When to initiate combined antiretroviral therapy to reduce mortality and AIDS-defining illness in HIV-infected persons in developed countries: an observational study

Abstract

Background: Most clinical guidelines recommend that AIDS-free, HIV-infected persons with CD4 cell counts below 0.350 × 10(9) 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 × 10(9) 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 × 10(9) 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 × 10(9) 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 × 10(9) 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 × 10(9) cells/L increases AIDS-free survival. However, mortality did not vary substantially with the use of CD4 thresholds between 0.300 and 0.500 × 10(9) cells/L.

Appendix Figure

Follow-up for 6 hypothetical persons whose data are consistent with multiple cART initiation strategies for CD4 cell count thresholds of 0.500 and 0.350 × 10⁹ cells/L.

Figure

Survival (top) and AIDS-free survival (bottom) for combined antiretroviral therapy initiation at CD4 cell count thresholds ranging from 0.200 to 0.500 × 10⁹ cells/L.