TAG HIV Basic Science, Vaccines, and Cure Project Blog

Case Report Suggests Antiretroviral Prophylaxis May Have Attenuated HIV Infection

Several large trials are now underway exploring the efficacy of either tenofovir (Viread) or a tenofovir/emtricabine combination pill (Truvada) as pre-exposure prophylaxis (PrEP) to protect against HIV infection. Concerns have been raised regarding what might happen to people who become infected despite the drugs, particularly in terms of the development of resistance. A new case report just published in the Journal of AIDS by Nicole Prada and colleagues from the Aaron Diamond AIDS Research Center suggests that Truvada might have attenuated HIV infection in an individual receiving the drug for post-exposure prophylaxis (PEP), without causing resistance.

The individual involved was prescribed a four-week course of Truvada as PEP due to high risk sexual activity; this was then extended for two weeks after additional possible exposures were reported. After a three-week break, another four-week course was prescribed subsequent to additional exposures. HIV antibodies began to become detectable during the second course of PEP, but evolved very slowly over several months. The viral load at time of diagnosis was 213 copies and, after stopping the second course of PEP, viral load measured 647 copies and has remained around that level during follow-up. It is uncertain whether HIV infection was acquired prior to or during the first course of PEP; it is not thought to have occurred during the three week break from Truvada. Importantly, no mutations associated with resistance to either tenofovir or emtricabine could be detected. The researchers investigated whether the individual possessed any of the most common host factors known to be associated with slowed disease progression, including heterozygosity for the CCR5 delta32 mutation and possession of HLA B57 or B27; none of these factors were present (although the authors note that this was not an exhaustive analysis). The study authors suggest that this case report may offer hope that PrEP can attenuate HIV replication in individuals who experience breakthrough infections, conceivably impacting both the health of the individual and also reducing the possibility of onward transmission.

JAIDS Journal of Acquired Immune Deficiency Syndromes. September 2, 2008, Publish Ahead of Print

Drug-Susceptible HIV-1 Infection Despite Intermittent Fixed-Dose Combination Tenofovir/Emtricitabine as Prophylaxis Is Associated With Low-Level Viremia, Delayed Seroconversion, and an Attenuated Clinical Course.

Rapid Communication

Prada, Nicole PhD; Davis, Brandi BS; Jean-Pierre, Patrick MS; Roche, Matthew La BS; Duh, Fuh-Mei MS; Carrington, Mary PhD; Poles, Michael MD; Mehandru, Saurabh MD; Mohri, Hiroshi MD, PhD; Markowitz, Martin MD

Abstract:

Background: Continued high rates of HIV-1 transmission have fueled interest in the use of antiretrovirals to prevent infection. Attenuated infection with failure of tenofovir as prophylaxis has been reported in animal models. Here, we report a case of HIV-1 infection despite intermittent use of fixed-dose combination tenofovir and emtricitabine (FTC).

Methods: The patient was treated with tenofovir DF/FTC for reported repeated high-risk sexual exposures. After seroconversion, he was subjected to routine laboratory testing, CCR5 and HLA genotyping, and biopsy of gastrointestinal (GI) tissue. Resistance testing was performed both as bulk sequencing of plasma and cloning and sequencing of virus derived from plasma, peripheral blood mononuclear cells, and GI tissue.

Results: In this patient with no readily identifiable modifying host factors, acute HIV-1 infection with tenofovir DF/FTC-susceptible HIV-1 was associated with an attenuated clinical course, very low postseroconversion HIV-1 RNA levels, slow kinetics of seroconversion, and relative sparing of mucosal CD4+ T cells in the GI tract.

Conclusions: Despite the failure of tenofovir DF/FTC as prophylaxis, selection for drug-resistant transmission did not occur and the blunting of postinfection levels of viremia likely reduced the probability of subsequent forward transmissions during the acute phase. These results support continued investigations of the use of antiretrovirals as a means to reduce HIV-1 transmission.

