Goujard C, Emilie D, Roussillon C, et al. Continuous versus intermittent treatment strategies during primary HIV-1 infection: the randomized ANRS INTERPRIM Trial. AIDS. 2012 Aug 7.
To assess whether fixed-cycles of antiretroviral treatment interruption (ART-STI) combined or not with pegylated interferon alpha-2b (peg-IFN) could lower viral load and achieve healthier immune system in patients diagnosed during primary HIV-1-infection (PHI).
Multicenter study conducted in France.
Randomized controlled trial.
Patients with primary HIV-1 infection, defined by a detectable plasma HIV-RNA and a negative or incomplete Western-blot (≤3 bands). Patients with co-infection by hepatitis B or C virus, with a history of autoimmune or blood disease, or with any contraindication to IFN were not included. Ninety-one percent of participants were men, with a median age of 34 years; 72% of them were infected through homosexual contacts. All patients except three presented with symptoms.
Mean plasma HIV-RNA level 20 and 24 weeks after the last treatment interruption (weeks 92 and 96).
Patients were randomized to receive (1) continuous antiretroviral therapy (ART) for 72 weeks or (2) ART for 36 weeks followed by three 4-week sequential treatment interruptions (at weeks 36-40, 48-52 and 60-64) or ART for 36 weeks followed by three 4-week sequential treatment interruptions (at weeks 36-40, 48-52 and 60-64) with subcutaneous peg IFN 1.0 µg/kg/week during weeks 0-13 and at weeks 38-40, 50-52 and 62-42 (3 doses during every sequential treatment interruption). Individual investigators decided on what ART regimen to use.
Ninety-one patients were randomized. Median HIV-RNA was 5.7 log10 copies/mL. ART was initiated within a median time of 38 days from infection. The majority of patients (84%) began ART with two nucleoside reverse transcriptase inhibitors and one ritonavir-boosted protease inhibitor. Six months after the last sequential treatment interruption, median HIV-RNA did not differ between groups: 4.3 log10 copies/mL (interquartile range [IQR], 3.7-4.6) in the continuous ART group, 3.9 log10 copies/mL (IQR, 3.2-4.6) in the sequential treatment interruption group that did not receive peg IFN and 3.9 log10 copies/mL (IQR, 3.2-4.4) in group that received peg IFN. The median delay between the final ART interruption and the first HIV-RNA >400 copies/mL did not differ among groups. Four patients maintained undetectable HIV-RNA levels at week 96 (one from the structure treatment interruption group and three from the peg IFN group).
Eighty-seven percent of patients had undetectable HIV-RNA at 32 weeks with no differences among the three arms. However, participants in all three arms had significant rebound, on the order of 10,000 copies/mL, and none of the strategies was associated with significant differences among viral set points at the end of the trial.
How allocation was made and whether it was concealed or not were not stated in the report. The study was unblinded but had biological endpoints (plasma viral load). All outcomes were reported, and there was no evidence of selective outcome reporting or other potential sources of bias. Overall the risk of bias was moderate, largely because of lack of clarity about allocation.
Primary HIV infection is a time of intensive viral replication and shedding in which HIV is seeded through the body and a viral "set-point", or viral load after the period of primary infection is over, is established. A high viral set point is associated with more rapid progression to clinical disease and immunologic failure. Several studies have attempted to lower the viral set point with early ART, which is then subsequently discontinued,(1, 2, 3, 4, 5, 6, 7) but results have been mixed with beneficial effects not sustained in the majority of individuals. The intervention in this study was based on observations that suggested that IFN given together with ART could rapidly control HIV 4 replication and induce a rapid decay of the HIV reservoir.(8) Unfortunately, in all three treatment arms, HIV began replication soon after treatment was discontinued at 72 weeks.
Given the rapid reemergence of HIV replication following completion of treatment, strategies to contain residual HIV replication will likely have to focus on continuous therapy for life without discontinuation following initial treatment. This is consistent with current proposed strategies to "test and treat" all infected individuals as soon as they are diagnosed.
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