Safety and Pharmacokinetics of Monoclonal Antibodies VRC07-523LS and PGT121 Administered Subcutaneously for Human Immunodeficiency Virus Prevention.

BACKGROUND: Effective, long-acting prevention approaches are needed to reduce human immunodeficiency virus (HIV) incidence. We evaluated the safety and pharmacokinetics of VRC07-523LS and PGT121 administered subcutaneously alone and in combination as passive immunization for young women in South Africa. METHODS: CAPRISA 012A was a randomized, double-blinded, placebo-controlled, dose-escalation phase 1 trial. We enrolled 45 HIV-negative women into 9 groups and assessed safety, tolerability, pharmacokinetics, neutralization activity, and antidrug antibody levels. Pharmacokinetic modeling was conducted to predict steady-state concentrations for 12- and 24-weekly dosing intervals. RESULTS: VRC07-523LS and PGT121, administered subcutaneously, were safe and well tolerated. Most common reactogenicity events were injection site tenderness and headaches. Nine product-related adverse events were mild and transient. Median VRC07-523LS concentrations after 20 mg/kg doses were 9.65 µg/mL and 3.86 µg/mL at 16 and 24 weeks. The median week 8 concentration after the 10 mg/kg PGT121 dose was 8.26 µg/mL. Modeling of PGT121 at 20 mg/kg showed median concentrations of 1.37 µg/mL and 0.22 µg/mL at 16 and 24 weeks. Half-lives of VRC07-523LS and PGT121 were 29 and 20 days. Both antibodies retained neutralizing activity postadministration and no antidrug antibodies were detected. CONCLUSIONS: Subcutaneous administration of VRC07-523LS in combination with optimized versions of PGT121 or other antibodies should be further assessed for HIV prevention.

Long-term adherence to antiretroviral therapy in a South African adult patient cohort: a retrospective study.

BACKGROUND: South Africa has the highest HIV prevalence and supports the largest antiretroviral therapy (ART) programme globally. With the introduction of a test and treat policy, ensuring long term optimal adherence to ART (≥95%) is essential for successful patient and public health outcomes. The aim of this study was to assess long-term ART adherence to inform best practices for chronic HIV care. METHOD: Long-term ART adherence was retrospectively analysed over a median duration of 5 years (interquartile range [IQR]: 5.3-6.5) in patients initially enrolled in a randomised controlled trial assessing tuberculosis and HIV treatment integration and subsequently followed post-trial in an observational cohort study in Durban, South Africa. The association between baseline patient characteristics and adherence over time was estimated using generalized estimating equations (GEE). Adherence was assessed using pharmacy pill counts conducted at each study visit and compared to 6 monthly viral load measurements. A Kaplan Meier survival analysis was used to estimate time to treatment failure. The McNemar test (with exact p-values) was used to determine the effect of pill burden and concurrent ART and tuberculosis treatment on adherence. RESULTS: Of the 270 patients included in the analysis; 54.8% were female, median age was 34 years (IQR:29-40) and median time on ART was 70 months (IQR = 64-78). Mean adherence was ≥95% for each year on ART. Stable patients provided with an extended 3-month ART supply maintained adherence > 99%. At study end, 96 and 94% of patients were optimally adherent and virologically suppressed, respectively. Time since ART initiation, female gender and primary breadwinner status were significantly associated with ≥95% adherence to ART. The cumulative probability of treatment failure was 10.7% at 5 years after ART initiation. Concurrent ART and tuberculosis treatment, or switching to a second line ART regimen with higher pill burden, did not impair ART adherence. CONCLUSION: Optimal long-term adherence with successful treatment outcomes are possible within a structured ART programme with close adherence monitoring. This adherence support approach is relevant to a resource limited setting adopting a test and treat strategy.

Tenofovir Gel for the Prevention of Herpes Simplex Virus Type 2 Infection.

