Antiretrovirals for Acute HIV Infection — Not Ready for Prime Time

Abstracts & Commentary

By Dean L. Winslow, MD, FACP, Chief, Division of AIDS Medicine, Santa Clara Valley Medical Center; Clinical Professor of Medicine, Stanford University School of Medicine. Dr. Winslow is a consultant for Bayer Diagnostics, and is on the speaker's bureau for GlaxoSmithKline and Pfizer.
This article originally appeared in the November 2006 issue of Infectious Disease Alert. It was edited by Stan Deresinski, MD, FACP, and peer reviewed by Connie Price, MD. Dr. Deresinski is Clinical Professor of Medicine, Stanford University; Associate Chief of Infectious Diseases, Santa Clara Valley Medical Center, and Dr. Price is Assistant Professor, University of Colorado School of Medicine. Dr. Deresinski serves on the speaker's bureau for Merck, Pharmacia, GlaxoSmithKline, Pfizer, Bayer, and Wyeth, and does research for Merck. Dr. Price reports no financial relationships relevant to this field of study.

Synopsis: A multicenter, observational study retrospectively compared 59 individuals with acute or early HIV infection who elected to receive antiretroviral (ARV) therapy for 12 weeks to 337 patients who declined treatment. Initiation of ARV treatment within 2 weeks of presumed infection appeared to result in a trend toward higher CD4 counts and lower HIV RNA levels at 24 weeks. In contrast, a prospective trial of 20 patients with acute HIV infection who were randomized to antiretroviral therapy for 24 weeks vs no treatment showed no differences in either CD4 count or HIV RNA between treated and untreated patients 6 months after ARV was stopped.

Sources: Hecht FM, et al. A multicenter observational study of the potential benefits of initiating combination antiretroviral therapy during acute HIV infection. J Infect Dis. 2006;194:725-733; Streeck H, et al. Immunological and virological impact of highly active antiretroviral therapy initiated during acute HIV-1 infection. J Infect Dis. 2006;194:734-739.

The optimal time to initiate antiretroviral therapy (arv) in chronically-infected asymptomatic patients is now felt to be when the CD4+ lymphocyte count falls to approximately 350 cells/uL,1 based on the probability of developing an AIDS-defining illness within a relatively short period of time, as shown in a meta-analysis of cohort studies.2 While evidence clearly supports treatment of chronic infection using these parameters, it remains unknown whether treatment during acute (within 2 weeks of infection) or early (2 weeks- 6 months after infection) HIV infection confers clinical benefit. It has been postulated that ARV therapy, instituted during acute or early infection, can reduce T-cell loss by limiting viral replication prior to activation of significant numbers of T-cells and, possibly, lower the viral set point even after ARVs have been discontinued. While this possible benefit has been widely discussed, only anecdotal, retrospective, cohort studies have suggested that such a benefit of early ARV treatment occurs.

The first study, by Hecht and colleagues, evaluated patients followed in the Acute Infection and Early Disease Research Program cohort who self-selected acute (n = 13) or early (n = 45) ARV treatment for 12 weeks (then stopped), and used the 337 patients who declined treatment as the control group. In the acute treatment group, there was an apparent trend toward higher CD4 counts and lower HIV RNA levels at 72 weeks, only in adjusted analyses. However, looking at the actual scatter plots, the trend is not at all impressive, and relies on some interesting (and creative) statistical methods to draw the lines supporting this conclusion. The unadjusted analyses show no significant benefit of therapy of acute infection. ARV therapy, initiated greater than 2 weeks following infection, was associated with modest, but diminishing CD4 benefit at 72 weeks and no evidence of viral load benefit at the same time point, using adjusted analyses. For all the measures examined, the confidence intervals overlapped considerably. The weak suggestion of benefit of ARV treatment of acute HIV infection is largely negated by the nonrandomized design of the trial, the small number of patients who received treatment, and the fact that very creative statistical methods needed to be used to parse out any suggestion of benefit.

The second study by Streeck and colleagues prospectively assessed 20 patients with acute HIV infection, 12 of whom initiated ARV treatment for 24 weeks then terminated therapy and 8 who did not receive therapy. In the treated group, suppression of viremia, increased CD4 counts, enhanced differentiation of HIV-1-specific CD+ T cells from memory to effector phenotype at week 24, and higher virus-specific interferon-gamma+ CD8+ T cell responses after viral rebound at week 48 were observed. However, no differences in HIV viremia or CD4 counts were found 6 months after discontinuation of ARV's compared to the untreated patients.

While it remains important to diagnose acute HIV infection to prevent the high rate of secondary transmission to sexual contacts of acutely infected individuals, benefits of early institution of antiretroviral therapy in this population appears to have negligible clinical benefits. It would appear that a study large enough and powered adequately to clearly demonstrate any long lasting clinical benefit of ARV therapy in this population would be prohibitively expensive and require years to conduct. My personal opinion is that these resources could be much better applied to providing additional antiretroviral drugs to patients in the developing world.

References

1. Hammer SM, et al. Treatment of adult HIV infection: 2006 recommendations of the International AIDS Society-USA Panel. JAMA. 2006;296:827-843.

2. Egger M, et al. Prognosis of HIV-1 infected patients starting highly active antiretroviral therapy: A collaborative analysis of prospective studies. Lancet. 2002;360:119-129. Erratum in: Lancet. 2002;360:1178.