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Young men of color who have sex with men are vulnerable to HIV and experience poor PrEP uptake and retention. We conducted a secondary data analysis and calculated adjusted Prevalence Odds Ratios (aPORs) for PrEP retention along with 95% CIs at 90, 180, and 360 days at an organization running safety net clinics in Texas for gay and bisexual men. We found statistically significant association with age, race, in-clinic versus telehealth appointments, and having healthcare insurance. White clients had an aPOR of 1.29 [1.00, 1.67] as compared to Black clients at 90 days. Age group of 18-24 had a lower aPOR than all other age groups except 55 or older at all three time periods. Clients who met providers in person had an aPOR of 2.6 [2.14, 3.19] at 90, 2.6 [2.2, 3.30] at 180 days and 2.84 [2.27, 3.54] at 360 days. Our findings highlight the need for population-specific targeted interventions.

Lower PrEP retention for black and young MSM in TexasOur study findings suggest that of all clients who start PrEP, Black clients and younger clients had a higher chance of not continuing PrEP as compared to White clients and older clients respectively. This analysis was done for a clinic that pre-dominantly offers services to gay and bisexual men. We also found that those who were attending clinic in person had higher chances of continuing. Further those who are insured also had higher chances of continuing.

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This study aimed to evaluate the interest in event-driven PrEP (ED-PrEP) among men who have sex with men (MSM) using daily PrEP in Mexico's PrEP demonstration project between 2019 and 2020. We compared participants interested or not in ED-PrEP during their first-month visit and identified associated factors. Of 1,021 MSM attending their first-month visit, 7% had previous knowledge of ED-PrEP, but 40% were interested in ED-PrEP. However, over 50% perceived the scheme as less protective than daily PrEP. Having doubts about ED-PrEP's level of protection was related to less interest in the scheme (aOR = 0.11; CI = 0.07-0.18), just like reporting perceived barriers such as having frequent sex (aOR = 0.06; CI = 0.03-0.14), unplanned sex (aOR = 0.17; CI = 0.11-0.27), forgetting the medicine (aOR = 0.06; CI = 0.03-0.12), or difficulty carrying the medicine (aOR = 0.13; CI = 0.07-0.25). Finally, reporting not taking PrEP for >20 days in the last month (aOR = 0.05; CI = 0.01-0.27) diminished interest in ED-PrEP. In conclusion, few MSM daily PrEP users knew about ED-PrEP yet many were interested in it, suggesting the importance of awareness campaigns regarding ED-PrEP's effectiveness. The lack of interest in ED-PrEP among participants with poor adherence to daily PrEP indicates that they might prefer long-acting PrEP or HIV prevention strategies without medication.

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Women of color are disproportionately impacted by HIV. Although PrEP effectively prevents HIV infection, PrEP coverage and knowledge remain low in this population. To address barriers to PrEP, we implemented women-centered and culturally appropriate Information Sessions (IS) delivered by staff from the population they serve to increase knowledge, awareness, and use of PrEP through telemedicine (e.g., PlushCare). Our analysis focuses on Latina women (LW) participants, given the dearth of literature dedicated to the needs of LW. We partnered with a woman-led community-based organization (CBO) to implement the strategy with LW clients. Health educators conducted 26 IS with 94 LW (20 in Spanish and 6 in English). Participants who completed the IS were invited for interviews to assess the acceptability and appropriateness of the IS to increase knowledge and awareness of PrEP and PlushCare. Four themes emerged from the thematic analysis: (1) IS increased knowledge and awareness of PrEP and PlushCare; (2) perceived acceptability and appropriateness of IS; (3) insufficient reasons to warrant use of PrEP; and (4) positive attitudes about PlushCare. Our findings suggest that a women-centered and culturally appropriate IS implemented through a trusted, woman-led CBO is an acceptable and appropriate implementation strategy to inform LW about PrEP.

