Topical prophylaxis for HIV prevention in women: becoming a reality.
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ABSTRACT:
SUBMITTER: Verma NA
PROVIDER: S-EPMC3110084 | biostudies-literature | 2011 Jun
REPOSITORIES: biostudies-literature
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Topical prophylaxis for HIV prevention in women: becoming a reality.
Verma Natasha A NA Lee Anna C AC Herold Betsy C BC Keller Marla J MJ
Current HIV/AIDS reports 20110601 2
Strategies to protect against sexual transmission of HIV include the development of products formulated for topical application, which limit the toxicities associated with systemic oral pre-exposure prophylaxis. Following several clinical trial failures, attention is now focused on antiretroviral (ARV) agents. Highly potent ARV topical formulations provide a female-controlled, targeted, and feasible option for HIV prevention. A recently completed tenofovir gel trial was the first to demonstrate ...[more]
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Project description:BackgroundAntiretroviral preexposure prophylaxis is a promising approach for preventing human immunodeficiency virus type 1 (HIV-1) infection in heterosexual populations.MethodsWe conducted a randomized trial of oral antiretroviral therapy for use as preexposure prophylaxis among HIV-1-serodiscordant heterosexual couples from Kenya and Uganda. The HIV-1-seronegative partner in each couple was randomly assigned to one of three study regimens--once-daily tenofovir (TDF), combination tenofovir-emtricitabine (TDF-FTC), or matching placebo--and followed monthly for up to 36 months. At enrollment, the HIV-1-seropositive partners were not eligible for antiretroviral therapy, according to national guidelines. All couples received standard HIV-1 treatment and prevention services.ResultsWe enrolled 4758 couples, of whom 4747 were followed: 1584 randomly assigned to TDF, 1579 to TDF-FTC, and 1584 to placebo. For 62% of the couples followed, the HIV-1-seronegative partner was male. Among HIV-1-seropositive participants, the median CD4 count was 495 cells per cubic millimeter (interquartile range, 375 to 662). A total of 82 HIV-1 infections occurred in seronegative participants during the study, 17 in the TDF group (incidence, 0.65 per 100 person-years), 13 in the TDF-FTC group (incidence, 0.50 per 100 person-years), and 52 in the placebo group (incidence, 1.99 per 100 person-years), indicating a relative reduction of 67% in the incidence of HIV-1 with TDF (95% confidence interval [CI], 44 to 81; P<0.001) and of 75% with TDF-FTC (95% CI, 55 to 87; P<0.001). Protective effects of TDF-FTC and TDF alone against HIV-1 were not significantly different (P=0.23), and both study medications significantly reduced the HIV-1 incidence among both men and women. The rate of serious adverse events was similar across the study groups. Eight participants receiving active treatment were found to have been infected with HIV-1 at baseline, and among these eight, antiretroviral resistance developed in two during the study.ConclusionsOral TDF and TDF-FTC both protect against HIV-1 infection in heterosexual men and women. (Funded by the Bill and Melinda Gates Foundation; Partners PrEP ClinicalTrials.gov number, NCT00557245.).
| S-EPMC3770474 | biostudies-literature
Project description:The RV144 HIV-vaccine trial highlighted the importance of envelope-specific non-neutralizing antibody (nNAb) Fc-mediated functions as immune correlates of reduced risk of infection. Since pre-exposure prophylaxis (PrEP) and HIV-vaccines are being used as a combination prevention strategy in at risk populations, the effects of PrEP on nNAb functions both mucosally and systemically remain undefined. Previous animal and human studies demonstrated reduced HIV-specific antibody binding avidity post-HIV seroconversion with PrEP, which in turn may affect antibody functionality. In seroconverters from the CAPRISA 004 tenofovir gel trial, we previously reported significantly higher detection and titres of HIV-specific binding antibodies in the plasma and genital tract (GT) that distinguished the tenofovir from the placebo arm. We hypothesized that higher HIV-specific antibody titres and detection reflected corresponding increased antibody-dependent neutrophil-mediated phagocytosis (ADNP) and NK-cell-activated antibody-dependent cellular cytotoxic (ADCC) activities. HIV-specific V1V2-gp70, gp120, gp41, p66, and p24 antibodies in GT and plasma samples of 48 seroconverters from the CAPRISA 004 tenofovir gel trial were tested for ADCP and ADCC at 3, 6- and 12-months post-HIV-infection. GT gp41- and p24-specific ADNP were significantly higher in the tenofovir than the placebo arm at 6 and 12 months respectively (p < 0.05). Plasma gp120-, gp41-, and p66-specific ADNP, and GT gp41-specific ADCC increased significantly over time (p < 0.05) in the tenofovir arm. In the tenofovir arm only, significant inverse correlations were observed between gp120-specific ADCC and gp120-antibody titres (r = -0.54; p = 0.009), and gp41-specific ADNP and gp41-specific antibody titres at 6 months post-infection (r = -0.50; p = 0.015). In addition, in the tenofovir arm, gp41-specific ADCC showed significant direct correlations between the compartments (r = 0.53; p = 0.045). Certain HIV-specific nNAb activities not only dominate specific immunological compartments but can also exhibit diverse functions within the same compartment. 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.
