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Continuous versus intermittent treatment strategies during primary HIV-1 infection: the randomized ANRS INTERPRIM Trial
Global Health Sciences Literature Digest
Published September 7, 2012
Journal Article

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.

Objective

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).

Setting

Multicenter study conducted in France.

Study Design

Randomized controlled trial.

Population

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.

Main Outcome Measures

Mean plasma HIV-RNA level 20 and 24 weeks after the last treatment interruption (weeks 92 and 96).

Methods

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.

Results

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).

Conclusions

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.

Risk of Bias

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.

In Context

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.

Programmatic Implications

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.

References

  1. Markowitz M, Jin X, Hurley A, et al. Discontinuation of antiretroviral therapy commenced early during the course of human immunodeficiency virus type 1 infection, with or without adjunctive vaccination. J Infect Dis 2002; 186:634-43.
  2. Hoen B, Cooper DA, Lampe FC, et al. Predictors of virological outcome and safety in primary HIV type 1-infected patients initiating quadruple antiretroviral therapy: QUEST GW PROB3005. Clin Infect Dis 2007; 45:381-90.
  3. Goujard C, Marcellin F, Hendel-Chavez H, et al. Interruption of antiretroviral therapy initiated during primary HIV-1 infection: impact of a therapeutic vaccination strategy combined with interleukin (IL)-2 compared with IL-2 alone in the ANRS 095 Randomized Study. AIDS Res Hum Retroviruses 2007; 23:1105-13.
  4. Lampe FC, Porter K, Kaldor J, Law M, Kinloch-de Loes S, Phillips AN. Effect of transient antiretroviral treatment during acute HIV infection: comparison of the Quest trial results with CASCADE natural history study. Antivir Ther 2007; 12:189-93.
  5. Lewin SR, Murray JM, Solomon A, et al. Virologic determinants of success after structured treatment interruptions of antiretrovirals in acute HIV-1 infection. J Acquir Immune Defic Syndr 2008; 47:140-47.
  6. Kaufmann DE, Lichterfeld M, Altfeld M, et al. Limited durability of viral control following treated acute HIV infection. PLoS Med 2004; 1:e36.
  7. Desquilbet L, Goujard C, Rouzioux C, et al. Does transient HAART during primary HIV-1 infection lower the virological set-point? AIDS 2004; 18:2361-69.
  8. Emilie D, Burgard M, Lascoux-Combe C, et al. Early control of HIV replication in primary HIV-1 infection treated with antiretroviral drugs and pegylated IFN alpha: results from the Primoferon A (ANRS 086) Study. AIDS 2001; 15:1435-1437.