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The promise of multipurpose prevention technologies (MPTs) for the prevention of HIV and unintended pregnancy are on the horizon. While many are still in clinical development, others are closer to becoming a realistic, accessible option for users, like the dual prevention pill (DPP). Researchers, governments, donors, and implementers will have to collaboratively address systemic challenges to successfully introduce and scale-up MPTs. To ensure the rollout of MPTs is successful, the global community should address user and country-specific needs, coordinate with advocates and policymakers, and set a realistic plan for product introduction and scale-up that considers the needs of both family planning (FP) and HIV programs, while laying the groundwork for future new product introduction. To achieve these aims, global and regional stakeholder coordination should emphasize country-led, person-centered decision-making while addressing: (1) procurement and supply chain barriers; (2) the potential burden on health systems; and (3) the impact on current programs.

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Background: Persons living in sub-Saharan Africa (SSA) face disproportionate risk from overlapping epidemics of HIV and bacterial sexually transmitted infections (STIs). Pre-exposure prophylaxis (PrEP) for prevention is gradually being scaled up globally including in several settings in SSA, which represents a key opportunity to integrate STI services with HIV pre-exposure prophylaxis (PrEP). However, there is limited literature on how to successfully integrate these services, particularly in the SSA context. Prior studies and reviews on STI and PrEP services have largely focused on high income countries. Methods: We conducted a scoping review of prior studies of integration of STI and PrEP services in SSA. We searched PubMed, EMBASE, Cochrane, and CINAHL, in addition to grey literature to identify studies that were published between January 2012 and December 2022, and which provided STI and PrEP services in SSA, with or without outcomes reported. Citations and abstracts were reviewed by two reviewers for inclusion. Full texts were then retrieved and reviewed in full by two reviewers. Results: Our search strategy yielded 1951 records, of which 250 were retrieved in full. Our final review included 61 reports of 45 studies. Most studies were conducted in Southern (49.2%) and Eastern (24.6%) Africa. Service settings included public health clinics (26.2%), study clinics (23.0%), sexual and reproductive care settings (23.0%), maternal and child health settings (8.2%), community based services (11.5%), and mobile clinics (3.3%). A minority (11.4%) of the studies described only syndromic STI management while most (88.6%) included some form of etiological laboratory STI diagnosis. STI testing frequency ranged from baseline testing only to monthly screening. Types of STI tested for was also variable. Few studies reported outcomes related to implementation of STI services. There were high rates of curable STIs detected by laboratory testing (baseline genitourinary STI rates ranged from 5.6-30.8% for CT, 0.0-11.2% for GC, and 0.4-8.0% for TV). Discussion: Existing studies have implemented a varied range of STI services along with PrEP. This range reflects the lack of specific guidance regarding STI services within PrEP programs. However, there was limited evidence regarding implementation strategies for integration of STI and PrEP services in real world settings.

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HIV/AIDS and maternal mortality are the two leading causes of death among women of reproductive age in sub-Saharan Africa. A growing body of research investigates opportunities for multipurpose prevention technologies (MPTs) that prevent unintended pregnancy, HIV, and/or other sexually transmitted infections (STIs) with a single product. More than two dozen MPTs are currently in development, most of them combining contraception with HIV pre-exposure prophylaxis, with or without protection from other STIs. If successful, such MPTs could offer women benefits at multiple levels: greater motivation for effective use; lower product administration burden; accelerated integration of HIV, STI, and reproductive health services; and opportunities to circumvent stigma by using contraception as a "fig leaf" for HIV and/or STI prevention. However, even if women find respite from product burden, lack of motivation, and/or stigma in contraceptive-containing MPTs, their use of MPTs will be interrupted, often multiple times, over the reproductive lifecourse due to desire for pregnancy, pregnancy and breastfeeding, menopause, and changes in risk. Interruptions to the benefits of MPTs could be avoided by combining HIV/STI prevention with other life-stage-appropriate reproductive health products. New product concepts could include combining prenatal supplements with HIV and STI prevention, emergency contraception with HIV post-exposure prophylaxis, or hormone replacement therapies for menopause with HIV and STI prevention. Research is needed to optimize the MPT pipeline based on the populations underserved by available options and the capacity of resource-constrained health systems to deliver novel preventative healthcare products.

