPT. The primary end point was clinical AIDS, non-AIDS-defining cancer, non-AIDS-defining invasive bacterial disease, or death from any cause at 30 months. A total of 204 events were recorded during follow-up; the most common events during the study were tuberculosis (42%), invasive bacterial diseases (27%) and death (23%). Ultimately, early initiation of ART and 6 months of IPT independently resulted in a 44% lower risk of severe HIV-related illness and 35% lower risk of death compared with deferred initiation of ART and no IPT. This benefit was observed to be robust across different endpoint definitions and CD4 count strata.
Observational Cohort Studies
Observational cohort studies that have involved HAART-treated cohorts have provided additional information regarding the timing of initiating antiretroviral therapy among asymptomatic patients.
- ART Cohort Collaboration: The ART Cohort Collaboration group has published 3-year follow-up data on 12,574 antiretroviral-naïve adult patients who started antiretroviral therapy with at least 3 drugs. This study included a total of 13 European and North American cohort studies and the authors found that baseline CD4 cell count when starting antiretroviral therapy was the dominant prognostic factor (Figure 3). Although they also showed plasma HIV RNA levels correlated with risk of progression to a new clinical AIDS-defining event or death, this association was only significant for HIV RNA levels greater than 100,000 copies/ml (Figure 4). Subsequent 5-year follow-up from the ART Cohort Collaboration group showed the risk of death or development of an AIDS-defining illness was significantly less in patients who started antiretroviral therapy with a CD4 count between 200 to 350 cells/mm3 than those who started with a CD4 count less than 200 cells/mm3; in this study, however, baseline HIV RNA levels did not predict mortality. An additional follow-up analysis with this cohort collaboration reported a similar rate of progression to AIDS/death with initiation of therapy at a CD4 count of 451 to 550 cells/mm3 when compared with deferral of therapy at a CD4 count of 351 to 450 cells/mm3.
- British Columbia Cohort: In another large observational study, investigators from British Columbia retrospectively examined the rates of disease progression to AIDS or death among 1,219 antiretroviral-naïve patients starting triple drug antiretroviral therapy. This study revealed a low rate of disease progression to AIDS or death among patients who had a CD4 count of at least 200 cells/mm3 (Figure 5). In addition, progression to a new clinical AIDS-defining event or death was most pronounced for patients with HIV RNA levels greater than 100,000 copies/ml (Figure 6).
- Johns Hopkins Cohort: A study from Johns Hopkins found that among 1173 patients treated with antiretroviral therapy, those with a baseline CD4 count less than 200 cells/mm3 had a more rapid 3-year disease progression than those who had a baseline of 201 to 350 cells/mm3, even if durable virologic suppression was obtained (Figure 7). This same study showed no differences in 3-year disease progression when comparing patients with a baseline CD4 count of 201 to 350 cells/mm3 and those with a baseline greater than 350 cells/mm3. In another study from Johns Hopkins, investigators examined clinical disease progression in 333 patients who had a baseline CD4 count of 350 to 499 cells/mm3 and after a median duration of follow-up of 21 to 31 months, found no differences among those who received antiretroviral therapy compared with those who did not receive antiretroviral therapy.
- Swiss Cohort Study: In one European study, benefit from earlier treatment was suggested. This study, performed by The Swiss Cohort, compared early initiation of antiretroviral therapy (CD4 counts greater than 350 cells/mm3) deferred therapy (patients monitored without therapy) and found an approximate 5-fold decrease in disease progression to AIDS in the subsequent 3-year period among those who initiated therapy early (Figure 8). Nevertheless, the benefit of early therapy was offset by high rates of adverse effects in the treated group.
- AIDS Spectrum of Disease Project: A retrospective analysis conducted by the AIDS Spectrum of Disease Project found a modest benefit from starting antiretroviral therapy with a baseline CD4 count between 200 to 350 cells/mm3 when compared with CD4 counts less than 200 cells/mm3 and the investigators recommended not waiting until the CD4 count decreases to less than 200 cells/mm3 prior to starting antiretroviral therapy (Figure 9).
- NA-ACCORD: The North American AIDS Cohort Collaborative Collaboration on Research and Design (NA-ACCORD) recently published results from their two parallel analyses of the impact of early versus deferred antiretroviral therapy in 17,517 asymptomatic, antiretroviral-naïve patients in the U.S. and Canada. In the first analysis, which involved 8362 patients, 25% initiated antiretroviral therapy at a CD4 count of 351 to 500 cells/mm3 and 75% deferred therapy. The group of patients who deferred antiretroviral therapy had a 69% increased risk of death when compared with the early therapy group (P < 0.001). The second analysis involved 9,155 patients and 24% initiated antiretroviral therapy at a CD4 count greater than 500 cells/mm3 and 75% deferred therapy. The patients in the deferred therapy group had a 94% increased risk of death when compared with those patients who were in the early therapy group. The investigators concluded early initiation of therapy before the CD4 cell count declined below two predetermined thresholds significantly improved survival when compared with deferred therapy.