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Combination emtricitabine and tenofovir disoproxil fumarate prevents vaginal SHIV infection in macaques harboring C. trachomatis and T. vaginalis
 
 
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"PrEP with FTC/TDF is a novel HIV prevention strategy that was approved by the FDA in 2012. Although studies have generally shown that drug concentrations are highly predictive of protection [1], it is not known if the efficacy of PrEP can be diminished in subpopulations at higher risk of HIV infection due to, for instance, co-infection with other STIs. Chlamydia trachomatis (CT) and Trichomonas vaginalis (TV) are among the most prevalent STIs and have been associated with an increased risk of HIV acquisition in women.Given the difficulty of addressing this question clinically, during trials or PrEP implementation, alternative experimental approaches such as animal models may help assess the effect of STIs on PrEP under well-controlled experimental conditions. Here we integrated a repeat exposure macaque SHIV transmission model with a model of co-infection with CT and TV to assess potential effects of CT/TV on PrEP with FTC/TDF."
 
Abstract
 
Genital inflammation associated with STIs increases susceptibility to HIV but it is unclear if the increased risk can reduce the efficacy of pre-exposure prophylaxis (PrEP). We investigated if co-infection of macaques with Chlamydia trachomatis and Trichomonas vaginalis decreases the prophylactic efficacy of oral FTC/TDF. Macaques were exposed to SHIV vaginally each week for up to 16 weeks and received placebo or FTC/TDF peri-coitally. All placebos were infected with SHIV while 4/6 PrEP-treated animals remained uninfected (p=0.03). Oral FTC/TDF maintains efficacy in a macaque model of STI coinfection, although the infection of 2 macaques signals a modest loss of PrEP activity.........
 
"After 16 SHIV challenges, only 2/6 PrEP-treated animals (DC42 and BB495) were infected while all 5 placebo controls were infected after a median of 2 SHIV exposures (Figure 1B). Infection in PrEP-treated macaques was significantly less likely than in animals receiving placebo (p=0.03). Based upon infection rates per exposure, the efficacy of FTC/TDF in STI-infected macaques (91% [95% CL=56.3-98.7]) was not different to that previously seen in animals that also received FTC/TDF PrEP but were not co-infected with STIs (100% [95% CL=54.1-100]; p=0.69, conditional logistic regression model 2-way interaction term) [3].....Absolute SHIV RNA levels in vaginal and rectal secretions were reduced in PrEP breakthrough infections compared to placebo (p=0.02 and p=0.03, respectively)...
 
In summary, we show that a peri-coital FTC/TDF regimen is effective in macaques co-infected with CT/TV, although the infection of two animals signals a modest loss of PrEP activity. Our analysis suggests a possible role for inflammation and cellular activation in PrEP failure, and highlights the need for further studies with other STIs to better define potential modulations of PrEP activity.
 
Although the protection conferred by FTC/TDF was statistically significant, two of the macaques became infected with SHIV during PrEP .......Although CT/TV are non-ulcerative, they can induce cervical petechiae while Chlamydia can also cause mucosal perturbations such as cervical erosion or ectropion [13, 14]. Disruptions in tissue integrity may potentially facilitate virus entry and access to target cells in the lamina propria. Unfortunately, our study design did not incorporate colposcopic evaluations to understand if more severe clinical signs of STI infection might account for the two PrEP breakthrough infections. Infection of these animals might be related to tissue inflammation and recruitment and activation of HIV target cells due to CT/TV infection, which may provide an expanded source of highly permissive cells that may be harder to protect by PrEP. Elevated dATP and dCTP concentrations in vaginal tissues supports cellular activation which may have reduced but not eliminated the antiviral activity of TFV-DP and FTC-TP given the observed reduction in SHIV shedding."
 
BACKGROUND
 
PrEP with FTC/TDF is a novel HIV prevention strategy that was approved by the FDA in 2012. Although studies have generally shown that drug concentrations are highly predictive of protection [1], it is not known if the efficacy of PrEP can be diminished in subpopulations at higher risk of HIV infection due to, for instance, co-infection with other STIs. Chlamydia trachomatis (CT) and Trichomonas vaginalis (TV) are among the most prevalent STIs and have been associated with an increased risk of HIV acquisition in women [2]. Both STIs can modulate local immune factors and cause an influx of immune cells to the vaginal mucosa. These biological changes likely contribute to the increased HIV risk and also raise questions about their effect on the effectiveness of PrEP. For instance, a high density of immune cells at the vaginal mucosa might conceivably require more drug coverage of susceptible target cells and alter drug protection thresholds. Likewise, cellular activation increases intracellular dNTP concentrations which could reduce the antiviral activity of FTC-TP and TFV-DP.
 
The effect of CT/TV on PrEP in women cannot accurately be assessed from subgroup analysis in clinical trials because baseline prevalence of CT/TV infection is generally low and participants are frequently tested and treated for their STIs. Given the difficulty of addressing this question clinically, during trials or PrEP implementation, alternative experimental approaches such as animal models may help assess the effect of STIs on PrEP under well-controlled experimental conditions. Here we integrated a repeat exposure macaque SHIV transmission model with a model of co-infection with CT and TV to assess potential effects of CT/TV on PrEP with FTC/TDF.

 
 
 
 
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