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Introduction: In 2019, there were over 1.1 million people living with human immunodeficiency virus (HIV) and 2.4 million people living with hepatitis C virus (HCV) in the United States. One in seven (14%) are unaware of their HIV infection and almost half of all HCV infections are undiagnosed. People with unstable housing are disproportionately affected by HIV and HCV. The present study will evaluate interventions by community pharmacists that may reduce HIV and HCV transmission and promote linkage to care. Methods: This study was conducted in an independent community pharmacy in Spokane, Washington. Eligible study participants were walk-in patients of the pharmacy, over the age of 18, and experiencing homelessness. Pharmacy patients were excluded if they had a history of HIV or HCV diagnosis, received a screening for HIV or HCV in the last six months or were unable to give informed consent. The intervention included administration of HIV and HCV point-of-care testing (POCT) using a blood sample, risk determination interview, comprehensive HIV and HCV education, and personalized post-test and risk mitigation counseling followed by referral to partnering health clinics. Results: Fifty participants were included in the final data analysis. Twenty-two participants (44%) had a reactive HCV POCT, and one participant had a reactive HIV POCT. Of the 94% of participants who reported illicit drug use, 74% reported injection drug use. Seventy-six percent (n = 38) qualified for PrEP. Pharmacist referrals were made for 28 participants and 71% were confirmed to have established care. Conclusion: Individuals experiencing homelessness are at an increased risk for acquiring HIV and HCV due to risky sexual behaviors and substance misuse. PrEP is underutilized in the U.S. and pharmacist involvement in the HIV and HCV care continuum may have a significant impact in improving linkage and retention in care of difficult to treat populations.

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Screening, Brief Intervention, and Referral to Treatment (SBIRT) is a supplementary intervention that can be incorporated into the Pre-Exposure Prophylaxis (PrEP) Care Continuum, complementing initiatives and endeavors focused on Human Immunodeficiency Virus (HIV) prevention in clinical care and community-based work. Referencing the Transtheoretical Model of Change and the PrEP Awareness Continuum, this conceptual analysis highlights how SBIRT amplifies ongoing HIV prevention initiatives and presents a distinct chance to address identified gaps. SBIRT's mechanisms show promise of fit and feasibility through (a) implementing universal Screening (S), (b) administering a Brief Intervention (BI) grounded in motivational interviewing aimed at assisting individuals in recognizing the significance of PrEP in their lives, (c) providing an affirming and supportive Referral to Treatment (RT) to access clinical PrEP care, and (d) employing client-centered and destigmatized approaches. SBIRT is uniquely positioned to help address the complex challenges facing PrEP awareness and initiation efforts. Adapting the SBIRT model to integrate and amplify HIV prevention efforts merits further examination.

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The use of antiretrovirals (ARVs) as oral, topical, or long-acting pre-exposure prophylaxis (PrEP) has emerged as a promising strategy for HIV prevention. Clinical trials testing Truvada® [tenofovir disoproxil fumarate (TDF)/tenofovir (TFV) and emtricitabine (FTC)] as oral or topical PrEP in African women showed mixed results in preventing HIV infections. Since oral and topical PrEP effectiveness is dependent on adequate drug delivery and availability to sites of HIV infection such as the blood and female genital tract (FGT); host biological factors such as drug transporters have been implicated as key regulators of PrEP. Drug transporter expression levels and function have been identified as critical determinants of PrEP efficacy by regulating PrEP pharmacokinetics across various cells and tissues of the blood, renal tissues, FGT mucosal tissues and other immune cells targeted by HIV. In addition, biological factors such as genetic polymorphisms and genital inflammation also influence drug transporter expression levels and functionality. In this review, drug transporters and biological factors modulating drug transporter disposition are used to explain discrepancies observed in PrEP clinical trials. This review also provides insight at a pharmacological level of how these factors further increase the susceptibility of the FGT to HIV infections, subsequently contributing to ineffective PrEP interventions in African women.

