Pre-exposure prophylaxis (PrEP) adherence remains a challenge among young men who have sex with men (MSM). We developed and tested a smartphone application ("app"), "DOT Diary", which combines ...automated directly observed therapy (DOT) with information about PrEP protection levels, pill-taking reminders, a sexual behavior diary, and a PrEP dosing calendar. To contextualize trial results, we qualitatively explored participants' app experiences. The trial enrolled 100 young MSM in San Francisco and Atlanta. Participants were randomized 2:1 to DOT Diary versus standard-of-care and followed for 24 weeks. Interviews were conducted with 24 intervention participants. Data were analyzed using a memo-writing approach. Most expressed overall satisfaction with the app ("it was good for its purpose"), despite concerns about technical glitches. The most popular app features were the monthly calendar showing days PrEP was taken and information about level of protection based on pills taken. The DOT component helped participants establish PrEP routines. The reminders were "annoying but effective" at motivating dosing. Opinions about the sexual behavior diary varied. Overall, DOT Diary was acceptable; participants were willing to use it daily to record pill-taking. Critical components included the information about PrEP protection levels and calendar, while others may be modified to improve future success.Trial registration: ClinicalTrials.gov identifier: NCT03771638.Pre-exposure prophylaxis (PrEP) adherence remains a challenge among young men who have sex with men (MSM). We developed and tested a smartphone application ("app"), "DOT Diary", which combines automated directly observed therapy (DOT) with information about PrEP protection levels, pill-taking reminders, a sexual behavior diary, and a PrEP dosing calendar. To contextualize trial results, we qualitatively explored participants' app experiences. The trial enrolled 100 young MSM in San Francisco and Atlanta. Participants were randomized 2:1 to DOT Diary versus standard-of-care and followed for 24 weeks. Interviews were conducted with 24 intervention participants. Data were analyzed using a memo-writing approach. Most expressed overall satisfaction with the app ("it was good for its purpose"), despite concerns about technical glitches. The most popular app features were the monthly calendar showing days PrEP was taken and information about level of protection based on pills taken. The DOT component helped participants establish PrEP routines. The reminders were "annoying but effective" at motivating dosing. Opinions about the sexual behavior diary varied. Overall, DOT Diary was acceptable; participants were willing to use it daily to record pill-taking. Critical components included the information about PrEP protection levels and calendar, while others may be modified to improve future success.Trial registration: ClinicalTrials.gov identifier: NCT03771638.
Abstract Recombinant adenovirus serotype 5 (rAd5) vaccine vectors for HIV-1 and other pathogens have been shown to be limited by high titers of Ad5 neutralizing antibodies (NAbs) in the developing ...world. Alternative serotype rAd vectors have therefore been constructed. Here we report Ad5, Ad26, Ad35, and Ad48 NAb titers in 4381 individuals from North America, South America, sub-Saharan Africa, and Southeast Asia. As expected, Ad5 NAb titers were both frequent and high magnitude in sub-Saharan Africa and Southeast Asia. In contrast, Ad35 NAb titers proved infrequent and low in all regions studied, and Ad48 NAbs were rare in all regions except East Africa. Ad26 NAbs were moderately common in adults in sub-Saharan Africa and Southeast Asia, but Ad26 NAb titers proved markedly lower than Ad5 NAb titers in all regions, and these relatively low Ad26 NAb titers did not detectably suppress the immunogenicity of 4 × 1010 vp of a rAd26-Gag/Pol/Env/Nef vaccine in rhesus monkeys. These data inform the clinical development of alternative serotype rAd vaccine vectors in the developing world.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Post-exposure prophylaxis (PEP) is currently recommended after certain high-risk exposures, and pre-exposure prophylaxis (PrEP) is undergoing evaluation in clinical trials. Media reports have ...suggested substantial levels of community PrEP use despite its unproven effectiveness.
We conducted a cross-sectional survey of 1819 HIV-uninfected gay/bisexual men in California to assess PEP and PrEP awareness and use.
Overall, 47% reported PEP awareness and 4% ever used PEP. Men who were older than 25 years of age (odds ratio OR = 2.2, 95% confidence interval CI: 1.5 to 3.1), were white (OR = 2.2, 95% CI: 1.6 to 3.0), had an annual income >$100,000 (OR = 2.0, 95% CI: 1.2 to 3.4), self-identified as gay/homosexual (OR = 2.4, 95% CI: 1.4 to 4.3), and had unprotected anal sex (OR = 1.8, 95% CI: 1.3 to 2.3) or sex under the influence of a drug (OR = 2.0, 95% CI: 1.5 to 2.7) were more likely to be aware of PEP, whereas speed users (OR = 0.6, 95% CI: 0.4 to 0.9) were less likely to be aware of PEP. Only 16% reported PrEP awareness, and <1% ever used PrEP. Unprotected anal sex (OR = 1.6, 95% CI: 1.1 to 2.3) and sex under the influence of a drug (OR = 1.5, 95% CI: 1.0 to 2.2) were associated with PrEP awareness.
