HIV This Week

Kitahata MM, Gange SJ, Abraham AG, Merriman B, Saag MS, Justice AC, Hogg RS, Deeks SG, Eron JJ, Brooks JT, Rourke SB, Gill MJ, Bosch RJ, Martin JN, Klein MB, Jacobson LP, Rodriguez B, Sterling TR, Kirk GD, Napravnik S, Rachlis AR, Calzavara LM, Horberg MA, Silverberg MJ, Gebo KA, Goedert JJ, Benson CA, Collier AC, Van Rompaey SE, Crane HM, McKaig RG, Lau B, Freeman AM, Moore RD, for the NA-ACCORD Investigators*. Effect of Early versus Deferred Antiretroviral Therapy for HIV on Survival. N Engl J Med 2009;360.

The optimal time for the initiation of antiretroviral therapy for asymptomatic patients with human immunodeficiency virus (HIV) infection is uncertain. Kitahata and colleagues conducted two parallel analyses involving 17,517 asymptomatic patients with HIV infection in the United States and Canada who received medical care during the period from 1996 through 2005. None of the patients had undergone previous antiretroviral therapy. In each group, the authors stratified the patients according to the CD4+ count (351 to 500 cells per cubic millimetre or >500 cells per cubic millimetre) at the initiation of antiretroviral therapy. In each group, they compared the relative risk of death for patients who initiated therapy when the CD4+ count was above each of the two thresholds of interest (early-therapy group) with that of patients who deferred therapy until the CD4+ count fell below these thresholds (deferred-therapy group). The results of the first analysis, which involved 8362 patients, 2084 (25%) initiated therapy at a CD4+ count of 351 to 500 cells per cubic millimetre, and 6278 (75%) deferred therapy. After adjustment for calendar year, cohort of patients, and demographic and clinical characteristics, among patients in the deferred-therapy group there was an increase in the risk of death of 69%, as compared with that in the early-therapy group (relative risk in the deferred-therapy group, 1.69; 95% confidence interval [CI], 1.26 to 2.26; P<0.001). In the second analysis involving 9155 patients, 2220 (24%) initiated therapy at a CD4+ count of more than 500 cells per cubic millimetre and 6935 (76%) deferred therapy. Among patients in the deferred-therapy group, there was an increase in the risk of death of 94% (relative risk, 1.94; 95% CI, 1.37 to 2.79; P<0.001). The authors concluded that the early initiation of antiretroviral therapy before the CD4+ count fell below two prespecified thresholds significantly improved survival, as compared with deferred therapy.

Editors' note: Most observational studies do not take account of the lead-time bias that is introduced by unobserved person-time among individuals who do not present for care until their CD4+ cell count drops below the threshold of interest (e.g. 200 cells/ul). These individuals have survived without clinical progression until the time of their diagnosis. This analysis, which used methods to take account of lead-time bias, suggests an approximate 70% increase in survival when antiretroviral treatment is initiated in the 350-500 CD4+/ µ l count range rather than at lower CD4+ counts.

The aim was to review the available data that contribute to the debate on the optimal time to initiate highly active antiretroviral therapy in HIV-infected individuals with a CD4 cell count more than 350 cells/microl. Although few randomized data exist that can contribute to this debate, a number of findings from observational studies generally support earlier initiation of highly active antiretroviral therapy. In particular, the findings that death rates remain higher in HIV-infected individuals than in uninfected individuals, even when successfully treated, and that both AIDS and several serious non-AIDS events are more common in those with a lower CD4 cell count (even when this count is above 350 cells/microl), suggest that earlier initiation of highly active antiretroviral therapy may prevent much of the excess morbidity and mortality that remains in this patient group. Currently, the data would generally support initiation of highly active antiretroviral therapy in patients with CD4 cell counts more than 350 cells/microl. However, given the strong potential for confounding in observational studies and the lack of adjustment for lead-time bias in many analyses, it is not possible to rule out possible long-term detrimental effects of earlier use of highly active antiretroviral therapy until the results from fully powered randomized trials that directly address this issue become available.

Editors' note: Current discussions of when to initiate antiretroviral treatment focus on issues such as the inequity of two-tiered start criteria (CD4+ counts less than 200 / µ l in most resource-constrained settings and CD4+ less than 350 in most high-income countries), the logistical and other challenges experienced now in reaching toward universal access with current CD4+ count less than 200 criteria, the need to focus resources first to encourage earlier HIV testing in many countries, the concerns about long-term known and unknown toxicities of antiretroviral drugs, and the belief that the lifelong high adherence requirements of antiretroviral treatment may be too demanding for patients who then risk developing resistance, exhausting their future drug options. Although this review of available data on the impact of earlier antiretroviral treatment initiation suggests positive benefits for individuals, there is equipoise for a randomised controlled trial. The START (Strategic Timing of AntiRetroviral Treatment) trial now beginning enrolment will assess whether treatment initiation in patients with CD4+ counts greater than 500 cells/ul is superior than delaying treatment initiation until CD4+ cell counts fall below 350.

Clinicians may defer antiretroviral treatment for patients with suboptimal adherence. Braithwaite and colleagues used a validated computer simulation of HIV disease progression to compare alternative treatment thresholds for patients with suboptimal adherence. Earlier treatment increased life expectancy across a wide adherence range (50%-100% of doses taken). Delaying treatment for patients with suboptimal adherence may not always be appropriate.

Editors' note: Improving adherence substantially increases life expectancy and quality adjusted life years (QALYs). This modelling work shows that, in all adherence strata, the immunological benefit of early antiretroviral treatment initiation outweighs the harms of greater resistance mutation accumulation and reduced future drug options. It suggests that patients with anticipated suboptimal adherence do not warrant distinct criteria for starting antiretroviral treatment. They are likely to benefit substantially from surveillance to detect poor adherence and strategies to improve it, such as treating hazardous levels of alcohol consumption and prompting prescription refills.