BACKGROUND: Globally, herpes simplex virus type 2 (HSV-2) infection is the most common cause of genital ulcer disease. Effective prevention strategies for HSV-2 infection are needed to achieve the goals of the World Health Organization global strategy for the prevention and control of sexually transmitted infections. METHODS: We assessed the effectiveness of pericoital tenofovir gel, an antiviral microbicide, in preventing HSV-2 acquisition in a subgroup of 422 HSV-2-negative women enrolled in the Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004 study, a double-blind, randomized, placebo-controlled trial. Incident HSV-2 cases were identified by evidence of seroconversion on an HSV-2 IgG enzyme-linked immunosorbent assay between study enrollment and exit. A confirmatory analysis was performed by Western blot testing. RESULTS: The HSV-2 incidence rate was 10.2 cases per 100 person-years (95% confidence interval [CI], 6.8 to 14.7) among 202 women assigned to tenofovir gel, as compared with 21.0 cases per 100 person-years (95% CI, 16.0 to 27.2) among 222 women assigned to placebo gel (incidence rate ratio, 0.49; 95% CI, 0.30 to 0.77; P=0.003). The HSV-2 incidence rate among the 25 women with vaginal tenofovir concentrations of 10,000 ng per milliliter or more was 5.7 cases per 100 person-years, as compared with 15.5 cases per 100 person-years among the 103 women with no detectable vaginal tenofovir (incidence rate ratio, 0.37; 95% CI, 0.04 to 1.51; P=0.14). As confirmed by Western blot testing, there were 16 HSV-2 seroconversions among women assigned to tenofovir gel as compared with 36 among those assigned to the placebo gel (incidence rate ratio, 0.45; 95% CI, 0.23 to 0.82; P=0.005). CONCLUSIONS: In this study in South Africa, pericoital application of tenofovir gel reduced HSV-2 acquisition in women. (Funded by the U.S. Agency for International Development and others; ClinicalTrials.gov number, NCT00441298.).

Assessing Adherence to Antiretroviral Therapy in a Rural Paediatric Cohort in KwaZulu-Natal, South Africa.

Achieving optimal adherence to ARV's in a rural paediatric population is challenging. Monitoring adherence by frequent viral load assay is not always feasible or sustainable in rural communities. A relatively cheaper, reliable, valid and sustainable measure of adherence for children is required for routine management. This study retrospectively assessed adherence outcomes using monthly pill count and viral load data, including reasons reported for non-adherence, in a paediatric cohort in rural KwaZulu-Natal, South Africa. Between 2008 and 2013, 78 children, mean age of 7.1 years, were enrolled in the CAPRISA 052 AIDS Treatment Programme. Monthly treatment adherence by pill count was categorized as either high (≥95 %) or low (<95 %). Overall median monthly adherence to treatment by pill count was 87.8 % at month 6, 88.9 % at month 12 and 90.8 % at month 24. However, the proportion of children with an undetectable viral load (<400 copies/ml) was 84.0 % (63/74), 86.6 % (58/67), and 84.5 % (49/58) at the three time points respectively. Agreement between pill count and viral load showed that only 33.9, 36. 3 and 30.6 % of children were truly adherent by pill count at months 6, 12 and 24 respectively. In conclusion, this treatment programme demonstrated that adherence of >95 % by pill count is not an ideal indicator of virological suppression in children aged 6 months to 13 years. Viral load assessment remains the gold standard for assessing treatment success in this age group.

Individualised motivational counselling to enhance adherence to antiretroviral therapy is not superior to didactic counselling in South African patients: findings of the CAPRISA 058 randomised controlled trial.

Concerns that standard didactic adherence counselling may be inadequate to maximise antiretroviral therapy (ART) adherence led us to evaluate more intensive individualised motivational adherence counselling. We randomised 297 HIV-positive ART-naïve patients in Durban, South Africa, to receive either didactic counselling, prior to ART initiation (n = 150), or an intensive motivational adherence intervention after initiating ART (n = 147). Study arms were similar for age (mean 35.8 years), sex (43.1 % male), CD4+ cell count (median 121.5 cells/µl) and viral load (median 119,000 copies/ml). Virologic suppression at 9 months was achieved in 89.8 % of didactic and 87.9 % of motivational counselling participants (risk ratio [RR] 0.98, 95 % confidence interval [CI] 0.90-1.07, p = 0.62). 82.9 % of didactic and 79.5 % of motivational counselling participants achieved >95 % adherence by pill count at 6 months (RR 0.96, 95 % CI 0.85-1.09, p = 0.51). Participants receiving intensive motivational counselling did not achieve higher treatment adherence or virological suppression than those receiving routinely provided didactic adherence counselling. These data are reassuring that less resource intensive didactic counselling was adequate for excellent treatment outcomes in this setting.