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HIV pre-exposure prophylaxis (HIV-PrEP) is effective in reducing the likelihood of HIV acquisition in HIV-negative people at high risk of exposure. Guidelines recommend testing for sexually transmitted infections (STIs) before starting, and periodically on PrEP, including bacterial infections, HIV, hepatitis C virus, and, for those who are non-immune, hepatitis B virus. Diagnosed infections can be promptly treated to reduce onward transmission. HTLV-1 is not mentioned; however, it is predominantly sexually transmitted, causes adult T-cell leukaemia/lymphoma (ATL) or myelopathy in 10% of those infected, and is associated with an increased risk of death in those without any classically HTLV-associated condition. The 2021 WHO Technical Report on HTLV-1 called for the strengthening of global public health measures against its spread. In this scoping review, we, therefore, (1) discuss the epidemiological context of HIV-PrEP and HTLV-1 transmission; (2) present current knowledge of antiretrovirals in relation to HTLV-1 transmission prevention, including nucleos(t)ide reverse transcriptase inhibitors (NRTIs) and integrase strand transfer inhibitors (INSTIs); and (3) identify knowledge gaps where data are urgently required to inform global public health measures to protect HIV-PrEP users from HTLV-1 acquisition. We suggest that systematic seroprevalence studies among PrEP-using groups, including men who have sex with men (MSM), people who inject drugs (PWIDs), and female sex workers (FSWs), are needed. Further data are required to evaluate antiretroviral efficacy in preventing HTLV-1 transmission from in vitro studies, animal models, and clinical cohorts. PrEP delivery programmes should consider prioritizing the long-acting injectable INSTI, cabotegravir, in HTLV-1 endemic settings.

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Background: Oral pre-exposure prophylaxis (PrEP) and antiretroviral therapy (ART) can effectively prevent HIV infections among men who have sex with men (MSM), but the emergence and transmission of HIV drug-resistance (HIVDR) may compromise their benefits. The costs and benefits of expanding PrEP and ART coverage in the presence of HIVDR in China remain unknown. Methods: We developed a comprehensive dynamic transmission model incorporating the transmitted (TDR) and acquired (ADR) HIV drug resistance. The model was calibrated by the HIV surveillance data from 2009 to 2019 among MSM in Jiangsu Province, China, and validated by the dynamic prevalence of ADR and TDR. We aimed to investigate the impact of eight intervention scenarios (no PrEP, 20%, 50% or 80% of PrEP, without (77% coverage) or with (90% coverage) expanded ART) on the HIV epidemic trend and cost-effectiveness of PrEP over the next 30 years. Findings: 20% or 50% PrEP + 90% ART would be cost-effective, with an incremental cost-effectiveness ratio (ICER) of 25,417 (95% confidence interval [CI]: 12,390-38,445) or 47,243 (23,756-70,729), and would yield 154,949 (89,662-220,237) or 179,456 (102,570-256,342) incremental quality-adjusted life-years (QALYs) over the next 30 years. No PrEP + 90% ART would yield 125,211 (73,448-176,974) incremental QALYs and be cost-saving. However, 20-80% PrEP + 77% ART and 80% PrEP + 90% ART with ICER of $77,862-$98,338 and $63,332, respectively, and were not cost-effective. A reduction of 64% in the annual cost of oral PrEP would make it highly cost-effective for 50% PrEP + 90% ART. Interpretation: 20% or 50% PrEP + 90% ART is cost-effective for HIV control in the presence of HIVDR. Expanded ART alone may be the optimal policy under the current limited budgets. Funding: National Natural Science Foundation of China, the National S&T Major Project Foundation of China.