Tenofovir Gel as a Rectal Microbicide: Evidence for Protection and Priming of T Cell Responses in the SIV Challenge Model

The new PLoS Medicine features a study conducted by Martin Cranage and colleagues evaluating tenofovir gel as a potential rectal microbicide in the SIV challenge model. The researchers report that application of the gel two hours prior to exposure to the SIVmac251/32H challenge virus protected six out of nine macaques. Of the remaining three, two showed lowered viral loads post-infection compared to controls. Interestingly, most of the protected animals also displayed detectable SIV-specific T cell responses even though sensitive assays could find no trace of virus.

The PLoS editor’s summary raises the concern that these SIV-specific T cells may be associated with enhanced susceptibility to infection upon re-exposure; however, Cranage et al note in their discussion that transient tenofovir treatment immediately post SIV infection has been shown to lead to induction of SIV-specific T cell responses, and macaques in this study subsequently resisted both homologous and heterologous SIV challenges. The question of whether the SIV-specific T cell responses observed in Cranage’s study have the potential to be protective can only be definitively addressed by another experiment in which the macaques are re-challenged with SIV.

An additional implication of these data is that human trials of microbicides and pre-exposure prophylaxis (PrEP) should include monitoring for HIV-specific T cell responses.

PLoS Medicine Vol. 5, No. 8, e157 doi:10.1371/journal.pmed.0050157

Prevention of SIV Rectal Transmission and Priming of T Cell Responses in Macaques after Local Pre-exposure Application of Tenofovir Gel

Martin Cranage1*, Sally Sharpe2, Carolina Herrera1, Alethea Cope1, Mike Dennis2, Neil Berry3, Claire Ham3, Jonathan Heeney4,5, Naser Rezk6, Angela Kashuba6, Peter Anton7, Ian McGowan7¤, Robin Shattock1

1 Centre for Infection, Division of Cellular & Molecular Medicine, St George's University of London, London, United Kingdom, 2 Centre for Emergency Preparedness and Response, Health Protection Agency, Porton Down, Salisbury, United Kingdom, 3 Division of Retrovirology, National Institute for Biological Standards & Control, South Mimms, United Kingdom, 4 Department of Virology, Biomedical Primate Research Centre, Rijswijk, The Netherlands, 5 Department of Veterinary Medicine, University of Cambridge, Cambridge, United Kingdom, 6 University of North Carolina Centers for Aids Research (CFAR) Clinical Pharmacology and Analytical Chemistry Core, Chapel Hill, North Carolina, United States of America, 7 Center for Prevention Research, David Geffen School of Medicine at the University of California Los Angeles (UCLA), Los Angeles, California, United States of America

Background

The rectum is particularly vulnerable to HIV transmission having only a single protective layer of columnar epithelium overlying tissue rich in activated lymphoid cells; thus, unprotected anal intercourse in both women and men carries a higher risk of infection than other sexual routes. In the absence of effective prophylactic vaccines, increasing attention is being given to the use of microbicides and preventative antiretroviral (ARV) drugs. To prevent mucosal transmission of HIV, a microbicide/ARV should ideally act locally at and near the virus portal of entry. As part of an integrated rectal microbicide development programme, we have evaluated rectal application of the nucleotide reverse transcriptase (RT) inhibitor tenofovir (PMPA, 9-[(R)-2-(phosphonomethoxy) propyl] adenine monohydrate), a drug licensed for therapeutic use, for protective efficacy against rectal challenge with simian immunodeficiency virus (SIV) in a well-established and standardised macaque model.

