Sterne JA, May M, Costagliola D, de Wolf F, Phillips AN, Harris R, et al.

Timing of initiation of antiretroviral therapy in AIDS-free HIV-1-infected patients: a collaborative analysis of 18 HIV cohort studies. Lancet. Apr 18 2009;373(9672):1352-63.

Background The 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. Methods We 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 L, 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 (198995) 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 L. Findings Data 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 251350 cells per L was associated with higher rates of AIDS and death than starting therapy in the range 351450 cells per L (hazard ratio [HR] 128, 95% CI 104157). 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 113, 080160, for deferred initiation of treatment at CD4 cell count 251350 cells per L compared with initiation at 351 450 cells per L). Interpretation Our results suggest that 350 cells per L should be the minimum threshold for initiation of antiretroviral therapy, and should help to guide physicians and patients in deciding when to start treatment. Funding

UK Medical Research Council.

[Best Evidence] Severe P, Juste MA, Ambroise A, Eliacin L, Marchand C, Apollon S, et al. Early versus standard antiretroviral therapy for HIV-infected adults in Haiti. N Engl J Med. Jul 15 2010;363(3):257-65

Early versus standard antiretroviral therapy for HIV-infected adults in Haiti.

N Engl J Med. 2010; 363(3):257-65 (ISSN: 1533-4406)
Severe P; Juste MA; Ambroise A; Eliacin L; Marchand C; Apollon S; Edwards A; Bang H; Nicotera J; Godfrey C; Gulick RM; Johnson WD; Pape JW; Fitzgerald DW Groupe Haitien d'Etude du Sarcome de Kaposi et des Infections Opportunistes, Port au Prince, Haiti. BACKGROUND: For adults with human immunodeficiency virus (HIV) infection who have CD4+ Tcell counts that are greater than 200 and less than 350 per cubic millimeter and who live in areas with limited resources, the optimal time to initiate antiretroviral therapy remains uncertain. METHODS: We conducted a randomized, open-label trial of early initiation of antiretroviral therapy, as compared with the standard timing for initiation of therapy, among HIV-infected adults in Haiti who had a confirmed CD4+ T-cell count that was greater than 200 and less than 350 per cubic millimeter at baseline and no history of an acquired immunodeficiency syndrome (AIDS) illness. The primary study end point was survival. The early-treatment group began taking zidovudine, lamivudine, and efavirenz therapy within 2 weeks after enrollment. The standard-treatment group started the same regimen of antiretroviral therapy when their CD4+ T-cell count fell to 200 per cubic millimeter or less or when clinical AIDS developed. Participants in both groups underwent monthly follow-up assessments and received isoniazid and trimethoprim-sulfamethoxazole prophylaxis with nutritional support. RESULTS: Between 2005 and 2008, a total of 816 participants--408 per group--were enrolled and were followed for a median of 21 months. The CD4+ T-cell count at enrollment was approximately 280 per cubic millimeter in both groups. There were 23 deaths in the standard-treatment group, as compared with 6 in the early-treatment group (hazard ratio with standard treatment, 4.0; 95% confidence interval [CI], 1.6 to 9.8; P=0.001). There were 36 incident cases of tuberculosis in the standard-treatment group, as compared with 18 in the early-treatment group (hazard ratio, 2.0; 95% CI, 1.2 to 3.6; P=0.01). CONCLUSIONS: Early initiation of antiretroviral therapy decreased the rates of death and incident tuberculosis. Access to antiretroviral therapy should be expanded to include all HIV-infected adults who have CD4+ T-cell counts of less than 350 per cubic millimeter, including those who live in areas with limited resources. (ClinicalTrials.gov number, NCT00120510.)

Cain LE, Logan R, Robins JM, et al. When to initiate combined antiretroviral therapy to reduce mortality and AIDS-defining illness in HIV-infected persons in developed countries: an observational study. Ann Intern Med. Apr 19 2011;154(8):509-15

When to initiate combined antiretroviral therapy to reduce mortality and AIDS-defining illness in HIV-infected persons in developed countries: an observational study.
Ann Intern Med. 2011; 154(8):509-15 (ISSN: 1539-3704)
; Cain LE; Logan R; Robins JM; Sterne JA; Sabin C; Bansi L; Justice A; Goulet J; van Sighem A; de Wolf F; Bucher HC; von Wyl V; Esteve A; Casabona J; del Amo J; Moreno S; Seng R; Meyer L; Perez-Hoyos S; Muga R; Lodi S; Lanoy E; Costagliola D; Hernan MA Harvard School of Public Health, Boston, MA, USA. 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.

Hecht FM, Wang L, Collier A, Little S, Markowitz M, Margolick J, et al. A multicenter observational study of the potential benefits of initiating combination antiretroviral therapy during acute HIV infection. J Infect Dis. Sep 15 2006;194(6):725-33

A multicenter observational study of the potential benefits of initiating combination antiretroviral therapy during acute HIV infection.
J Infect Dis. 2006; 194(6):725-33 (ISSN: 0022-1899)
Hecht FM; Wang L; Collier A; Little S; Markowitz M; Margolick J; Kilby JM; Daar E; Conway B; Holte S; University of California San Francisco, San Francisco, CA 94110, USA. rhecht@php.ucsf.edu OBJECTIVE: Uncontrolled studies have suggested a benefit, after treatment discontinuation, of initiating highly active antiretroviral therapy (HAART) during primary human immunodeficiency virus (HIV) infection. We assessed whether initiation of HAART within 2 weeks of (acute treatment) or between 2 weeks and 6 months after (early treatment) HIV seroconversion was associated with improvements in the viral load and the CD4+ T cell count after discontinuation of treatment in an observational cohort. METHODS: Subjects from the multicenter Acute Infection and Early Disease Research Program cohort were enrolled in the present study within 6 months of HIV seroconversion and self-selected whether to initiate HAART. Subjects who received acute (n=13) or early (n=45) treatment received HAART for at least 12 weeks and then subsequently stopped treatment, whereas untreated subjects (n=337) declined treatment. HIV RNA levels and CD4+ T cell counts at 24, 48, and 72 weeks after treatment cessation in the 2 treatment groups were compared with those noted in the untreated group during the same periods of observation after enrollment. RESULTS: The acute treatment group had lower mean HIV RNA levels at 24 weeks without therapy (-0.48 log(10) copies/mL [95% confidence interval {CI}, -0.82 to -0.13 log(10) copies/mL]) and higher mean CD4+ T cell counts (112 cells/ mu L [95% CI, 20-205 cells/ microL]), compared with the untreated group at 24 weeks. The differences in the laboratory values for the acute treatment group versus the untreated group at 72 weeks without therapy were as follows: for the HIV RNA level, -0.35 log(10) copies/mL (95% CI, -0.91 to 0.21 log(10) copies/mL) and, for the CD4 T+ cell count, 112 cells/ microL (95% CI, -15 to 213 cells/ microL). The early treatment group had lower HIV RNA levels at 24 weeks than did the untreated group, but differences were no longer apparent by week 48; CD4+ T cell counts were higher in the early treatment group at week 24 (116 cells/ microL [95% CI, 75-157 cells/ microL]) and week 72 (70 cells/ microL [95% CI, 2-138 cells/ microL]). CONCLUSIONS: Initiation of HAART within 2 weeks of antibody seroconversion was associated with viral load and CD4+ T cell count benefits for 24 weeks after termination of HAART, with there being trends toward a longer-term benefit. Later initiation of HAART was associated with a persistent but decreasing CD4+ T cell count benefit and a loss of the viral load benefit by week 72 after discontinuation of treatment.