Monitoring microbicide gel use with real-time notification of the container's opening events: results of the CAPRISA Wisebag study.

Accurate estimation of the effectiveness of a microbicide for HIV prevention requires valid measurement of adherence to product use. A microbicide gel applicator container (Wisebag), fitted with cell phone technology to transmit opening events and text message reminders, was developed to monitor each opening event of the container as a proxy for gel use and adherence. Ten women were enrolled in a pilot study and followed for up to 4 months. Wisebag opening (WBO) dates and times were recorded and correlated with self-reported sex acts and gel applicator returns. During the 33 monthly follow-up visits, 47.8 % (77/161) of the recorded number of WBO events were concordant with the number of empty (used) applicators returned. The discrepancies were likely due to removal of more than one applicator during a single opening event. When the date and time of the WBO event data was assessed in relation to three different self-report adherence measures, agreement was fairly modest. The Wisebag was found to be acceptable as a storage container and the cell phone reminders generated were useful in supporting the dosing strategy. We recommend that the Wisebag be considered for larger scale and lengthier testing in microbicide trials.

Measuring adherence by visual inspection of returned empty gel applicators in the CAPRISA 004 microbicide trial.

In the CAPRISA 004 trial, adherence was estimated as the proportion of reported sex acts covered by two gel doses, which was assessed by counting returned empty gel applicators. The returned empty applicators were inspected visually in a standardized manner for residue on the outside of the applicator, as an indicator of vaginal insertion. Over 15 months, spanning 11,839 study visits by 838 women, a total of 59,800 returned empty applicators were inspected. By visual assessment, 77.5 % of these applicators appeared to have been inserted. To test the accuracy of the assessment we fitted a Cox model and found that the risk for HIV infection was doubled when less than half of the returned empty applicators had been assessed as not inserted in the vagina. Visual inspection enhanced both the accuracy of the adherence measurement and aided identification of mechanical problems with applicator use experienced by women in the trial.

COVID-19 vaccine hesitancy in KwaZulu-Natal, South Africa: A survey of unvaccinated adults.

Background: Concerns and misconceptions surrounding coronavirus disease 2019 (COVID-19) vaccines may account for vaccine hesitancy and low uptake. Aim: To determine prevalence of COVID-19 vaccine hesitancy, vaccine-related misconceptions, and predictors of vaccine hesitancy among South Africans. Setting: Community setting in five districts in KwaZulu- Natal province. Methods: Between August 20, 2021, and September 27, 2021, we conducted a cross-sectional survey, interviewing 300 unvaccinated adults amid the national vaccination campaign. Predictors of hesitancy were identified through multivariable logistic regression analysis. Results: Participants had a median age of 29 years (IQR: 23-39), 86.7% were Black African, 63.2% were male, 53.3% resided in rural communities, and 59.3% (95% CI: 53.8% - 64.9%) were classified as vaccine hesitant. The primary reason for not vaccinating was a lack of trust in the vaccine (62.1%). Factors associated with reduced vaccine hesitancy included age (participants aged 35-49 years: OR: 0.28, 95% CI: 0.18-0.64, p = 0.003; participants over 50 years: OR: 0.18, 95% CI: 0.07-0.47, p = 0.0004), previous COVID-19 infection (OR: 0.31, 95% CI: 0.11-0.87, p = 0.03), and receiving vaccine information from healthcare workers (OR: 0.32, 95% CI: 0.10-1.0, p = 0.05). Unemployed (OR: 2.14, 95% CI: 1.1-4.2, p = 0.03) and self-employed individuals (OR: 2.98, 95% CI: 1.27-7.02, p = 0.01) were more likely to be vaccine hesitant. Conclusion: COVID-19 vaccine hesitancy rates are high in KwaZulu-Natal. Uptake could be enhanced by healthcare workers leading information campaigns with messages targeting younger individuals, the unemployed, and the self-employed. Contribution: This survey provides evidence to improve COVID-19 vaccination uptake in South Africa.

Safety and pharmacokinetics of escalating doses of neutralising monoclonal antibody CAP256V2LS administered with and without VRC07-523LS in HIV-negative women in South Africa (CAPRISA 012B): a phase 1, dose-escalation, randomised controlled trial.

