HIV This Week

Optimal time for initiation of antiretroviral therapy in asymptomatic, HIV-infected, treatment-naive adults.

Siegfried N, Uthman OA, Rutherford GW. Cochrane Database Syst Rev. 2010;3:CD008272

According to consensus, initiation of therapy is best based on CD4 cell count, a marker of immune status, rather than on viral load, a marker of virologic replication. For patients with advanced symptoms, treatment should be started regardless of CD4 count. However, the point during the course of HIV infection at which antiretroviral therapy is best initiated in asymptomatic patients remains unclear. Guidelines issued by various agencies provide different initiation recommendations according to resource availability. This can be confusing for clinicians and policy-makers when determining the best time to initiate therapy. Optimizing the initiation of antiretroviral therapy is clearly complex and must, therefore, be balanced between individual and broader public health needs. The objective of the study was to assess the evidence for the optimal time to initiate antiretroviral therapy in treatment-naive, asymptomatic, HIV-infected adults. The authors formulated a comprehensive and exhaustive search strategy in an attempt to identify all relevant studies regardless of language or publication status (published,unpublished, in press, and in progress). In August 2009, they searched the following electronic journal and trial databases: MEDLINE, EMBASE, and CENTRAL. They also searched the electronic conference database of NLM Gateway, individual conference proceedings and prospective trials registers. They contacted researchers and relevant organizations and checked reference lists of all included studies. Randomized controlled trials that compared the effect of antiretroviral therapy consisting of three drugs initiated early in the disease at high CD4 counts as defined by the trial were selected. Early initiation could be at levels of 201-350, 351-500, or >500 cells/microL, with the comparison group initiating antiretroviral therapy at CD4 counts below 200 x 10(6) cells/microL or as defined by the trial. Two review authors independently assessed study eligibility, extracted data, and graded methodological quality. Data extraction and methodological quality were checked by a third author who resolved differences when these arose. Where clinically meaningful to do so, they meta-analysed dichotomous outcomes using the relative risk (RR) and report the 95% confidence intervals (95% CIs).  They found that one completed trial (N = 816) and one sub-group (N = 249) of a larger trial met inclusion criteria. They combined the mortality data for both trials comparing initiating antiretroviral therapy at CD4 levels at 350 cells/microL or between 200 and 350 cells/microL with deferring initiation of antiretroviral therapy to CD4 levels of 250 cells/microL or 200 cells/microL. There was a statistically significant reduction in death when starting antiretroviral therapy at higher CD4 counts. Risk of death was reduced by 74% (RR = 0.26; 95% CI: 0.11, 0.62; P = 0.002). Risk of tuberculosis was reduced by 50% in the groups starting antiretroviral therapy early; this was not statistically significant, with the reduction as much as 74% or an increased risk of up to 12% (RR = 0.54; 95% CI:0.26, 1.12; P = 0.01). Starting antiretroviral therapy at enrolment (when participants had CD4 counts of 350 cells/microL) rather than deferring to starting at a CD4 count of 250 cells/microL reduced the risk of disease progression by 70%; this was not statistically significant, with the reduction in risk as much as 97% or an increased risk of up to 185% (RR = 0.30; 95% CI: 0.03, 2.85; P = 0.29).One randomised controlled clinical trial found no statistically significant difference in the number of independent Grade  3 or 4 adverse events occurring in the early and standard antiretroviral therapy groups when the authors conducted an intention-to-treat analysis (RR = 1.72; 95% CI: 0.98, 3.03; P = .06). However, when analyzing only participants who actually commenced antiretroviral therapy in the deferred group (n = 160), the trial authors report a statistically significant increase in the incidence of zidovudine-related anaemia (8.1%) compared with those in the early initiation group (3.4%) (RR = 0.42; 95% CI: 0.20, 0.88; P = 0.02). The authors conclude that there is evidence of moderate quality that initiating antiretroviral therapy at CD4 levels higher than 200 or 250 cells/microL reduces mortality rates in asymptomatic, antiretroviral therapy-naive, HIV-infected people. Practitioners and policy-makers may consider initiating antiretroviral therapy at levels </= 350 cells/microL for patients who present to health services and are diagnosed with HIV early in the infection.

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Editors’ note: Why do people say that there is equipoise (meaning that we really don’t know which way the answer will go) for the trials that are currently underway to determine whether it is beneficial to start antiretroviral treatment at even higher CD4 counts than the 350 cells/µl currently recommended by WHO? It is because the two small trials described here only looked at CD4 counts under 350 cells/µl. Pooled data from the Haiti study (816 people) and the antiretroviral treatment naive sub-sample from the SMART study (248 people) found that starting antiretroviral treatment between 200-250 and 350 CD4+ cells/µl compared with under 200 cells/µl reduces mortality in treatment-naïve people living with HIV who have no symptoms. A small proof of concept trial http://clinicaltrials.gov/ct2/show/NCT00491556 is recruiting 100 people aged 18-24 to start treatment above 350 cells or wait until their CD4 counts fall below 350 cells while a large trial, Strategic Timing of Antiretroviral Treatment (START) http://clinicaltrials.gov/ct2/show/NCT00867048, is  enrolling 4000 antiretroviral-naive people with CD4 counts greater than 500 cells/µl at 87 sites in 23 countries. Participants will be randomized to start antiretroviral treatment immediately or wait until their first CD4 count of less than 350 cells/µl or clinical signs of AIDS. At issue is whether adherence challenges, long-term side-effects, chances of developing other illnesses, resistance to HIV medicines, frequency of doctor visits, and cost of medical care associated with early antiretroviral treatment are outweighed by reduced risk of HIV disease progression conferred by these medicines. The bottom line for most people is which strategy improves general health, quality of life, and satisfaction.