When to Initiate Combined Antiretroviral Therapy to Reduce Mortality and AIDS-Defining Illness in HIV-Infected Persons in Developed Countries

Abstract

Background Most clinical guidelines recommend that AIDS-free, HIV-infected persons with CD4 cell counts below 0.350 × 109 cells/L initiate combined antiretroviral therapy (cART), but the optimal CD4 cell count at which cART should be initiated remains a matter of debate. Objective To identify the optimal CD4 cell count at which cART should be initiated. Design Prospective observational data from the HIV-CAUSAL Collaboration and dynamic marginal structural models were used to compare cART initiation strategies for CD4 thresholds between 0.200 and 0.500 × 109 cells/L. Setting HIV clinics in Europe and the Veterans Health Administration system in the United States. Patients 20 971 HIV-infected, therapy-naive persons with baseline CD4 cell counts at or above 0.500 × 109 cells/L and no previous AIDS-defining illnesses, of whom 8392 had a CD4 cell count that decreased into the range of 0.200 to 0.499 × 109 cells/L and were included in the analysis. Measurements Hazard ratios and survival proportions for all-cause mortality and a combined end point of AIDS-defining illness or death. Results Compared with initiating cART at the CD4 cell count threshold of 0.500 × 109 cells/L, the mortality hazard ratio was 1.01 (95% CI, 0.84 to 1.22) for the 0.350 threshold and 1.20 (CI, 0.97 to 1.48) for the 0.200 threshold. The corresponding hazard ratios were 1.38 (CI, 1.23 to 1.56) and 1.90 (CI, 1.67 to 2.15), respectively, for the combined end point of AIDS-defining illness or death. Limitations CD4 cell count at cART initiation was not randomized. Residual confounding may exist. Conclusion Initiation of cART at a threshold CD4 count of 0.500 × 109 cells/L increases AIDS-free survival. However, mortality did not vary substantially with the use of CD4 thresholds between 0.300 and 0.500 ×109 cells/L. Primary Funding Source National Institutes of Health.

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.…”

Adult antiretroviral therapy guidelines 2014

“…Some observational data suggest that reduced morbidity and mortality are associated with starting ART earlier (at CD4 + count thresholds of ≥500 cells/μL). [3][4][5][6] However, these data are derived from retrospective studies with methodological issues and probable residual confounding. If there is benefit to patients starting ART at CD4 + counts >350 cells/μL, the benefit is likely to be small, since HIVrelated events at high CD4 + counts are rare.…”

Causal inference in epidemiological studies with strong confounding

“…Indeed, these models not only allow the investigation of causal effects defined by static interventions but also the effect of dynamic interventions that do not result in identical exposure levels for all experimental units. In fact, the effect of such dynamic interventions may be more interesting for some subject-matter research than the effect of static interventions in both point-treatment studies (e.g., to determine attributable effect [27]) and longitudinal studies (e.g., to optimize drug treatments [18, 28, 29]).…”