BACKGROUND: Young women in sub-Saharan Africa continue to bear a high burden of HIV infection. Combination anti-HIV monoclonal antibodies are a potential HIV prevention technology that could overcome adherence challenges of daily oral pre-exposure prophylaxis. In this phase 1 clinical trial we aimed to determine the safety and pharmacokinetic profile of the broadly neutralising monoclonal antibody CAP256V2LS. METHODS: CAPRISA 012B, a first-in-human dose-escalation phase 1 trial evaluated the safety, pharmacokinetics, and neutralisation activity of CAP256V2LS alone and in combination with VRC07-523LS in young HIV-negative women in Durban, South Africa. Groups 1 and 2 were open label with CAP256V2LS administered at 5 mg/kg and 10 mg/kg intravenously and 5 mg/kg, 10 mg/kg, and 20 mg/kg subcutaneously. In group 3, participants were randomly allocated to receive a combination of CAP256V2LS and VRC07-523LS at 10 mg/kg and 20 mg/kg subcutaneously comixed with ENHANZE, a recombinant human hyaluronidase. Once safety was established in the first three participants, dose escalation took place sequentially following review of safety data. Primary endpoints were the proportion of participants with mild, moderate, and severe reactogenicity or adverse events, graded as per the Division of AIDS toxicity grading. The trial is registered on the Pan African Clinical Trial Registry, PACTR202003767867253, and is recruiting. FINDINGS: From July 13, 2020, to Jan 13, 2021, 42 HIV-negative women, aged 18-45 years, were enrolled. All 42 participants, eight with intravenous and 34 with subcutaneous administration, completed the trial. There were no serious adverse events or dose-limiting toxicities. Most commonly reported symptoms following intravenous administration were headaches in seven (88%) and nausea in four (50%) participants. Commonly reported symptoms following subcutaneous administration were headache in 31 (91%), chills in 25 (74%), and malaise or fatigue in 19 (56%) participants. Adverse events included transient lymphocytopenia in eight (19%), proteinuria in nine (21%), elevated aspartate aminotransferase in ten (24%), and alanine aminotransferase in five (12%) participants. INTERPRETATION: CAP256V2LS administered alone and in combination with VRC07-523LS was safe with favourable pharmacokinetics and neutralisation activity, supporting further assessment in larger clinical studies. FUNDING: European and Developing Countries Clinical Trials Partnership, South African Medical Research Council, and South African Department of Science and Innovation.

The influence of tuberculosis treatment on efavirenz clearance in patients co-infected with HIV and tuberculosis.

PURPOSE: Drug interactions are of concern when treating patients co-infected with human immunodeficiency virus (HIV) and tuberculosis. Concomitant use of efavirenz (EFV) with the enzyme inducer rifampicin might be expected to increase EFV clearance. We investigated the influence of concomitant tuberculosis treatment on the plasma clearance of EFV. METHODS: Fifty-eight patients were randomized to receive their EFV-containing antiretroviral therapy either during or after tuberculosis treatment. Steady-state EFV plasma concentrations (n = 209 samples) were measured, 83 in the presence of rifampicin. Data were analyzed using a non-linear mixed effects model, and the model was evaluated using non-parametric bootstrap and visual predictive checks. RESULTS: The patients had a median age of 32 (range 19-55) years and 43.1% were women. There was a bimodal distribution of apparent clearance, with slow EFV metabolizers accounting for 23.6% of the population and having a metabolic capacity 36.4% of that of the faster metabolizers. Apparent EFV clearance after oral administration in fast metabolizers was 12.9 L/h/70 kg whilst off tuberculosis treatment and 9.1 L/h/70 kg when on tuberculosis treatment. In slow metabolizers, the clearance estimates were 3.3 and 4.7 L/h/70 kg in the presence and absence of TB treatment, respectively. Overall there was a 29.5% reduction in EFV clearance during tuberculosis treatment. CONCLUSION: Unexpectedly, concomitant rifampicin-containing tuberculosis treatment reduced apparent EFV clearance with a corresponding increase in EFV exposure. While the reasons for this interaction require further investigation, cytochrome P450 2B6 polymorphisms in the population studied may provide some explanation.

