Genital inflammation undermines the effectiveness of tenofovir gel in preventing HIV acquisition in women

McKinnon, Lyle R.; Liebenberg, Lenine J.; Yende‐Zuma, Nonhlanhla; Archary, Derseree; Ngcapu, Sinaye; Sivro, Aida; Nagelkerke, Nico; Lerma, J. Gerardo García; Kashuba, Angela D. M.; Masson, Lindi; Mansoor, Leila E.; Karim, Quarraisha Abdool; Karim, Salim S. Abdool; Passmore, Jo‐Ann S.

doi:10.1038/nm.4506

Cited by 110 publications

(113 citation statements)

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“…There may also be beneficial effects of using PrEP along with an anti-inflammatory drug. A recent study from McKinnon et al showed that genital inflammation among African women using anti-HIV drug tenofovir in a vaginal gel reduced the effectiveness of the HIV prevention approach from 57% to 3% [22]. If vaginal inflammation can be reduced it may actually aid other prevention approaches.…”

Section: Discussionmentioning

confidence: 99%

Using safe, affordable and accessible non‐steroidal anti‐inflammatory drugs to reduce the number of HIV target cells in the blood and at the female genital tract

et al. 2018

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IntroductionAt its basic level, HIV infection requires a replication‐competent virus and a susceptible target cell. Elevated levels of vaginal inflammation has been associated with the increased risk of HIV infection as it brings highly activated HIV target cells (CCR5+CD4+ T cells; CCR5+CD4+CD161+ Th17 T cells) to the female genital tract (FGT) where they interact with HIV. Decreased HIV risk has been associated with a phenotype of decreased immune activation, called immune quiescence, described among Kenyan female sex workers who were intensely exposed to HIV yet remain uninfected. Current prevention approaches focus on limiting viral access. We took the novel HIV prevention approach of trying to limit the number of HIV target cells in the genital tract by reducing inflammation using safe, affordable and globally accessible anti‐inflammatory drugs.MethodsWe hypothesized that the daily administration of low doses of acetylsalicylic acid (ASA 81 mg) or hydroxychloroquine (HCQ 200 mg) would reduce inflammation thereby decreasing HIV target cells at the FGT. Low‐risk HIV seronegative women from Nairobi, Kenya were randomized for six weeks therapy of ASA (n = 37) or HCQ (n = 39) and tested to determine the impact on their systemic and mucosal immune environment.ResultsThe results showed that HCQ use was associated with a significant reduction in the proportion of systemic T cells that were CCR5+CD4+ (p = 0.01) and Th17 (p = 0.01). In the ASA arm, there was a 35% and 28% decrease in the proportion of genital T cells that were CD4+CCR5+ (p = 0.017) and Th17 (p = 0.04) respectively. Proteomic analyses of the cervical lavage showed ASA use was associated with significantly reduced amount of proteins involved in the inflammatory response and cell recruitment at the mucosa, although none of the individual proteins passed multiple comparison correction. These changes were more apparent in women with Lactobacillus dominant microbiomes.ConclusionTogether, these data indicate that taking low‐dose ASA daily was associated with significant reduction in HIV target cells at the FGT. This study provides proof‐of‐concept for a novel HIV‐prevention approach that reducing inflammation using safe, affordable and globally accessible non‐steroidal anti‐inflammatory agents is associated with significant reduction in the proportion of HIV‐target cells at the FGT.

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Section: Discussionmentioning

confidence: 99%

Using safe, affordable and accessible non‐steroidal anti‐inflammatory drugs to reduce the number of HIV target cells in the blood and at the female genital tract

et al. 2018

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“…Raised pre‐infection genital concentrations of inflammatory cytokines (macrophage inflammatory protein (MIP)‐1α and MIP‐1β) were present in women who acquired HIV infection compared to women who remained uninfected . These inflammatory changes were associated with elevated levels of highly activated T cells in the genital mucosa and decreased efficacy of the antiretroviral drug tenofovir, which is a reverse transcriptase inhibitor that was assessed for its effectiveness in preventing HIV infections . In rhesus macaques, the establishment of a productive simian immunodeficiency virus (SIV) infection in the genital mucosa required local chemokines, which facilitated recruitment of CD4+ T cells to the site of infection, and enabled SIV expansion and establishment of infection .…”