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Introduction: When an HIV cure becomes available, it will have consequences for people living with HIV (PLHIV) and key populations who are vulnerable to HIV. This qualitative study aimed to explore the perceived impact of two HIV cure scenarios (post-treatment control when HIV is suppressed without the need for ongoing antiretroviral treatment (ART) and complete HIV elimination) on the quality of life of PLHIV and key populations living without HIV in the Netherlands. Methods: Participants were purposefully sampled from the Amsterdam Cohort Studies, the AGEhIV Cohort Study, the outpatient clinic of the University Medical Centre Utrecht and the Dutch HIV Association to increase variability. Semi-structured in-depth interviews were conducted between October 2020 and March 2021 and thematically analysed. Results: Of the 42 interviewed participants, 29 were PLHIV and 13 represented key populations (i.e., men who have sex with men and people injecting drugs). Both PLHIV and participants from vulnerable key populations hoped that a cure would result in normalization of their lives by removing the need to disclose HIV, reducing stigma and guilt, increasing independence of ART, and liberating sexual behaviour. Both groups believed only HIV elimination could accomplish this desired impact. Conclusions: While the post-treatment control scenario seems a more plausible outcome of current HIV cure research, our findings highlight that participants may not perceive it as a true cure. Involvement of PLHIV and vulnerable key populations in devising acceptable and feasible experimental approaches to HIV cure is essential to ensure their future successful implementation.

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BACKGROUND: De novo steatosis is the main criteria for non-alcoholic fatty liver disease (NAFLD), which is becoming a clinically relevant comorbidity in HIV-infected patients. This may be due to the HIV virus itself, as well as long-term toxicities deriving from antiretroviral therapy. Therefore, HIV infected patients require prevention and monitoring regarding NAFLD. METHODS: This study investigated the differential role of body mass index (BMI) and combination antiretroviral treatment (cART) drugs on NAFLD progression. This single center prospective longitudinal observational study enrolled HIV monoinfected individuals between August 2013 to December 2018 with yearly visits. Each visit included liver stiffness and steatosis [defined as controlled attenuation parameter (CAP)>237 dB/m] assessment by annually transient elastography using an M- or XL-probe of FibroScan, and calculation of the novel FibroScan-AST (FAST) score. Risk factors for denovo/progressed steatosis and tripling of FAST-score increase were investigated using Cox regression model with time-dependent covariates. FINDINGS: 319 monoinfected HIV positive patients with at least two visits were included into the study, of which 301 patients had at least two valid CAP measurements. 51·5%(155) patients did not have steatosis at first assessment, of which 45%(69) developed steatosis during follow-up. A BMI>23 kg/m2 (OR: 4·238, 95% CI: 2·078-8·938; p < 0·0001), tenofovir-alafenamid (TAF) (OR: 5·073, 95% CI: 2·362-10·899); p < 0·0001) and integrase strand transfer inhibitors (INSTI) (OR: 2·354, 95% CI: 1·370-4·048; p = 0·002), as well as type 2 diabetes mellitus (OR: 7·605, 95% CI: 2·315-24·981; p < 0·0001) were independent predictors of de novo steatosis in multivariable analysis. Tenofovir disoproxilfumarate (TDF) was associated with a lower risk for weight gain and steatosis progression/onset using CAP value (HR: 0·28, 95% CI: 0·12-0·64; p = 0·003) and FAST scores (HR: 0·31, 95% CI: 0·101-0·945; p = 0·04). INTERPRETATION: Steatosis can develop despite non-obese BMI in patients with HIV monoinfection under cART, especially in male patients with BMI over 23 kg/m2. While TAF and INSTI increase the risk of progression of steatosis, TDF was found to be independently associated with a lower risk of a clinically significant weight gain and thereby, might slow down development and progression of steatosis. FUNDING: There was no additional funding received for this project. All funders mentioned in the 'declaration of interests' section had no influence on study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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BACKGROUND: Consistent use of Pre-Exposure Prophylaxis (PrEP), a biomedical intervention for HIV seronegative persons, has been shown to significantly decrease HIV acquisition. Black women are a viable population segment to consider for PrEP use as their HIV incidence is overwhelmingly higher than all other women groups. METHODS: We developed and piloted a cultural- and age- appropriate PrEP education intervention to determine Black college women's: 1) perceptions of and receptivity to PrEP use; and 2) preferences for PrEP information delivery. RESULTS: We recruited N = 43 Black college women. Most of our sample were sophomore and Juniors of whom identified as heterosexual (83%) and single (67%). Over 50% of young women had never been HIV tested and only 28% had been tested in the last 6 months; however, 100% of the women believed their HIV status was negative. Prior to participating in the study, most Black college women (67%) had not heard about PrEP and were unsure or apprehensive (72%) to initiate PrEP. The Black college women indicated that our educational intervention was extremely helpful (67%) for understanding and learning about PrEP. Post participating in our PrEP education module, regardless of delivery modality, participants reported being likely (62.55-70%) to initiate PrEP in the future. CONCLUSIONS: Results indicate that Black college women would strongly consider PrEP when provided with basic knowledge, regardless of delivery modality. Participants also showed greater appreciation for in-person delivery and found it to be significantly more helpful and of greater quality for learning about PrEP; comprehension or perceived usefulness of PrEP-related content was relatively the same between groups. PrEP content delivery -- via in-person or online methods - is contingent on learning style and presentation. TRIAL REGISTRATION: This study has been registered under the ISRCTN Registry as of July 6, 2020. The trial registration number is ISRCTN14792715 . This study was retrospectively registered.