Mental health outcomes and workplace quality of life among South African pharmacists during the COVID-19 pandemic: a cross-sectional study.

BACKGROUND: The effect of the COVID-19 pandemic on the mental health of healthcare workers is gaining attention globally. This study assessed the quality-of-working life (QoWL) and prevalence of, and risk factors for anxiety, depression and stress among South African pharmacists. METHODS: An online survey, after stratification by province, was sent to 3435 (target = 2454) randomly selected pharmacists between 14 April to 18 May 2021. Sociodemographic data were collected and mental health was assessed using the 7-item Generalized Anxiety Disorder scale, the 9-item Patient Health Questionnaire, Perceived Stress Scale and a modified Work-Related Quality-of-Life tool. Prevalence of anxiety, depression, stress and QoWL was estimated. A multivariate logistic regression analysis identified factors associated with mental health outcomes. RESULTS: A total of 953/2454 pharmacists (38.8%) responded. Of these, 56.5% were 40 years or younger, 78.5% were female, 45.4% were White race and 44.5% were practicing in a community pharmacy setting. Pharmacists demonstrated symptoms of anxiety (n = 605, 66.1%), depression (n = 561, 62.9%), stress (n = 642, 73.8%) and low QoWL (n = 409, 51.3%). Significant risk factors (aOR; 95%CI) for anxiety, depression and stress were female gender (1.96;1.36-2.83,1.84;1.27-2.67,1.58;1.05-2.38, history of mental health conditions (2.50; 1.52-4.13, 3.68; 2.19-6.19, 3.34;1.85-6.03) and significant COVID-19 mitigation changes to pharmacy practice (2.70; 1.36-5.38, 4.23; 2.06-8.70, 3.14;1.44-6.82), respectively. Practice changes were also associated with a low QoWL (5.19; 2.40-11.8). Compared to their Black/African colleagues, Indian pharmacists were at higher risk for anxiety (1.82; 1.03-3.23) and stress symptoms (2.28; 1.21-4.32), while risk for depression was significant amongst White pharmacists (1.86; 1.05-3.32). Pharmacists living apart from family were at significant risk for anxiety (1.66; 1.15-2.41), depression (1.52; 1.06-2.18) and low QoWL (1.60; 1.10-2.34). CONCLUSIONS: COVID-19 pandemic has had a significant negative impact on the mental health of South African pharmacists. Interventions to support the psychological well-being and improve QoWL of pharmacists are needed.

Implants for HIV prevention in young women: Provider perceptions and lessons learned from contraceptive implant provision.

Preventing new HIV infections, especially amongst young women, is key to ending the HIV epidemic especially in sub-Saharan Africa. Potent antiretroviral (ARV) drugs used as pre-exposure prophylaxis (PrEP) are currently being formulated as long-acting implantable devices, or nanosuspension injectables that release drug at a sustained rate providing protection from acquiring HIV. PrEP as implants (PrEP Implants) offers an innovative and novel approach, expanding the HIV prevention toolbox. Feedback from providers and future users in the early clinical product development stages may identify modifiable characteristics which can improve acceptability and uptake of new technologies. Healthcare workers (HCWs) perspectives and lessons learned during the rollout of contraceptive implants will allow us to understand what factors may impact the roll-out of PrEP implants. We conducted eighteen interviews with HCWs (9 Nurses and 9 Community Healthcare Workers) in rural KwaZulu-Natal, South Africa. HCWs listed the long-acting nature of the contraceptive implant as a key benefit, helping to overcome healthcare system barriers like heavy workloads and understaffing. However, challenges like side effects, migration of the implant, stakeholder buy-in and inconsistent training on insertion and removal hampered the roll-out of the contraceptive implant. For PrEP implants, HCWs preferred long-acting products that were palpable and biodegradable. Our findings highlighted that the characteristics of PrEP implants that are perceived to be beneficial by HCWs may not align with that of potential users, potentially impacting the acceptability and uptake of PrEP implants. Further our data highlight the need for sustained and multi-pronged approaches to training HCWs and introducing new health technologies into communities. Finding a balance between the needs of HCWs that accommodate their heavy workloads, limited resources at points of delivery of care and the needs and preferences of potential users need to be carefully considered in the development of PrEP implants.