PEP awareness and use were modest and PrEP use was rare among gay/bisexual men in California. Although PrEP is not currently recommended, community education on the availability of PEP is suggested.
Oral tenofovir disoproxil fumarate (TDF) for HIV prevention and treatment is associated with decreases in bone mineral density (BMD). Previous reports suggest that these changes may be reversible ...after discontinuation of TDF.
A metabolic substudy of 498 participants in a randomized, placebo-controlled HIV prevention trial of oral coformulated TDF with emtricitabine (TDF/FTC, Truvada) for HIV pre-exposure prophylaxis (PrEP) enrolling a global sample of men who have sex with men and trans women.
Participants underwent dual X-ray absorptiometry to quantify bone mineral density (BMD) in the hip and spine during PrEP and at 2 visits after stopping (median of 23 and 79 weeks post-PrEP, respectively). Results are stratified by pharmacologic measure of TDF/FTC adherence.
There was no significant difference in change in hip/spine BMD at any time point between placebo and those with low adherence. Adherent participants had a mean (standard error) BMD change at TDF/FTC discontinuation of -1.02% (0.24) in the hip and -1.84% (0.36) in the spine. After stop, annualized BMD increases of 1.13% per year (0.27) in hip and 1.81% per year (0.36) in spine BMD were observed in adherent participants compared with 0.19% (0.16) and 0.74% (0.21) in the placebo group, respectively (P = 0.003, both comparisons). On average, BMD returned to baseline levels by 1 year after PrEP stop. Recovery was consistent across age, baseline BMD z-score, and treatment duration.
Mean BMD returns to baseline levels within 12-18 months after TDF-based PrEP discontinuation in both hip and spine with consistency across participant subgroups.
clinicaltrials.gov NCT00458393.
Measurement of adherence to oral pre-exposure prophylaxis (PrEP) in real-time has been challenging. We developed DOT Diary, a smartphone application that combines automated directly observed therapy ...with a PrEP adherence visualization toolkit, and tested its ability to measure PrEP adherence and to increase adherence among a diverse cohort of young men who have sex with men (MSM). We enrolled 100 MSM in San Francisco and Atlanta and randomly assigned them 2:1 to DOT Diary versus standard of care. Concordance between DOT Diary measurement and drug levels in dried blood spots was substantial, with 91.0% and 85.3% concordance between DOT Diary and emtricitabine-triphosphate and tenofovir-diphosphate, respectively. There was no significant difference in the proportion of participants with detectable PrEP drug levels at 24 weeks between study arms. These results suggest DOT Diary is substantially better than self-reported measures of adherence, but additional interventions are needed to improve PrEP adherence over time.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
Recombinant viruses hold promise as vectors for vaccines to prevent infectious diseases with significant global health impacts. One of their major limitations is that preexisting anti-vector ...neutralizing antibodies can reduce T cell responses to the insert antigens; however, the impact of vector-specific cellular immunity on subsequent insert-specific T cell responses has not been assessed in humans. Here, we have identified and compared adenovirus-specific and HIV-specific T cell responses in subjects participating in two HIV-1 vaccine trials using a vaccine vectored by adenovirus serotype 5 (Ad5). Higher frequencies of pre-immunization adenovirus-specific CD4⁺ T cells were associated with substantially decreased magnitude of HIV-specific CD4⁺ T cell responses and decreased breadth of HIV-specific CD8⁺ T cell responses in vaccine recipients, independent of type-specific preexisting Ad5-specific neutralizing antibody titers. Further, epitopes recognized by adenovirus-specific T cells were commonly conserved across many adenovirus serotypes, suggesting that cross-reactivity of preexisting adenovirus-specific T cells can extend to adenovirus vectors derived from rare serotypes. These findings provide what we believe to be a new understanding of how preexisting viral immunity may impact the efficacy of vaccines under current evaluation for prevention of HIV, tuberculosis, and malaria.
BACKGROUND:HIV preexposure prophylaxis (PrEP) using daily oral tenofovir-disoproxil-fumarate/emtricitabine (TDF/FTC) is effective for preventing HIV acquisition, but concerns remain about its ...potential kidney toxicity. This study examined kidney function in individuals using PrEP in real-world clinical settings.
SETTING:Demonstration project in 2 sexually transmitted infection clinics and a community health center.
METHODS:We evaluated kidney function among men who have sex with men and transgender women taking tenofovir-disoproxil-fumarate/emtricitabine PrEP for up to 48 weeks. Serum creatinine and urine dipstick for protein were obtained at 12-week intervals. Kidney function was estimated using creatinine clearance (CrCl) (Cockcroft–Gault) and estimated glomerular filtration rate (eGFR) (CKD-EPI).
RESULTS:From October 2012 to January 2014, we enrolled 557 participants (median age 33). Mean creatinine increased from baseline to week 12 by 0.03 mg/dL (4.6%) (P < 0.0001); mean CrCl decreased by 4.8 mL/min (3.0%) (P < 0.0001). These changes remained stable through week 48 (P = 0.81, P = 0.71 respectively). There were 75/478 (15.7%) participants who developed worsening proteinuria at week 12 compared with baseline (P < 0.0001), and this percent remained stable through week 48 (P = 0.73). Twenty-five participants (5.1%) developed new-onset eGFR <70 mL/min/1.73 m; independent predictors of this outcome were age ≥40 years (OR 3.79, 95% CI1.43 to 10.03) and baseline eGFR <90 mL/min/1.73 m (OR 9.59, 3.69–24.94).
