tenofovir vaginal gel (GS-1278 gel) / Gilead, CONRAD - LARVOL DELTA

Perinatal outcomes associated with pre-exposure prophylaxis for HIV prevention during pregnancy: a systematic review and meta-analysis (AIDS 2024) - "There was no association with PTB when oral TDF/FTC PrEP, oral TDF PrEP, and tenofovir vaginal gel were compared to each other. There was no association of the dapivirine vaginal ring with PTB or NND, compared to placebo or oral TDF/FTC PrEP... We found no evidence of adverse perinatal outcomes associated with PrEP exposure during pregnancy. Our findings support the WHO recommendation to provide oral PrEP to women of reproductive age and pregnant women. More data is needed to assess the safety of all PrEP modalities in pregnancy."

Retrospective data • Review • Human Immunodeficiency Virus • Infectious Disease • Small for Gestational Age

Perinatal outcomes associated with pre-exposure prophylaxis for HIV prevention during pregnancy: a systematic review and meta-analysis. (PubMed, EClinicalMedicine) - "There was no association with PTB when oral TDF/emtricitabine (FTC) PrEP, oral TDF PrEP, and tenofovir vaginal gel were compared to each other. There was no association of the dapivirine vaginal ring with PTB or NND, compared to placebo or oral TDF/FTC PrEP...More data is needed to assess the safety of all PrEP modalities in pregnancy. None."

Journal • Retrospective data • Review • Human Immunodeficiency Virus • Infectious Disease • Small for Gestational Age

Development and verification of mechanistic vaginal absorption and metabolism model to predict systemic exposure after vaginal ring and gel application. (PubMed, Br J Clin Pharmacol) - "The current study provides first of its kind physiologically based pharmacokinetic framework integrating physiology, population and formulation data to carry out in silico mechanistic vaginal absorption studies, with the potential for virtual bioequivalence assessment in the future."

Journal

Tenofovir vaginal film as a potential MPT product against HIV-1 and HSV-2 acquisition: formulation development and preclinical assessment in non-human primates. (PubMed, Front Reprod Health) - "Secondary analyses of clinical trials evaluating TFV gel as pre-exposure prophylaxis (PrEP) for HIV have shown that gel formulations of TFV provide significant protection against both HIV and HSV-2 acquisition in women who had evidence of use...Macaque sized TFV film (11.2 mg) evaluated in a pigtail macaque model showed higher vaginal tissue concentrations of TFV and active TFV diphosphate compared to a 15 mg TFV loaded gel. These studies confirm that TFV films are stable, safe and efficiently deliver the drug in cervicovaginal compartments supporting their further clinical development."

Journal • Preclinical • Human Immunodeficiency Virus • Infectious Disease • Women's Health

Pre-infection plasma cytokines and chemokines as predictors of HIV disease progression. (PubMed, Sci Rep) - "Here we examined the relationship between pre-infection plasma cytokine expression and the rate of HIV disease progression in South African women who seroconverted during the CAPRISA 004 tenofovir gel trial...The strongest association with peak viral load was observed for SCGFβ, which was also inversely associated with lowest CD4:CD8 ratio < 180 days post infection and faster CD4 decline below 500 cells/µl (adjusted HR 4.537, 95% CI 1.475-13.954; p = 0.008) in multivariable analysis adjusting for age, study site, contraception, baseline HSV-2 status and trial arm allocation. Our results show that pre-infection systemic immune responses could play a role in HIV disease progression, especially in the early stages of infection."

Journal • Human Immunodeficiency Virus • Immunology • Infectious Disease • Inflammation • CD4 • CD8 • IFNA1 • IL16 • IL2

Genital immune cell activation and tenofovir gel efficacy: a case-control study. (PubMed, Clin Infect Dis) - "Genital inflammation (GI) undermines topical HIV pre-exposure prophylaxis (PrEP) efficacy through unknown mechanisms. Here, associations between activated endocervical CD4+ T cell numbers and higher deoxyadenosine triphosphate (dATP) concentrations suggest that competition for intracellular metabolites within HIV target cells may reduce the efficacy of antiretroviral-based PrEP in women with GI."