Section: Introductionmentioning

confidence: 99%

The genital tract and rectal microbiomes: their role in HIV susceptibility and prevention in women

et al. 2019

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Introduction Young women in sub‐Saharan Africa are disproportionately affected by HIV, accounting for 25% of all new infections in 2017. Several behavioural and biological factors are known to impact a young woman's vulnerability for acquiring HIV. One key, but lesser understood, biological factor impacting vulnerability is the vaginal microbiome. This review describes the vaginal microbiome and examines its alterations, its influence on HIV acquisition as well as the efficacy of HIV prevention technologies, the role of the rectal microbiome in HIV acquisition, advances in technologies to study the microbiome and some future research directions. Discussion Although the composition of each woman's vaginal microbiome is unique, a microbiome dominated by Lactobacillus species is generally associated with a “healthy” vagina. Disturbances in the vaginal microbiota, characterized by a shift from a low‐diversity, Lactobacillus ‐dominant state to a high‐diversity non‐ Lactobacillus ‐dominant state, have been shown to be associated with a range of adverse reproductive health outcomes, including increasing the risk of genital inflammation and HIV acquisition. Gardnerella vaginalis and Prevotella bivia have been shown to contribute to both HIV risk and genital inflammation. In addition to impacting HIV risk, the composition of the vaginal microbiome affects the vaginal concentrations of some antiretroviral drugs, particularly those administered intravaginally, and thereby their efficacy as pre‐exposure prophylaxis (PrEP) for HIV prevention. Although the role of rectal microbiota in HIV acquisition in women is less well understood, the composition of this compartment's microbiome, particularly the presence of species of bacteria from the Prevotellaceae family likely contribute to HIV acquisition. Advances in technologies have facilitated the study of the genital microbiome's structure and function. While next‐generation sequencing advanced knowledge of the diversity and complexity of the vaginal microbiome, the emerging field of metaproteomics, which provides important information on vaginal bacterial community structure, diversity and function, is further shedding light on functionality of the vaginal microbiome and its relationship with bacterial vaginosis (BV), as well as antiretroviral PrEP efficacy. Conclusions A better understanding of the composition, structure and function of the microbiome is needed to identify opportunities to alter the vaginal microbiome and prevent BV and reduce the risk of HIV acquisition.

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“…Bacteria possess a variety of enzymatic mechanisms for drug metabolism, including hydrolases, oxidoreductases, lyases, and transferases with established impact on dozens of licensed drugs . Genital inflammation, defined by the presence of pro‐inflammatory cytokines in CVL, was associated with no protective benefit of TFV gel in the CAPRISA 004 study compared to a 75% relative risk reduction in women without genital inflammation . These findings indicate a need for prospective assessment of microbial metabolism of PrEP drug candidates, reassessment of drug concentration‐based adherence measures in trials of topical drugs, and consideration of inflammation as an explanatory variable in future clinical trials.…”

Section: Understanding Heterogeneous Prep Outcomesmentioning

confidence: 99%

HIV Antiretroviral Pre‐Exposure Prophylaxis: Development Challenges and Pipeline Promise

Hendrix

2018

Clin Pharma and Therapeutics

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The US Food and Drug Administration (FDA) approved oral daily tenofovir/emtricitabine (Truvada) for pre-exposure prophylaxis of human immunodeficiency virus (HIV) infection in 2012 on the basis of two randomized controlled trials (RCTs), one in men who have sex with men (MSM) and another in HIV serodiscordant heterosexual couples. Subsequently, even greater efficacy has been demonstrated in MSM with rapid population-level incidence reductions in some locations. In contrast, studies of antiretroviral pre-exposure prophylaxis (PrEP) in heterosexual women showed only modest or no efficacy, largely attributed to low adherence. The mixed results of antiretroviral-based PrEP bear witness to unique drug development challenges at this complicated intersection of sexual behavior, public health, and drug development. Multiple innovative methods and formulation strategies followed to address unmet medical needs of persons struggling with daily oral PrEP adherence or preference for nonsystemic PrEP options. Clinical pharmacology plays essential roles throughout this PrEP development process, especially in early product development and through pharmacologically informed enhancement and interpretation of clinical trials.

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Genital inflammation undermines the effectiveness of tenofovir gel in preventing HIV acquisition in women

Cited by 110 publications

References 38 publications

Using safe, affordable and accessible non‐steroidal anti‐inflammatory drugs to reduce the number of HIV target cells in the blood and at the female genital tract

Using safe, affordable and accessible non‐steroidal anti‐inflammatory drugs to reduce the number of HIV target cells in the blood and at the female genital tract

The genital tract and rectal microbiomes: their role in HIV susceptibility and prevention in women

HIV Antiretroviral Pre‐Exposure Prophylaxis: Development Challenges and Pipeline Promise

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