| S-EPMC7357346 | biostudies-literature
Project description:The concept of precision medicine is becoming increasingly popular. The use of big data, genomics and other "omics" like metabolomics, proteomics and transcriptomics could make the dream of personalised medicine become a reality in the near future. As far as polygenic forms of diabetes like type 2 and type 1 diabetes are concerned, interesting leads are emerging, but precision diabetes is still in its infancy. However, with regard to monogenic forms of diabetes like maturity-onset diabetes of the young and neonatal diabetes mellitus, rapid strides have been made and precision diabetes has already become part of the clinical tools used at advanced diabetes centres. In patients with some monogenic form of diabetes, if the appropriate gene defects are identified, insulin injections can be stopped and be replaced by oral sulphonylurea drugs. In the coming years, rapid advances can be expected in the field of precision diabetes, thereby making the control of diabetes more effective and hopefully leading to prevention of its complications and improvement of the quality of life of people afflicted with diabetes.
| S-EPMC6558328 | biostudies-literature
Project description:ImportanceAntiretroviral preexposure prophylaxis (PrEP), using tenofovir disoproxil fumarate (TDF) and combination emtricitabine/tenofovir disoproxil fumarate (FTC+TDF), is efficacious for prevention of human immunodeficiency virus (HIV) acquisition. PrEP could reduce periconception HIV risk, but the effect on pregnancy outcomes is not well defined.ObjectiveTo assess pregnancy incidence and outcomes among women using PrEP during the periconception period.Design, setting, and participantsRandomized trial among 1785 HIV-serodiscordant heterosexual couples (the Partners PrEP Study) in which the female partner was HIV uninfected that demonstrated that PrEP was efficacious for HIV prevention, conducted between July 2008 and June 2013 at 9 sites in Kenya and Uganda.InterventionsDaily oral TDF (n = 598), combination FTC+TDF (n = 566), or placebo (n = 621) through July 2011, when PrEP demonstrated efficacy for HIV prevention. Thereafter, participants continued receiving active PrEP without placebo. Pregnancy testing occurred monthly and study medication was discontinued when pregnancy was detected.Main outcomes and measuresPregnancy incidence, birth outcomes (live births, pregnancy loss, preterm birth, congenital anomalies), and infant growth.ResultsA total of 431 pregnancies occurred. Pregnancy incidence was 10.0 per 100 person-years among women assigned placebo, 11.9 among those assigned TDF (incidence difference, 1.9; 95% CI, -1.1 to 4.9 [P = .22 vs placebo]), and 8.8 among those assigned FTC+TDF (incidence difference, -1.3; 95% CI, -4.1 to 1.5 [P = .39 vs placebo]). Before discontinuation of the placebo treatment group in July 2011, the occurrence of pregnancy loss (96 of 288 pregnancies) was 42.5% for women receiving FTC+TDF compared with 32.3% for those receiving placebo (difference for FTC+TDF vs placebo, 10.2%; 95% CI, -5.3% to 25.7%; P = .16) and was 27.7% for those receiving TDF alone (difference vs placebo, -4.6%; 95% CI, -18.1% to 8.9%; P = .46). After July 2011, the frequency of pregnancy loss (52 of 143 pregnancies) was 37.5% for FTC+TDF and 36.7% for TDF alone (difference, 0.8%; 95% CI, -16.8% to 18.5%; P = .92). Occurrence of preterm birth, congenital anomalies, and growth throughout the first year of life did not differ significantly for infants born to women who received PrEP vs placebo.Conclusions and relevanceAmong HIV-serodiscordant heterosexual African couples, differences in pregnancy incidence, birth outcomes, and infant growth were not statistically different for women receiving PrEP with TDF alone or combination FTC+TDF compared with placebo at conception. Given that PrEP was discontinued when pregnancy was detected and that CIs for the birth outcomes were wide, definitive statements about the safety of PrEP in the periconception period cannot be made. These results should be discussed with HIV-uninfected women receiving PrEP who are considering becoming pregnant.Trial registrationclinicaltrials.gov Identifier: NCT00557245.
