Safety, Adherence and Acceptability of Intermittent Tenofovir/Emtricitabine as HIV Pre-Exposure Prophylaxis (PrEP) among HIV-Uninfected Ugandan Volunteers Living in HIV-Serodiscordant Relationships: A Randomized, Clinical Trial

Background: Efficacy of oral pre-exposure prophylaxis (PrEP) in prevention of HIV acquisition has been evaluated using a daily regimen. However, adherence to long term daily medication is rarely perfect. Intermittent regimen may be a feasible alternative. Preclinical studies have demonstrated effectiveness of intermittent PrEP in SHIV prevention among animals. However, little is known about intermittent PrEP regimens. Design: Seventy two HIV-uninfected volunteers in HIV serodiscordant couple relationships in Uganda were randomly assigned to receive daily oral Tenofovir/Emtricitabine (TDF/FTC-Truvada) or placebo, or intermittent (Monday, Friday and within 2 hours after sex, not to exceed one dose per day) oral TDF/FTC or placebo in a 2:1:2:1 ratio. Volunteers and study staff were blinded to drug assignment, but not to regimen assignment. Methods: Volunteers were followed for 4 months after randomization, with monthly clinical and laboratory safety assessments and comprehensive HIV risk reduction services. Adherence was monitored using medication event monitoring system (MEMS) and self-report. Sexual activity data were collected via daily short text message (SMS) and self-report. HIV-specific immune responses were assessed by IFN-γ ELISPOT. Results: Both daily and intermittent oral TDF/FTC regimens were well tolerated. Median MEMS adherence rates were 98% (IQR: 93-100) for daily PrEP regimen, 91% (IQR: 73-97) for fixed intermittent dosing and 45% (IQR: 20-63) for post-coital dosing. SMS response rate was 74%, but increased to 80% after excluding server outages; results may have been affected by the novelty of this measure. The majority of volunteers expressed willingness with no particular preference for either regimen. Conclusions: Both daily and intermittent oral PrEP dosing regimens were safe. Adherence was high for daily and fixed intermittent dosing; post-coital dosing was associated with poor adherence. Fixed intermittent PrEP regimens may be feasible especially if a minimum effective drug concentration correlating with HIV prevention can be achieved with this dosing. Registration Clinicaltrials.gov number NCT0093134

Three phylogenetic groups have driven the recent population expansion of Cryptococcus neoformans.

Cryptococcus neoformans (C. neoformans var. grubii) is an environmentally acquired pathogen causing 181,000 HIV-associated deaths each year. We sequenced 699 isolates, primarily C. neoformans from HIV-infected patients, from 5 countries in Asia and Africa. The phylogeny of C. neoformans reveals a recent exponential population expansion, consistent with the increase in the number of susceptible hosts. In our study population, this expansion has been driven by three sub-clades of the C. neoformans VNIa lineage; VNIa-4, VNIa-5 and VNIa-93. These three sub-clades account for 91% of clinical isolates sequenced in our study. Combining the genome data with clinical information, we find that the VNIa-93 sub-clade, the most common sub-clade in Uganda and Malawi, was associated with better outcomes than VNIa-4 and VNIa-5, which predominate in Southeast Asia. This study lays the foundation for further work investigating the dominance of VNIa-4, VNIa-5 and VNIa-93 and the association between lineage and clinical phenotype

Knowledge, Attitudes, and Practices Regarding COVID-19 among Healthcare Workers in Uganda: A Cross-Sectional Survey.

Healthcare workers (HCWs) are at high risk of COVID-19. However, data on HCWs' knowledge, attitudes, and practices (KAP) toward COVID-19 are limited. Between September and November 2020, we conducted a questionnaire-based COVID-19 KAP survey among HCWs at three hospitals in Uganda. We used Bloom's cut-off of ≥80% to determine sufficient knowledge, good attitude, and good practice, and multivariate Poisson regression with robust variance for statistical analysis. Of 717 HCWs invited to participate, 657 (91.6%) agreed and were enrolled. The mean age (standard deviation) of enrollees was 33.2 (10.2) years; most were clinical HCWs (64.7%) and had advanced secondary school/other higher-level education (57.8%). Overall, 83.9% had sufficient knowledge, 78.4% had a positive attitude, and 37.0% had good practices toward COVID-19. Factors associated with KAP were: Knowledge: being a clinical HCW (aRR: 1.12; 95% CI: 1.02-1.23) and previous participation in health research (aRR: 1.10; 95% CI: 1.04-1.17); Attitude: age > 35 years (aRR: 0.88; 95% CI: 0.79-0.98); Practice: being a clinical HCW (aRR: 1.91; 95% CI: 1.41-2.59). HCWs in Uganda have good knowledge and positive attitude but poor practices towards COVID-19. Differences in COVID-19 KAP between clinical and non-clinical HCWs could affect uptake of COVID-19 interventions including vaccination

Characterization of Near Full-Length Transmitted/Founder HIV-1 Subtype D and A/D Recombinant Genomes in a Heterosexual Ugandan Population (2006-2011).

