Seroreversion in Patients Receiving Antiretrovirals During Early HIV Infection

Abstract & 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, Section Editor, HIV, is Associate Editor for Infectious Disease Alert.

Dr. Winslow is a consultant for Bayer Diagnostics and Pfizer/Agouron, and is on the speaker's bureau for Pfizer/Agouron.

Synopsis: All 5 patients who had seroreversion and eventually stopped ART experienced virologic rebound and antibody evolution.

Source: Hare CB, et al. Seroreversion in Subjects Receiving Antiretroviral Therapy during Acute/Early HIV Infection. Clin Infect Dis. 2006;42:700-708.

This paper from the Gladstone Institute at the University of California, San Francisco represents a substudy of intensively studied patients who were enrolled in the Options Project. This study enrolled patients within the first 12 months of HIV infection using a variety of criteria to define the approximate time of infection, and included both acutely infected patients (with negative/indeterminate antibody tests) and early infection (those who were antibody positive at the time of study entry). Patients chosen for this retrospective sub-study were those who initiated ART within 28 days of study enrollment and maintained an undetectable HIV RNA level for at least 24 weeks while receiving continuous ART. A battery of anti-HIV antibody tests was used to evaluate serial specimens. These included 2 second generation viral lysate-based ELISA's, a recombinant peptide HIV-1/HIV-2 EIA, and a third generation peptide-based HIV-1/HIV-2 EIA. Two different anti-HIV-1 Western blot assays and a detuned anti-HIV ELISA assay were evaluated as well. In addition, cellular immune responses to various HIV-1 peptide antigens were assessed using an ELISPOT assay which measures IFN-gamma production by antigen-specific CD4+ and CD8+ T cells.

As summarized above, only 12 patients likely had acute HIV infection as defined by a negative second generation anti-HIV EIA at screening, and all seroconverted, although one unequivocally seroconverted only on a third generation recombinant peptide-based assay. Six patients out of the entire cohort of initially seronegative and seropositive patients seroreverted by at least one EIA test while receiving ART. Five of the 6 patients who seroreverted stopped ART; all of these patients experienced virologic rebound and subsequent antibody evolution. Cytotoxic T lymphocyte responses to HIV gag peptides were detected in 4 of the 5 seroreverters who were tested.

Commentary

This paper is of interest for 2 reasons: It has implications for diagnosis of HIV infection, and it has interest from a pathogenesis standpoint on ART of acute/early HIV infection.

Due to the not infrequent referral of HIV-uninfected patients to the public hospital HIV clinic where I work in San Jose, it is our standard procedure to confirm with anti-HIV EIA and Western blot all new patients referred to our clinic, regardless of treatment status. Although clearly rare, the well-documented seroreversion (to second generation anti-HIV EIAs) described in this paper of 7% of patients who received ART for acute/early HIV infection could result in patients falling out of care or transmitting HIV to others while believing they were HIV-negative. While it would be wrong to suggest changing the current HIV testing algorithm (where EIA precedes confirmatory testing with Western blot), this rarely demonstrated cause of false-negative anti-HIV EIA results needs to be excluded by history (of ART for acute/early HIV infection) and brought to the attention of an attending physician so either a third generation EIA or Western blot can be ordered. It is of note that all 6 of the seroreverting patients retained at least equivocal antibody reactivity to gp160 at all time points studied. Again, it remains inappropriate to order Western blot assays routinely on EIA-negative patients since as many as one-third of normal healthy blood donors will have an indeterminate Western blot (usually with gag reactivity).1 It is also important to point out that routine ordering of HIV RNA by either RT-PCR or bDNA is also inappropriate since low-titer, false-positive HIV RNA levels are also commonly seen.

From a pathogenesis perspective, this study is interesting. It has been postulated that early institution of ART in patients with acute/early HIV infection may prove beneficial in by restricting viral evolution2 and, potentially, decrease the rate of disease progression.3,4 While this hypothesis remains unproven and should be tested in larger prospective randomized controlled trials, this study does show that the benefits of this approach appear to be limited since all seroreverting patients who discontinued ART experienced virologic rebound and antibody evolution once antiretrovirals were stopped.

References

  1. Tribe DE, et al. Antibodies Reactive with Human Immunodeficiency Virus Gag-Coded Antigens (Gag Reactive Only) are a Major Cause of Enzyme-Linked Immunosorbent Assay Reactivity in a Blood Donor Population. J Clin Microbiol. 1988;26:641-647.
  2. Altfeld M, et al. Cellular Immune Responses and Viral Diversity in Individuals Treated During Acute and Early HIV-1 Infection.J Exp Med. 2001;193:169-180.
  3. Mellors JW, et al. Quantitation of HIV-1 RNA in Plasma Predicts Outcome After Seroconversion. Ann Int Med. 1995;122:573-579.
  4. Smith D, et al. Virological and Immunological Effects of Combination Antiretroviral Therapy with Zidovudine, Lamivudine, and Indinavir During Primary Human Immunodeficiency Virus Type 1 Infection. J Infect Dis. 2000;182: 950-954.