Journal • Human Immunodeficiency Virus • Immunology • Infectious Disease • Inflammation • CD4

Higher mucosal antibody concentrations in women with genital tract inflammation. (PubMed, Sci Rep) - "Immunoglobulin (Ig) isotypes, IgG subclasses and 48 cytokines were measured prior to HIV infection in cervicovaginal lavages (CVL) from 66 HIV seroconverters (cases) and 66 matched HIV-uninfected women (controls) enrolled in the CAPRISA 004 and 008 1% tenofovir gel trials...The strong and significant positive correlations between mucosal antibodies and markers of GI suggest that GI may impact mucosal antibody profiles. These findings require further investigation to establish a plausible biological link between the local inflammatory milieu and its consequence on these genital antibodies."

Clinical • Journal • Human Immunodeficiency Virus • Immunology • Infectious Disease • Inflammation

HIV Incidence Among Pregnant and Nonpregnant Women in the FACTS-001 Trial: Implications for HIV Prevention, Especially PrEP Use. (PubMed, J Acquir Immune Defic Syndr) - "Pregnancy incidence was high despite trial participation being contingent on contraceptive use. We found no evidence that rates of HIV acquisition were elevated in pregnancy when compared with those in nonpregnant women. Risks from reductions in condom use may be offset by reduced sexual activity. Nevertheless, high HIV incidence in both pregnant and nonpregnant women supports consideration of introducing antiretroviral-containing pre-exposure prophylaxis for pregnant and nonpregnant women in high HIV prevalence settings."

Clinical • Journal • Human Immunodeficiency Virus • Infectious Disease

An Open-Label Pharmacokinetic and Pharmacodynamic Assessment of Tenofovir Gel and Oral Emtricitabine / Tenofovir Disoproxil Fumarate. (PubMed, AIDS Res Hum Retroviruses) - "Despite significant differences in systemic and mucosal drug concentrations, all three PrEP regimens were able to protect rectal explants from ex vivo HIV infection. These data suggest that there is a rationale for co-development of oral and topical antiretroviral PrEP for HIV prevention."

Clinical • Journal • PK/PD data • Human Immunodeficiency Virus • Infectious Disease

[VIRTUAL] Modeling the probability of HIV infection and its reduction by microbicides using deterministic mass transport theory coupled to viral dynamics (HIVR4P 2021) - "This model enhances predicting microbicide efficacy using PK information. Inputting product properties, it provides a mechanistic means of evaluating, screening and optimizing those properties, complementing in vitro and in vivo experiments. Further, it can simulate diverse patient populations."

Late-breaking abstract • Human Immunodeficiency Virus • Immunology • Infectious Disease

[VIRTUAL] Comparing Applicator vs. “As Lubricant” Delivery of Rectal Dapivirine Gel (MTN-033) (HIVR4P 2021) - "Tenofovir gel administered intrarectally with an applicator had lower acceptability as compared to a daily oral PrEP regimen and traditional lubricant use in prior phase II studies...Our data suggests that DPV gel was safe and easy to use. Further development of a lubricant microbicide strategy is warranted."

Hepatology • Human Immunodeficiency Virus • Infectious Disease

Treatment with Commonly Used Antiretroviral Drugs Induces a Type I/III Interferon Signature in the Gut in the Absence of HIV Infection. (PubMed, Cell Rep Med) - "Previously, we found that topical rectal tenofovir gel caused immunological changes in the mucosa. mRNA sequencing, digital droplet PCR, proteomics, and immunofluorescence confirm IFN I/III pathway stimulation in the gastrointestinal tract. Thus, oral TDF/FTC stimulates an IFN I/III signature throughout the gut, which could increase antiviral efficacy but also cause chronic immune activation in HIV prevention and treatment settings."