Detailed characterization of transmitted HIV-1 variants in Uganda is fundamentally important to inform vaccine design, yet studies on the transmitted full-length strains of subtype D viruses are limited. Here, we amplified single genomes and characterized viruses, some of which were previously classified as subtype D by sub-genomic pol sequencing that were transmitted in Uganda between December 2006 to June 2011. Analysis of 5' and 3' half genome sequences showed 73% (19/26) of infections involved single virus transmissions, whereas 27% (7/26) of infections involved multiple variant transmissions based on predictions of a model of random virus evolution. Subtype analysis of inferred transmitted/founder viruses showed a high transmission rate of inter-subtype recombinants (69%, 20/29) involving mainly A1/D, while pure subtype D variants accounted for one-third of infections (31%, 9/29). Recombination patterns included a predominance of subtype D in the gag/pol region and a highly recombinogenic envelope gene. The signal peptide-C1 region and gp41 transmembrane domain (Tat2/Rev2 flanking region) were hotspots for A1/D recombination events. Analysis of a panel of 14 transmitted/founder molecular clones showed no difference in replication capacity between subtype D viruses (n = 3) and inter-subtype mosaic recombinants (n = 11). However, individuals infected with high replication capacity viruses had a faster CD4 T cell loss. The high transmission rate of unique inter-subtype recombinants is striking and emphasizes the extraordinary challenge for vaccine design and, in particular, for the highly variable and recombinogenic envelope gene, which is targeted by rational designs aimed to elicit broadly neutralizing antibodies

Examining oral pre-exposure prophylaxis (PrEP) literacy among participants in an HIV vaccine trial preparedness cohort study

Background: PrEP literacy is influenced by many factors including the types of information available and how it is interpreted. The level of PrEP literacy may influence acceptability and uptake. Methods: We conducted 25 in-depth interviews in a HIV vaccine trial preparedness cohort study. We explored what participants knew about PrEP, sources of PrEP knowledge and how much they know about PrEP. We used the framework approach to generate themes for analysis guided by the Social Ecological Model and examined levels of PrEP literacy using the individual and interpersonal constructs of the SEM. Results: We found that PrEP awareness is strongly influenced by external factors such as social media and how much participants know about HIV treatment and prevention in the local community. However, while participants highlighted the importance of the internet/social media as a source of information about PrEP they talked of low PrEP literacy in their communities. Participants indicated that their own knowledge came as a result of joining the HIV vaccine trial preparedness study. However, some expressed doubts about the effectiveness of the drug and worried about side effects. Participants commented that at the community level PrEP was associated with being sexually active, because it was used to prevent the sexual transmission of HIV. As a result, some participants commented that one could feel judged by the health workers for asking for PrEP at health facilities in the community. Conclusion: The information collected in this study provided an understanding of the different layers of influence around individuals that are important to address to improve PrEP acceptability and uptake. Our findings can inform strategies to address the barriers to PrEP uptake, particularly at structural and community levels. Trial registration: https://clinicaltrials.gov/ct2/show/NCT04066881

Examining oral pre-exposure prophylaxis (PrEP) literacy among participants in an HIV vaccine trial preparedness cohort study

Background PrEP literacy is influenced by many factors including the types of information available and how it is interpreted. The level of PrEP literacy may influence acceptability and uptake. Methods We conducted 25 in-depth interviews in a HIV vaccine trial preparedness cohort study. We explored what participants knew about PrEP, sources of PrEP knowledge and how much they know about PrEP. We used the framework approach to generate themes for analysis guided by the Social Ecological Model and examined levels of PrEP literacy using the individual and interpersonal constructs of the SEM. Results We found that PrEP awareness is strongly influenced by external factors such as social media and how much participants know about HIV treatment and prevention in the local community. However, while participants highlighted the importance of the internet/social media as a source of information about PrEP they talked of low PrEP literacy in their communities. Participants indicated that their own knowledge came as a result of joining the HIV vaccine trial preparedness study. However, some expressed doubts about the effectiveness of the drug and worried about side effects. Participants commented that at the community level PrEP was associated with being sexually active, because it was used to prevent the sexual transmission of HIV. As a result, some participants commented that one could feel judged by the health workers for asking for PrEP at health facilities in the community. Conclusion The information collected in this study provided an understanding of the different layers of influence around individuals that are important to address to improve PrEP acceptability and uptake. Our findings can inform strategies to address the barriers to PrEP uptake, particularly at structural and community levels. Trial registration https://clinicaltrials.gov/ct2/show/NCT0406688