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BACKGROUND: Routine HIV pre-exposure prophylaxis (PrEP) and HIV care appointments provide opportunities for screening men who have sex with men (MSM) for hepatitis C virus infection (HCV). However, levels of screening required for achieving the WHO elimination target of reducing HCV incidence by 90% by 2030 among all MSM are unknown. METHODS: An HCV/HIV transmission model was calibrated to UK prevalence of HIV among MSM (4·7%) and chronic HCV infection among HIV-positive MSM (9·9%) and HIV-negative MSM (1.2%). Assuming 12·5% coverage of PrEP among HIV-negative MSM, we evaluated the relative reduction in overall HCV incidence by 2030 (compared to 2018 levels) of HCV screening every 12/6-months (alongside completing direct acting antiviral treatment within 6-months of diagnosis) in PrEP users and/or HIV-diagnosed MSM. We estimated the additional screening required among HIV-negative non-PrEP users to reduce overall incidence by 90% by 2030. The effect of 50% reduction in condom use among PrEP users (risk compensation) was estimated. RESULTS: Screening and treating PrEP users for HCV every 12 or 6-months decreases HCV incidence by 67·3% (uncertainty range 52·7-79·2%) or 70·2% (57·1-80·8%), respectively, increasing to 75·4% (59·0-88·6%) or 78·8% (63·9-90·4%) if HIV-diagnosed MSM are also screened at same frequencies. Risk compensation reduces these latter projections by <10%. To reduce HCV incidence by 90% by 2030 without risk compensation, HIV-negative non-PrEP users require screening every 5·6 (3·8-9·2) years if MSM on PrEP and HIV-diagnosed MSM are screened every 6-months, shortening to 4·4 (3·1-6·6) years with risk compensation. For 25·0% PrEP coverage, the HCV elimination target can be reached without screening HIV-negative MSM not on PrEP, irrespective of risk compensation. INTERPRETATION: At low PrEP coverage, increased screening of all MSM is required to achieve the WHO HCV-elimination targets for MSM in the UK, whereas at higher PrEP coverage this is possible through just screening HIV-diagnosed MSM and PrEP users.