CONCLUSIONS:In a demonstration setting, daily tenofovir-disoproxil-fumarate/emtricitabine PrEP leads to reduced CrCl and eGFR; however, these eGFR changes are based on very small changes in serum creatinine and seem to be nonprogressive after the first 12 weeks. Future studies are needed to understand the prognostic significance of these small changes.
The reasons for recent declines in AIDS incidence and mortality may include advances in treatment, but these may be confounded by earlier declines in the incidence of human immunodeficiency virus ...(HIV) infection. To determine whether the declines in AIDS and mortality may, in part, stem from wider use of combination antiretroviral therapy, 622 HIV-positive men with well-characterized dates of seroconversion were followed. In this group, combination therapy came into widespread use in only 1996. In a Cox proportional hazards model, the 1996 calendar period was significantly associated with slower progression to AIDS (relative hazard RH = 0.19, 95% confidence interval CI, 0.05–0.69, P = .01) and death (RH = 0.45, 95% CI, 0.21–0.95, P = .04). Declines in incidence of HIV infection, changes in HIV virulence, and end-point underreporting cannot fully explain the decline in AIDS and death in 1996. The introduction of combination antiretroviral therapy as the standard of care may already have had measurable effects.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
At the 2019 Conference on Retroviruses and Opportunistic Infections (CROI), a plan for ending the HIV epidemic in the United States was presented. More rapid HIV diagnosis and treatment is a key ...component needed nationwide. In international settings, substantial scale up of HIV testing and treatment has led to substantial declines in HIV incidence. U=U (undetectable equals untransmittable) is a powerful concept that can reduce stigma and encourage engagement in testing and care, but raises a number of clinical questions. HIV testing remains a gateway to HIV prevention and treatment, and innovative testing strategies, including HIV self-testing, show promise. Opioid overdose deaths are on the rise, highlighting the need for comprehensive prevention efforts. Molecular data are being used to identify rapidly growing clusters of infections for intervention. Rates of sexually transmitted infections have increased substantially in recent years. A new preexposure prophylaxis (PrEP) combination, tenofovir alafenamide/emtricitabine (FTC), was demonstrated to be non inferior to tenofovir disoproxil fumarate/FTC, with improved bone and renal safety. PrEP uptake is increasing globally, but use is lower in several populations, including African Americans, cis- and transgender women, and youth. Same-day PrEP initiations are a promising approach to increasing access, but PrEP discontinuations remain a challenge.
HIV Vaccine Trials Network (HVTN) 505 was a phase 2b efficacy trial of a DNA/recombinant adenovirus 5 (rAd5) HIV vaccine regimen. Although the trial was stopped early for lack of overall efficacy, ...later correlates of risk and sieve analyses generated the hypothesis that the DNA/rAd5 vaccine regimen protected some vaccinees from HIV infection yet enhanced HIV infection risk for others. Here, we assessed whether and how host Fc gamma receptor (FcγR) genetic variations influenced the DNA/rAd5 vaccine regimen's effect on HIV infection risk. We found that vaccine receipt significantly increased HIV acquisition compared with placebo receipt among participants carrying the FCGR2C-TATA haplotype (comprising minor alleles of four
single-nucleotide polymorphism SNP sites) (hazard ratio HR = 9.79,
= 0.035) but not among participants without the haplotype (HR = 0.86,
= 0.67); the interaction of vaccine and haplotype effect was significant (
= 0.034). Similarly, vaccine receipt increased HIV acquisition compared with placebo receipt among participants carrying the FCGR3B-AGA haplotype (comprising minor alleles of the 3
SNPs) (HR = 2.78,
= 0.058) but not among participants without the haplotype (HR = 0.73,
= 0.44); again, the interaction of vaccine and haplotype was significant (
= 0.047). The FCGR3B-AGA haplotype also influenced whether a combined Env-specific CD8
T-cell polyfunctionality score and IgG response correlated significantly with HIV risk; an
SNP and two
SNPs influenced whether anti-gp140 antibody-dependent cellular phagocytosis correlated significantly with HIV risk. These results provide further evidence that Fc gamma receptor genetic variations may modulate HIV vaccine effects and immune function after HIV vaccination.
By analyzing data from the HVTN 505 efficacy trial of a DNA/recombinant adenovirus 5 (rAd5) vaccine regimen, we found that host genetics, specifically Fc gamma receptor genetic variations, influenced whether receiving the DNA/rAd5 regimen was beneficial, neutral, or detrimental to an individual with respect to HIV-1 acquisition risk. Moreover, Fc gamma receptor genetic variations influenced immune responses to the DNA/rAd5 vaccine regimen. Thus, Fc gamma receptor genetic variations should be considered in the analysis of future HIV vaccine trials and the development of HIV vaccines.
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