| S-EPMC4362516 | biostudies-literature
Project description:Preventing new HIV infections remains a global challenge. Young women continue to bear a disproportionate burden of infection. Oral pre-exposure prophylaxis (PrEP), offers a novel women-initiated prevention technology and PrEP trials completed to date underscore the importance of their inclusion early in trials evaluating new HIV PrEP technologies. Data from completed topical and systemic PrEP trials highlight the role of gender specific physiological and social factors that impact PrEP uptake, adherence and efficacy. Here we review the past and current developments of HIV-1 prevention options for women with special focus on PrEP considering the diverse factors that can impact PrEP efficacy. Furthermore, we highlight the importance of inclusion of female scientists, clinicians, and community advocates in scientific efforts to further improve HIV prevention strategies.
| S-EPMC9763292 | biostudies-literature
Project description:The development of topical inserts for the prevention of sexually transmitted infections (STIs), particularly human immunodeficiency virus (HIV), represents a promising alternative to oral and parenteral pre-exposure prophylaxis (PrEP) dosage forms. They may be used for vaginal and/or rectal administration of a variety of agents with antiviral activity. Topical inserts deliver drugs to the portal of viral entry, i.e., the genital or rectal mucosa, with low systemic exposure, and therefore are safer and have fewer side effects than systemic PrEP agents. They may dissolve fast, releasing the active drugs within minutes of insertion, or slowly for long-acting drug delivery. Furthermore, they are user-friendly being easy to administer, discreet and highly portable. They are also economical and easy to manufacture at scale and to distribute, with excellent stability and shelf-life. Altogether, topical inserts represent a particularly promising form of drug delivery for HIV and STI prevention. Highlighted within this review are end-user acceptability research dedicated to understanding preferred attributes for this form of drug delivery, advantages and disadvantages of the formulation platform options, considerations for their development, clinical assessment of select placebo prototypes, future directions, and the potential impact of this dosage form on the HIV prevention landscape.
| S-EPMC6723036 | biostudies-literature
Project description:Worldwide, HIV disproportionately affects women who are often unable to negotiate traditional HIV preventive strategies such as condoms. In the absence of an effective vaccine or cure, chemoprophylaxis may be a valuable self-initiated alternative. Topical microbicides have been investigated as one such option. The first generation topical microbicides were non-specific, broad-spectrum antimicrobial agents, including surfactants, polyanions, and acid buffering gels, that generally exhibited contraceptive properties. After extensive clinical study, none prevented HIV infection, and their development was abandoned. Second generation topical microbicides include agents with selective mechanisms of antiviral activity. Most are currently being used for, or have previously been explored as, drugs for treatment of HIV. The most advanced of these is tenofovir 1% gel: the first topical agent shown to significantly reduce HIV infection by 39% compared to placebo. This review summarizes the evolution of topical microbicides for HIV chemoprophylaxis, highlights important concepts learned, and offers current and future considerations for this area of research.