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There is mounting urgency regarding the mental health of gay, bisexual and other men who have sex with men (GBM). We examined how GBM are understanding the relationship between HIV and their mental health given the increasing biomedicalisation of HIV prevention and care. Our Grounded Theory analysis derived from qualitative interviews with 24 GBM living in Toronto, Canada, including both HIV-negative and HIV-positive men. Participants understood biomedical advances, such as undetectable viral load and pre-exposure prophylaxis (PrEP), as providing some relief from HIV-related distress. However, they offered ambivalent perspectives on the biomedicalisation of HIV. Some considered non-HIV-specific stressors (e.g. unemployment, racial discrimination) more significant than HIV-related concerns. These men expressed HIV-related distress as being under control due to biomedical advances or as always negligible when compared to non-HIV-specific stressors. Others emphasised the ongoing mental health implications of HIV (e.g. enduring risk and stigma). We describe a tension between optimistic responses to biomedicine's ability to ease the psychosocial burdens associated with HIV and the inability for biomedicine to address the social and economic determinants driving the dual epidemics of HIV and mental distress amongst GBM. We argue for more socio-material analysis over further sexual behavioural analysis of GBM mental health disparities.

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BACKGROUND: To investigate whether religious service attendance and faith leaders' messages about HIV and same-sex relationships are associated with acceptance of HIV prevention strategies. METHODS: Multivariable Poisson regression assessed whether attending religious services, faith leaders' messages about HIV and same-sex relationships, and supportiveness of those messages were associated with HIV testing, as well as knowledge of and willingness to use pre-exposure prophylaxis (PrEP) among 868 Black Americans [45% men; M (SD) = 34 (9) years-old] in the 2016 National Survey on HIV in the Black Community, USA. RESULTS: Participants who reported attending services monthly and/or hearing faith leaders' messages that were supportive of same-sex relationships had a significantly higher likelihood of willingness to use PrEP (adjusted Rate Ratio[ARR] = 1.76; 95% confidence interval [CI] = 1.09, 2.48) and aRR = 2.19; 95% CI = 1.35, 3.55, respectively), independent of HIV risk. Homophobia was significantly associated with higher likelihood of being aware of PrEP and testing for HIV testing in the past 12 months. CONCLUSIONS: Faith leaders' messaging can influence Black Americans' perceptions and uptake of HIV prevention strategies. Faith institutions and faith leaders should be involved in designing and disseminating HIV prevention strategies.

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Tenofovir (TFV) is used in combination with other antiretroviral drugs for human immunodeficiency virus (HIV) treatment and prevention. TFV requires two phosphorylation steps to become pharmacologically active; however, the kinases that activate TFV in cells and tissues susceptible to HIV infection have yet to be identified. Peripheral blood mononuclear cells (PBMC), vaginal, and colorectal tissues were transfected with siRNA targeting nucleotide kinases, incubated with TFV, and TFV-monophosphate (TFV-MP) and TFV-diphosphate (TFV-DP) were measured using mass spectrometry-liquid chromatography. Adenylate kinase 2 (AK2) performed the first TFV phosphorylation step in PBMC, vaginal, and colorectal tissues. Interestingly, both pyruvate kinase isozymes, muscle (PKM) or liver and red blood cell (PKLR), were able to phosphorylate TFV-MP to TFV-DP in PBMC and vaginal tissue, while creatine kinase, muscle (CKM) catalyzed this conversion in colorectal tissue. In addition, next-generation sequencing of the Microbicide Trials Network MTN-001 clinical samples detected 71 previously unreported genetic variants in the genes encoding these kinases. In conclusion, our results demonstrate that TFV is activated in a compartment-specific manner. Further, genetic variants have been identified that could negatively impact TFV activation, thereby compromising TFV efficacy in HIV treatment and prevention.

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