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.
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
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.