Methods and Findings

A total of 20 purpose-bred Indian rhesus macaques were used to evaluate the protective efficacy of topical tenofovir. Nine animals received 1% tenofovir gel per rectum up to 2 h prior to virus challenge, four macaques received placebo gel, and four macaques remained untreated. In addition, three macaques were given tenofovir gel 2 h after virus challenge. Following intrarectal instillation of 20 median rectal infectious doses (MID50) of a noncloned, virulent stock of SIVmac251/32H, all animals were analysed for virus infection, by virus isolation from peripheral blood mononuclear cells (PBMC), quantitative proviral DNA load in PBMC, plasma viral RNA (vRNA) load by sensitive quantitative competitive (qc) RT-PCR, and presence of SIV-specific serum antibodies by ELISA. We report here a significant protective effect (p = 0.003; Fisher exact probability test) wherein eight of nine macaques given tenofovir per rectum up to 2 h prior to virus challenge were protected from infection (n = 6) or had modified virus outcomes (n = 2), while all untreated macaques and three of four macaques given placebo gel were infected, as were two of three animals receiving tenofovir gel after challenge. Moreover, analysis of lymphoid tissues post mortem failed to reveal sequestration of SIV in the protected animals. We found a strong positive association between the concentration of tenofovir in the plasma 15 min after rectal application of gel and the degree of protection in the six animals challenged with virus at this time point. Moreover, colorectal explants from non-SIV challenged tenofovir-treated macaques were resistant to infection ex vivo, whereas no inhibition was seen in explants from the small intestine. Tissue-specific inhibition of infection was associated with the intracellular detection of tenofovir. Intriguingly, in the absence of seroconversion, Gag-specific gamma interferon (IFN-γ)-secreting T cells were detected in the blood of four of seven protected animals tested, with frequencies ranging from 144 spot forming cells (SFC)/106 PBMC to 261 spot forming cells (SFC)/106 PBMC.

Conclusions

These results indicate that colorectal pretreatment with ARV drugs, such as tenofovir, has potential as a clinically relevant strategy for the prevention of HIV transmission. We conclude that plasma tenofovir concentration measured 15 min after rectal administration may serve as a surrogate indicator of protective efficacy. This may prove to be useful in the design of clinical studies. Furthermore, in vitro intestinal explants served as a model for drug distribution in vivo and susceptibility to virus infection. The finding of T cell priming following exposure to virus in the absence of overt infection is provocative. Further studies would reveal if a combined modality microbicide and vaccination strategy is feasible by determining the full extent of local immune responses induced and their protective potential.

Tenofovir/FTC Combo Protects Macaques Against SHIV Infection

At the Conference on Retroviruses and Opportunistic Infections in Denver today, a presentation by CDC researcher Walid Heinene at showed that a combination of injected antiretroviral drugs (tenofovir and FTC, commercially available in pill form as Truvada) protected macaques against infection with an HIV/SIV hybrid called SHIV162p3. The study used a series of weekly low dose intrarectal challenges with SHIV162p3 which, unlike other available SHIVs, mimics primary HIV isolates in that it utilizes the CCR5 co-receptor to gain entry into CD4 T cells. Six macaques received once daily injections of tenofovir and FTC while six animals served as controls. Four controls became infected after four challenges (5/6 controls were infected by the 10th challenge) while none of the recipients of tenofovir/FTC became infected even after 14 challenges. The results were highly statistically significant. Heinene noted that the dose of FTC used in the trial was considered equivalent to that used in humans, but that the dose of tenofovir was "somewhat higher." A seperate ongoing study is evaluating FTC alone and Heinene reported that of the six macaques in that study, one became infected after five challenges and another after 10. So while FTC alone is less effective, it still offered statistically significant protections against SHIV162p3 challenge and is thus thought to have contributed to the complete protection seen in the tenofovir/FTC combination study. Heinene also noted that the animal in the FTC study that became infected after five weeks displayed a viral load peak that was three logs lower than that seen in controls. There was also no sign of FTC resistance in this animal. Follow up of this study continues. The results offer hope that Pre-Exposure Prophylaxis (or PreP) may be a feasible means of preventing HIV infection in humans. A number of studies of tenofovir PreP are ongoing and these data are likely to generate interest in conducting studies using Truvada.

This story was picked up by Maggie Fox at Reuters.