Journal • Gastrointestinal Disorder • Human Immunodeficiency Virus • Infectious Disease

Topical Tenofovir Pre-exposure Prophylaxis and Mucosal HIV-Specific Fc-Mediated Antibody Activities in Women. (PubMed, Front Immunol) - "Our previous findings of increased HIV specific antibody detection and titres in women who used tenofovir gel, and the limited differences in nNAb activities between the arms, suggest that prior PrEP did not modulate these nNAb functions post-HIV seroconversion. Together these data provide insight into envelope-specific-nNAb Fc-mediated functions at the site of exposure which may inform on ensuing immunity during combination HIV prevention strategies including PrEP and HIV vaccines."

Clinical • Journal • Gene Therapies • Human Immunodeficiency Virus • Infectious Disease

Frequency of Hepatitis B Virus Resistance Mutations in Women Using Tenofovir Gel as Pre-Exposure Prophylaxis. (PubMed, Viruses) - "All samples belonged to HBV genotype A. None of the known tenofovir resistance mutations (M240V/I, L180M, A194T, V214A, N238T) were identified in any individuals. While it is reassuring that no resistance mutations were found among women using topical tenofovir, the rapidly expanding access to oral tenofovir-containing HIV pre-exposure prophylaxis (PrEP), with higher systemic exposure to the drug, makes monitoring for potential HBV drug resistance important."

Clinical • Journal • Hepatitis B • Human Immunodeficiency Virus • Infectious Disease

Integrated provision of topical pre-exposure prophylaxis in routine family planning services in South Africa: a non-inferiority randomized controlled trial. (PubMed, J Int AIDS Soc) - "Provision of topical PrEP as part of an integrated FP service achieved higher adherence, and was as feasible, acceptable and effective in preventing HIV as provision through a research setting. This provides useful evidence for scale-up of oral PrEP in urban and rural high burden communities."

Clinical • Head-to-Head • Journal • Infectious Disease

[VIRTUAL] High Y-chromosome DNA concentrations are associated with increased cervical cytokine concentrations and activated cervical HIV target cell frequencies (AIDS 2020) - " Genital specimens were collected every 6 months (average 5 ± 1 visits) from 149 HIV-negative women participating in the CAPRISA 008 tenofovir gel open-label extension trial (n = 693 specimens)... Higher YcDNA concentrations were associated with raised levels of cytokines and MMPs, and with greater frequencies of HIV target cells at the female genital mucosa. Considering the association between YcDNA and these established biomarkers of genital inflammation and HIV risk, semen-induced alterations at the FGT may, therefore, have implications for HIV susceptibility in women."

Gene Therapies • Immunology • Infectious Disease • CSF3 • IL10 • IL13 • IL4 • IL6 • IL7 • IL9 • MMP1 • MMP10 • MMP13 • MMP2 • MMP3 • MMP7 • VEGFA

Impact of Case Definitions on Efficacy Estimation in Clinical Trials-A Proof-of-Principle Based on Historical Examples. (PubMed, Antibiotics (Basel)) - "After describing the structure of case definitions and its impact on efficacy estimations, we exemplify this impact using data from two clinical trials dealing with the effectiveness of the vaginal application of tenofovir gel for the prevention of HIV infections and with the therapeutic effects of fecal transplantation on recurrent Clostridiumdifficile infections...The potential risk of bias and uncertainty is high, irrespective of the complexity of the case definition. Accordingly, case definitions in clinical trials should focus on specificity in order to avoid the risk of bias."

Clinical • Journal • Infectious Disease • Transplantation

The genital tract and rectal microbiomes: their role in HIV susceptibility and prevention in women. (PubMed, J Int AIDS Soc) - "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."

Clinical • Journal • Review • Gene Therapies • Genetic Disorders • Immunology • Infectious Disease