| S-EPMC4144014 | biostudies-other
Project description:Adolescents are a critical population that is disproportionately impacted by the HIV epidemic. More than 2 million adolescents between the age group of 10 and 19 years are living with HIV, and millions are at risk of infection. HIV risks are considerably higher among girls, especially in high-prevalence settings such as eastern and southern Africa. In addition to girls, there are other vulnerable adolescent subgroups, such as teenagers, who use intravenous (IV) drugs, gay and bisexual boys, transgender youth, male sex workers, and people who fall into more than one of these categories. Pre-exposure prophylaxis (PrEP) is a new intervention for people at high risk for acquiring HIV, with an estimated HIV incidence of >3%. Recent data from trials show evidence of the efficacy of PrEP as a powerful HIV prevention tool in high-risk populations, including men who have sex with men, HIV-1-serodiscordant heterosexual couples, and IV drug users. The reported efficacy in those trials of the daily use of oral tenofovir, alone or in combination with emtricitabine, to prevent HIV infection ranged from 44% to 75% and was heavily dependent on adherence. Despite the proven efficacy of PrEP in adult trials, concerns remain about its feasibility in real-life scenarios due to stigma, cost, and limited clinician experience with PrEP delivery. Recent studies are attempting to expand the inquiry into the efficacy of such HIV prophylaxis approaches in adolescent populations, but there are still many gaps in knowledge, and no country has yet approved it for use with adolescents. The aim of this review was to identify and summarize the evidence from studies on PrEP for adolescents. We have compiled and reviewed published studies focusing on safety, feasibility, adherence to therapeutics, self-perception, and legal issues related to PrEP in people aged between 10 and 24 years.
| S-EPMC5716324 | biostudies-literature
Project description:Scarce data are available to assess sexual behaviour of individuals using antiretroviral pre-exposure prophylaxis for HIV prevention. Increased sexual risk taking by individuals using effective HIV prevention strategies, like pre-exposure prophylaxis, could offset the benefits of HIV prevention. We studied whether the use of pre-exposure prophylaxis in HIV-uninfected men and women in HIV-serodiscordant couples was associated with increased sexual risk behaviour.We undertook a longitudinal analysis of data from the Partners PrEP Study, a double-blind, randomised, placebo-controlled trial of daily oral pre-exposure prophylaxis among HIV-uninfected partners of heterosexual HIV-serodiscordant couples (n=3163, ?18 years of age). Efficacy for HIV prevention was publicly reported in July 2011, and participants continued monthly follow-up thereafter. We used regression analyses to compare the frequency of sex-unprotected by a condom-during the 12 months after compared with the 12 months before July 2011, to assess whether knowledge of pre-exposure prophylaxis efficacy for HIV prevention caused increased sexual risk behaviour.We analysed 56?132 person-months from 3024 HIV-uninfected individuals (64% male). The average frequency of unprotected sex with the HIV-infected study partner was 59 per 100 person-months before unmasking versus 53 after unmasking; we recorded no immediate change (p=0·66) or change over time (p=0·25) after July, 2011. We identified a significant increase in unprotected sex with outside partners after July, 2011, but the effect was small (average of 6·8 unprotected sex acts per year vs 6·2 acts in a predicted counterfactual scenario had patients remained masked, p=0·04). Compared with before July, 2011, we noted no significant increase in incident sexually transmitted infections or pregnancy after July, 2011.Pre-exposure prophylaxis, provided as part of a comprehensive prevention package, might not result in substantial changes in risk-taking sexual behaviour by heterosexual couples.The Bill & Melinda Gates Foundation and the US National Institute of Mental Health.
| S-EPMC3920826 | biostudies-literature
Project description:Purpose of reviewTo review current laboratory and clinical data on the frequency and relative risk of drug resistance and range of mutations selected from approved and investigational antiretroviral agents used for preexposure prophylaxis (PrEP) of HIV-1 infection, including tenofovir disproxil fumarate (TDF)-based oral PrEP, dapivirine ring, injectable cabotegravir (CAB), islatravir, lenacapavir and broadly neutralizing antibodies (bNAbs).Recent findingsThe greatest risk of HIV-1 resistance from PrEP with oral TDF/emtricitabine (FTC) or injectable CAB is from starting or continuing PrEP after undiagnosed acute HIV infection. By contrast, the dapivirine intravaginal ring does not appear to select nonnucleoside reverse transcriptase inhibitor resistance in clinical trial settings. Investigational inhibitors including islatravir, lenacapavir, and bNAbs are promising for use as PrEP due to their potential for sustained delivery and low risk of cross-resistance to currently used antiretrovirals, but surveillance for emergence of resistance mutations in more HIV-1 gene regions (gag, env) will be important as the same drugs are being developed for HIV therapy.SummaryPrEP is highly effective in preventing HIV infection. Although HIV drug resistance from PrEP use could impact future options in individuals who seroconvert on PrEP, the current risk is low and continued monitoring for the emergence of resistance and cross-resistance during product development, clinical studies, and product roll-out is advised to preserve antiretroviral efficacy for both treatment and prevention.
| S-EPMC9245149 | biostudies-literature