Utility of different adherence measures for PrEP: Patterns and incremental value

Measuring PrEP adherence remains challenging. In 2009-2010, the International AIDS Vaccine Initiative randomized phase II trial participants to daily tenofovir disoproxil fumarate/emtricitabine or placebo in Uganda and Kenya. Adherence was measured by electronic monitoring (EM), self-report (SR), and drug concentrations in plasma and hair. Each adherence measure was categorised as low, moderate, or high and also considered continuously; the incremental value of combining measures was determined. Forty-five participants were followed over 4 months. Discrimination for EM adherence by area under receiver operating curves (AROC) was poor for SR (0.53) and best for hair (AROC 0.85). When combining hair with plasma or hair with self-report, discrimination was improved (AROC > 0.9). Self-reported adherence was of low utility by itself. Hair level was the single best PK measure to predict EM-assessed adherence; the other measurements had lower discrimination values. Combining short-term (plasma) and long-term (hair) metrics could be useful to assess patterns of drug-taking in the context of PrEP

Utility of different adherence measures for PrEP: Patterns and incremental value

Measuring PrEP adherence remains challenging. In 2009-2010, the International AIDS Vaccine Initiative randomized phase II trial participants to daily tenofovir disoproxil fumarate/emtricitabine or placebo in Uganda and Kenya. Adherence was measured by electronic monitoring (EM), self-report (SR), and drug concentrations in plasma and hair. Each adherence measure was categorised as low, moderate, or high and also considered continuously; the incremental value of combining measures was determined. Forty-five participants were followed over 4 months. Discrimination for EM adherence by area under receiver operating curves (AROC) was poor for SR (0.53) and best for hair (AROC 0.85). When combining hair with plasma or hair with self-report, discrimination was improved (AROC > 0.9). Self-reported adherence was of low utility by itself. Hair level was the single best PK measure to predict EM-assessed adherence; the other measurements had lower discrimination values. Combining short-term (plasma) and long-term (hair) metrics could be useful to assess patterns of drug-taking in the context of PrEP

Quality of life and associated factors among HIV positive patients after completion of treatment for Cryptococcal meningitis

Background Cryptococcal meningitis (CCM) remains one of the leading causes of mortality among HIV infected patients. Due to factors such as the severity of CCM pathology, the quality of life (QOL) of patients post-treatment is likely to be poor. Few studies have reported on QOL of CCM patients post treatment completion. We used data collected among patients in the CryptoDex trial (ISRCTN59144167) to determine QOL and associated factors at week 10 and six months from treatment initiation. Methodology CryptoDex was a double-blind placebo-controlled trial of adjunctive dexamethasone in HIV infected adults with CCM, conducted between 2013 and 2015 in six countries in Asia and Africa. QOL was determined using the descriptive and Visual Analog Scales (VAS) of the EuroQol Five-Dimension-Three-Level (EQ-5D-3L) tool. We derived index scores, and described these and the VAS scores at 10 weeks and 6 months; and used linear regression to determine the relationship between various characteristics and VAS scores at both time points. VAS scores were interpreted as very good (81–100), good (51–80), normal (31–50) and bad/very bad (0–30). Results Of 451 patients enrolled in the trial, 238 had QOL evaluations at week 10. At baseline, their mean age (SD) was 35.2(8.5) years. The mean index scores (SD) were 0.785(0.2) and 0.619(0.4) among African and Asian patients respectively at week 10, and 0.879(0.2) and 0.731(0.4) among African and Asian patients respectively at month six. The overall mean VAS score (SD) at 10 weeks was 57.2 (29.7), increasing significantly to 72(27.4) at month six (p<0.001). At week 10, higher VAS score was associated with greater weight (p = 0.007) and being African (p<0.001), while lower VAS score was associated with positive yeast culture at day 14 (p = 0.026). At month six, higher VAS score remained associated with African origin (p = 0.006) while lower VAS score was associated with positive yeast culture (p = 0.006). Lower VAS scores were associated with higher number of inpatient days at 10 weeks and 6 months (p = 0.003 and 0.002 respectively). Conclusion QOL was good among patients that had completed therapy for CCM, but below perfect. Strategies to improve QOL among CCM survivors are required