Timing of initiation of antiretroviral therapy in AIDS-free HIV-1-infected patients: a collaborative analysis of 18 HIV cohort studies

Abstract

SummaryBackgroundThe CD4 cell count at which combination antiretroviral therapy should be started is a central, unresolved issue in the care of HIV-1-infected patients. In the absence of randomised trials, we examined this question in prospective cohort studies.MethodsWe analysed data from 18 cohort studies of patients with HIV. Antiretroviral-naive patients from 15 of these studies were eligible for inclusion if they had started combination antiretroviral therapy (while AIDS-free, with a CD4 cell count less than 550 cells per μL, and with no history of injecting drug use) on or after Jan 1, 1998. We used data from patients followed up in seven of the cohorts in the era before the introduction of combination therapy (1989–95) to estimate distributions of lead times (from the first CD4 cell count measurement in an upper range to the upper threshold of a lower range) and unseen AIDS and death events (occurring before the upper threshold of a lower CD4 cell count range is reached) in the absence of treatment. These estimations were used to impute completed datasets in which lead times and unseen AIDS and death events were added to data for treated patients in deferred therapy groups. We compared the effect of deferred initiation of combination therapy with immediate initiation on rates of AIDS and death, and on death alone, in adjacent CD4 cell count ranges of width 100 cells per μL.FindingsData were obtained for 21 247 patients who were followed up during the era before the introduction of combination therapy and 24 444 patients who were followed up from the start of treatment. Deferring combination therapy until a CD4 cell count of 251–350 cells per μL was associated with higher rates of AIDS and death than starting therapy in the range 351–450 cells per μL (hazard ratio [HR] 1·28, 95% CI 1·04–1·57). The adverse effect of deferring treatment increased with decreasing CD4 cell count threshold. Deferred initiation of combination therapy was also associated with higher mortality rates, although effects on mortality were less marked than effects on AIDS and death (HR 1·13, 0·80–1·60, for deferred initiation of treatment at CD4 cell count 251–350 cells per μL compared with initiation at 351–450 cells per μL).InterpretationOur results suggest that 350 cells per μL should be the minimum threshold for initiation of antiretroviral therapy, and should help to guide physicians and patients in deciding when to start treatment.FundingUK Medical Research Council.

Effects of early versus delayed initiation of antiretroviral treatment on clinical outcomes of HIV-1 infection: results from the phase 3 HPTN 052 randomised controlled trial

“…Detailed analyses of several large cohorts show a benefit of treatment initiation at higher CD4 cell counts. 3–6 The strengths and limitations of these earlier studies have been addressed. 6,14,15 …”

“…1,2 However, the best timing of treatment initiation in people with high CD4 cell counts remains unknown. Findings of observational studies of treatment for HIV-1 infection lend support to early initiation of antiretroviral treatment, 3–6 but data from randomised studies are scarce. In a randomised trial from Haiti, 7 HIV-1 disease progression was delayed and survival extended when antiretroviral treatment was started at CD4 counts of 200–350 cells per μL, compared with initiation at CD4 counts of less than 200 cells per μL.…”

Virological failure and development of new resistance mutations according to CD4 count at combination antiretroviral therapy initiation

“…Although morbidity and mortality benefits of starting combination antiretroviral therapy (cART) at CD4 counts > 350 cells/μL have been reported in cohort studies 1, 2, there is little randomized evidence on the individual risk–benefit ratio of initiating combination antiretroviral therapy (cART) at higher CD4 counts 3. The randomized controlled Strategic Timing of AntiRetroviral Treatment (START) trial has recently investigated the optimal timing of cART initiation in order to improve morbidity and mortality outcomes in HIV‐positive individuals 4.…”

Gender, socio-economic status, migration origin and neighbourhood of residence are barriers to HIV testing in the Paris metropolitan area

“…) when a late diagnosis is known to be associated with an increased risk of mortality after entry into the health-care system (Sterne et al, 2009). In France, HIV testing policy is based on the opt-in approach.…”