There continues to be tremendous interest in the study of individuals identified during the first weeks to months of HIV infection -- the so-called acute or primary infection phase. This includes defining early pathologic events as well as issues surrounding HIV transmission and the potential utility of antiretroviral treatment during this stage of disease. A major reason for the intense interest surrounding the acute infection period is the fact that this stage of disease is a virologically and immunologically dynamic time. A symposium presented at the Interscience Conference on Antimicrobial Agents and Chemotherapy included presentations by leaders in the field who provided an overview of the pathogenesis and treatment of primary HIV infection.

Mario Roederer from the Vaccine Research Center of the U.S. National Institutes of Health described data assessing early events of HIV infection in a non-human primate model.¹ His data show that within the first two weeks of infection, there is a massive and largely irreversible loss of memory CD4+ T cells in mucosal lymphoid tissue, a region that accounts for a large proportion of the total-body CD4+ T-lymphocyte pool. Roederer further showed that most of this loss could be accounted for by direct viral infection of these tissues, with upwards of 50% of memory CD4+ T cells in the mucosal lymphoid compartment being infected during the first weeks of infection. He noted that in animal models, the pathogenic effect of early infection occurs long before anyone could hope to identify the presence of acute infection in humans. Roederer then demonstrated that the level of CD4+ T-cell loss in the mucosa predicts immunologic outcomes in the animal model, arguing that if these observations can be extrapolated to humans, an intervention would need to occur pre-exposure, such as with a vaccine. Roederer then supported this hypothesis using data from recent vaccine studies of non-human primates that did indeed demonstrate a reduction in the loss of CD4+ T cells in immunized animals.

Marty Markowitz from the Aaron Diamond AIDS Research Center in New York presented related studies performed in humans who were identified as having primary infection.² He emphasized that it is not possible to study early infection in individuals at the very early time points achieved in non-human primates. Nevertheless, Markowitz was able to show that studies of mucosal tissue in humans with primary infection largely parallel the results seen in animal models. He further demonstrated that reconstitution of this compartment with combination antiretroviral therapy is incomplete.

Susan Little, from the University of California, San Diego, presented data on the rationale for and potential utility of early antiretroviral treatment in humans presenting with primary HIV infection.³ She stated that the rationale for treatment is to prevent or reverse the pathologic effects of infection, preserve CD4+ T cells in blood, reduce transmission and preserve HIV-specific immune responses that might allow for withdrawal of therapy. It was emphasized that much of the early immunologic loss occurs before therapy can be initiated, and there is little evidence that early treatment prevents this damage or enhances the likelihood of immunologic reconstitution.

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Image by Susan J. Little, M.D.; reprinted with permission. Click here to download the complete poster.

Little presented additional data on the prevalence and importance of transmitted drug-resistant virus and the incidence of superinfection. Published data from the Acute Infection and Early Disease Research Program (AIEDRP) revealed that HIV superinfection following primary infection occurred at a rate of 5.0% per year (95% confidence interval: 1.7%-13.3%) among a group of 78 treatment-naive individuals.⁴ All three of the superinfected individuals were male and were likely exposed through homosexual behaviors. These data highlight that infection with HIV does not necessarily protect against dual infection with another HIV subtype.

One unpublished AIEDRP data set presented by Little showed that 50% of individuals who chose to defer therapy had their CD4+ cell count decline to less than 350 cells/mm³ within the first 1.8 years from the estimated date of infection. Little also showed that the group that did choose to start treatment had a high level of success, with only 13% experiencing virologic failure in the first three years of treatment. Nevertheless, it was emphasized that there is no definitive clinical trial demonstrating clinical benefits associated with early therapy.

Recently published data from the AIEDRP cohort analyzed outcomes in individuals with primary HIV infection who started and then later stopped antiretroviral treatment.⁵ These individuals were compared with a contemporary, non-randomized control group that did not start therapy at the time they were diagnosed with acute infection. Plasma HIV-RNA levels were lower at weeks 24, 48 and 72 for patients who initiated and stopped early treatment in comparison with those who did not start treatment, even after adjusting for baseline viral levels and CD4+ cell count. Viral load reductions were the greatest and best sustained in those who started treatment prior to antibody seroconversion as opposed to those treated after seroconversion, but within the first six months of infection. Little did emphasize that the numbers for this study were small, it was not a randomized trial, and the plasma HIV-RNA differences, although significant, were modest (~0.5 log₁₀ copies/mL). Moreover, the results conflict with other related studies. Appropriately, her conclusions were that the role of antiretroviral therapy during primary HIV infection needs further study and that no definitive recommendations can be made as of yet.

As mentioned above, it has become increasingly clear that acute HIV infection represents a highly dynamic stage of disease in which considerable immunologic damage occurs. It also appears to be a time during which the risk of HIV transmission is increased, which, at the very least, illustrates the need to diagnose people as early as possible in order to provide counseling to prevent transmission. However, the ability of antiretroviral treatment during the primary HIV infection stage to mitigate immunologic damage, reduce the risk of transmission and/or enhance future control of HIV remains unknown, and remains an area of ongoing research.

Footnotes

1. Roederer M. Pathogenesis of acute HIV-1 infection in non-human primates. In: Program and abstracts of the 46th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 27-30, 2006; San Francisco, Calif. Abstract 560a.

2. Markowitz MH. Pathogenesis of acute HIV-1 infection in humans. In: Program and abstracts of the 46th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 27-30, 2006; San Francisco, Calif. Abstract 560b.

3. Little SJ. Therapy of acute HIV-1 infection: an update. In: Program and abstracts of the 46th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 27-30, 2006; San Francisco, Calif. Abstract 560d.
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4. Smith DM, Wong JK, Hightower GK, et al. Incidence of HIV superinfection following primary infection. JAMA. September 8, 2004;292(10):1177-1178.

5. Hecht FM, Wang L, Collier A, et al, for the AIEDRP Network. A multicenter observational study of the potential benefits of initiating combination antiretroviral therapy during acute HIV infection. J Infect Dis. September 15, 2006;194(6):725-733.