Short-course antiretroviral therapy in primary HIV infection

Abstract

Background: Short-course antiretroviral therapy (ART) in primary human immunodeficiency virus (HIV) infection may delay disease progression but has not been adequately evaluated.

Methods: We randomly assigned adults with primary HIV infection to ART for 48 weeks, ART for 12 weeks, or no ART (standard of care), with treatment initiated within 6 months after seroconversion. The primary end point was a CD4+ count of less than 350 cells per cubic millimeter or long-term ART initiation.

Results: A total of 366 participants (60% men) underwent randomization to 48-week ART (123 participants), 12-week ART (120), or standard care (123), with an average follow-up of 4.2 years. The primary end point was reached in 50% of the 48-week ART group, as compared with 61% in each of the 12-week ART and standard-care groups. The average hazard ratio was 0.63 (95% confidence interval [CI], 0.45 to 0.90; P=0.01) for 48-week ART as compared with standard care and was 0.93 (95% CI, 0.67 to 1.29; P=0.67) for 12-week ART as compared with standard care. The proportion of participants who had a CD4+ count of less than 350 cells per cubic millimeter was 28% in the 48-week ART group, 40% in the 12-week group, and 40% in the standard-care group. Corresponding values for long-term ART initiation were 22%, 21%, and 22%. The median time to the primary end point was 65 weeks (95% CI, 17 to 114) longer with 48-week ART than with standard care. Post hoc analysis identified a trend toward a greater interval between ART initiation and the primary end point the closer that ART was initiated to estimated seroconversion (P=0.09), and 48-week ART conferred a reduction in the HIV RNA level of 0.44 log(10) copies per milliliter (95% CI, 0.25 to 0.64) 36 weeks after the completion of short-course therapy. There were no significant between-group differences in the incidence of the acquired immunodeficiency syndrome, death, or serious adverse events.

Conclusions: A 48-week course of ART in patients with primary HIV infection delayed disease progression, although not significantly longer than the duration of the treatment. There was no evidence of adverse effects of ART interruption on the clinical outcome. (Funded by the Wellcome Trust; SPARTAC Controlled-Trials.com number, ISRCTN76742797, and EudraCT number, 2004-000446-20.).

Figure 1. Study Enrollment, Randomization, and Outcomes

The primary end point was a confirmed CD4+ count of less than 350 cells per cubic millimeter or the initiation of long-term antiretroviral therapy (ART). One additional patient in the standard-care group is known to have died after November 7, 2010 (a patient in Johannesburg, who died in January 2011). HIV denotes human immunodeficiency virus.

Figure 2. Time from Randomization to End Points According to Study Group

Panels A and D show data for the primary end point, and Panels B and C show data for the individual components of the primary end point. Primary HIV infection was defined as infection meeting one or more of the following criteria: a positive HIV-antibody test within 6 months after a negative test (criterion 1), a negative HIV-antibody test with a positive reverse-transcription–polymerase-chain-reaction assay for HIV RNA (criterion 2), a low level of HIV antibodies (optical density units [OD], <0.6) according to a serologic testing algorithm for recent infection (subtype B strain only) (criterion 3), an equivocal HIV-antibody test with a repeat test within 2 weeks showing an increase in the level of HIV antibodies (criterion 4), or clinical manifestations of symptomatic HIV seroconversion illness supported by antigen positivity and less than 4 positive bands on Western blot analysis (criterion 5). The time of seroconversion was estimated as the midpoint between the most recent negative or equivocal test and the first positive test for patients who met criterion 1 or 4; as the date of the test for patients who met criterion 2, 3 (if OD ≤0.01), or 5; and as the date of the test − [(OD × 150) ÷ 2] days for patients who met criterion 3 if the antibody level was greater than 0.01 OD.

Figure 3. Changes in the CD4+ Count and HIV RNA Level

Panel A shows the output from the statistical model for the decline in the CD4+ count from 24 weeks after completion of the study regimen in the 48-week and 12-week ART groups and from randomization in the standard-care group. Panel B shows the differences from baseline in HIV RNA levels at 12, 24, 36, 48, and 60 weeks after completion of the study regimen in the 48-week and 12-week ART groups and from randomization in the standard-care group, with adjustment for the baseline value. Some measurements were censored owing to initiation of long-term ART. I bars indicate 95% confidence intervals.

Figure 4

Statistical Model of the CD4+ Response to the Initiation of Long-Term ART