A Randomized Trial of Time-Limited Antiretroviral Therapy in Acute/Early HIV Infection.

BACKGROUND: It has been proposed that initiation of antiretroviral treatment (ART) very soon after establishment of HIV infection may be beneficial by improving host control of HIV replication and delaying disease progression. METHODS: People with documented HIV infection of less than 12 months' duration in Baltimore MD and seven Canadian sites were randomized to either a) observation and deferred ART, or b) immediate treatment with ART for 12 months. All subjects not receiving ART were followed quarterly and permanent ART was initiated according to contemporaneous treatment guidelines. The endpoint of the trial was total ART-free time from study entry until initiation of permanent ART. RESULTS: One hundred thirteen people were randomized, 56 to the observation arm and 57 to the immediate treatment arm. Twenty-three had acute (<2 months) infection and 90 early (2-12 months) infection. Of those randomized to the immediate treatment arm, 37 completed 12 months of ART according to protocol, 9 declined to stop ART after 12 months, and 11 were nonadherent to the protocol or lost to follow-up. Comparing those in the observation arm to either those who completed 12 months of ART or all 56 who were randomized to immediate ART, there was no significant difference between the arms in treatment-free interval after study entry, which was about 18 months in both arms. CONCLUSIONS: This study did not find a benefit from administration of a brief, time-limited (12-month) course of ART in acute or early HIV infection. TRIAL REGISTRATION: ClinicalTrials.gov NCT00106171.

HIV-1 Gag evolution in recently infected human leukocyte antigen-B*57 patients with low-level viremia.

We studied viral evolution in five human leukocyte antigen (HLA)-B*57 patients recently infected with HIV-1. Escape mutations in HLA-B*57-restricted Gag epitopes were present at study entry in all patients, but were not associated with significant increases in viremia. Conversely, no new escape mutations in HLA-B*57-restricted epitopes or known compensatory mutations were detected in patients who experienced significant increases in viremia. Thus, the development of escape mutations alone does not determine virologic outcome in recently infected HLA-B*57 patients.

HIV-1 evolution following transmission to an HLA-B*5801-positive patient.

The human immunodeficiency virus type 1 (HIV-1)-specific immune responses of patients with the HLA-B*57/5801 alleles who spontaneously control viral replication serve as an important model for T cell-based HIV-1 vaccines. Determining the breadth of this response and the extent of virologic escape in primary infection in these patients is therefore critical. Here we document the development of mutations in 3 HLA-B*5801-restricted epitopes in gag, nef, and pol in an HLA-B*5801-positive patient who had a viral load of only 1159 copies/mL at day 167 after infection. A full genome sequence analysis was performed to determine the extent of mutations in HLA-B*5801-restricted epitopes, and longitudinal sequence data of specific genes were combined with enzyme-linked immunospot assay analysis of critical epitopes to determine the importance of escape mutations. Thus, relative control of viral replication can be maintained in spite of the rapid development of multiple escape mutations within cytotoxic T lymphocyte epitopes.

Tolerability and efficacy of PI versus NNRTI-based regimens in subjects receiving HAART during acute or early HIV infection.

BACKGROUND: Little is known about modifications to highly active antiretroviral therapy (HAART) initiated during acute or early HIV infection. METHODS: Reasons for first modifications of HAART regimens were recorded using the AIDS Clinical Trials Group form among 363 subjects who initiated HAART within 1 year of seroconversion from 2005 in the Acute Infection and Early Disease Research Program. Modifications recorded as due to "patient choice" or "physician choice" were clarified by query to the recording site. Times to events were analyzed by Kaplan-Meier methods; significance of differences was assessed by the log-rank test. RESULTS: Two hundred five of 363 (56%) subjects modified therapy, at a median of 425 days after initiation, by changing drugs, discontinuing treatment, or removing or adding drugs. Most modifications were attributed to toxicity (n = 105, 51%), most of which was low grade; regimen simplification (n = 18, 5%); and achievement of viral suppression (n = 15, 7%). Time to first modification was shorter for those with shorter time from infection to initiation (P = 0.005) and those having higher CD4 lymphocyte count at initiation (P = 0.06). Modifications occurred sooner in subjects receiving regimens taken more than once daily (P < 0.001) or with more than 2 pills daily (P < 0.001). Most regimens were nonnucleoside reverse transcriptase inhibitor based or protease inhibitor based, and these did not differ significantly in rate and timing of modification. CONCLUSIONS: HAART initiated early in HIV infection was modified in the majority of cases, usually due to minor toxicities whose incidence was similar for protease inhibitor-based and nonnucleoside reverse transcriptase inhibitor-based regimens. Convenience of regimens (lower pill burden and dosing frequency) was associated with a lower rate of modification.

A phase I/II study of nevirapine for pre-exposure prophylaxis of HIV-1 transmission in uninfected subjects at high risk.

OBJECTIVE: To evaluate the safety, tolerability, and trough levels of three pre-exposure prophylaxis regimens of nevirapine among HIV-1-uninfected subjects at high risk for HIV-1 infection. METHODS: A phase I/II trial (HIVHOP 101) in which 33 such uninfected subjects received a 200 mg tablet of nevirapine once weekly (cohort A, n = 12), twice weekly (cohort B, n = 12), or every other day (cohort C, n = 9) for 12 weeks. Clinical signs/symptoms, laboratory parameters, and nevirapine trough levels were assessed at entry and at 1, 2, 4, 6, 9, and 12 weeks, with a follow-up sample at 16 weeks. RESULTS: No subject experienced clinical symptoms attributed to nevirapine, including rash. There were no significant changes in liver enzyme levels from baseline to week 12 in the three cohorts, except for glutamyl transpeptidase in cohort B. Median nevirapine trough levels at weeks 1 and 12 were 119 ng/ml (range, < 25-205) and 135 ng/ml (range, < 25-1065), respectively, for cohort A, 569 ng/ml (range, 135-2641) and 431 ng/ml (range, 42-2454) for cohort B, and 1942 ng/ml (range, 1214-2482) and 943 ng/ml (range, 262-5281) for cohort C. No subject became HIV-1 antibody positive by week 16. CONCLUSIONS: A single dose of nevirapine taken once weekly, twice weekly, or every other day for 12 weeks was safely tolerated by the subjects in this small study, and resulted in nevirapine levels well above the IC (inhibitory concentration of 50%: 10 ng/ml) over the 12-week period in nearly all evaluable subjects. (50)