Prospective study of oral pre-exposure prophylaxis initiation and adherence among young women in KwaZulu-Natal, South Africa.

INTRODUCTION: Oral tenofovir disoproxil fumarate/emtricitabine pre-exposure prophylaxis (PrEP), introduced into South Africa (SA) in 2016, has increasingly become part of HIV prevention standard of care. Given the urgent need for increased HIV prevention efforts for young women in SA, we conducted an implementation study to explore oral PrEP initiation and adherence, and the impact of oral PrEP on HIV incidence in this group. METHODS: This prospective cohort study (CAPRISA 082) was conducted at two sites (urban and rural) in KwaZulu-Natal, between March 2016 and February 2018. HIV-negative, sexually active women, aged 18-30 years, were enrolled and followed for approximately 10 months. Oral PrEP was offered as part of a comprehensive HIV prevention package. Adherence to oral PrEP was measured using pill counts and tenofovir-diphosphate (TFV-DP) levels. Characteristics of oral PrEP initiators versus non-initiators were compared using risk ratios. HIV incidence rates were measured using Poisson regression. RESULTS: Of 425 women enrolled, 262 (62%) initiated oral PrEP. Uptake was significantly higher at the rural site compared to the urban site (78% [n = 203/259] vs. 36% [n = 59/166], respectively, p-value<0.001). Approximately 25% and 50% had stopped using oral PrEP by 3 and 12 months post-initiation, respectively. Median pill count adherence was 90% (interquartile range: 81-97%); however, TFV-DP was only detected in 13% of samples tested, that is 56/431 samples from 97 (37%) participants who initiated oral PrEP. In total, 11 women seroconverted yielding an HIV incidence rate of 2.81 per 100 person-years (95% confidence interval: 1.40-5.03). Nine of 11 seroconverters had initiated oral PrEP; however, all showed drug levels equivalent to taking one to zero tablets per week. Among women who initiated oral PrEP, >50% had discontinued using oral PrEP by study end, with side effects, such as diarrhoea, nausea, headaches and rash, being the most frequent reason for discontinuation. CONCLUSIONS: Despite moderate oral PrEP initiation and high pill count adherence, adherence as measured by TFV-DP levels was low and early discontinuation was high. The overall HIV incidence rate was high underscoring the critical need to address barriers to oral PrEP initiation, adherence and continued use, as well as expanding HIV prevention options for young women.

Women for science and science for women: Gaps, challenges and opportunities towards optimizing pre-exposure prophylaxis for HIV-1 prevention.

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.

Integrated provision of topical pre-exposure prophylaxis in routine family planning services in South Africa: a non-inferiority randomized controlled trial.

INTRODUCTION: Tenofovir-containing oral pre-exposure prophylaxis (PrEP) is recommended for those at substantial risk as part of combination HIV prevention. However, there are limited data, beyond clinical trial settings, to guide the introduction of PrEP in healthcare services with adequate levels of adherence. Since young women in Africa are at high risk of HIV and likely to utilize family planning (FP) services, the feasibility, acceptability and effectiveness of integrating topical PrEP provision into routine FP services was assessed. METHODS: This two-arm, randomized controlled, non-inferiority, open-label extension trial was undertaken in urban and rural KwaZulu-Natal, South Africa. HIV-negative eligible women (n = 372) from the parent trial (Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004) were randomized to receive tenofovir gel either through intervention (FP clinics, n = 189) or control clinics (CAPRISA research clinics, n = 183). Non-inferiority was predefined as gel use in the intervention clinics would be no more than 20% lower than in the control clinics. Adherence, retention and HIV incidence rates were assessed. RESULTS: Women were enrolled between November 2012 and October 2014, and followed up for 682.3 women-years (mean = 22 months). Baseline characteristics of women in intervention and control clinics were comparable and retention rates were 92.1% and 92.3% respectively. Women in intervention clinics and control clinics returned on average 5.2 (95% confidence interval (CI): 4.7 to 5.7) and 5.7 (CI: 5.2 to 6.2) used gel applicators per month respectively, with a mean difference of -0.47 (CI: -1.16 to 0.21). Per-protocol estimates were on average 5.5 (CI: 5.0 to 6.1) and 5.8 (CI: 5.3 to 6.3) respectively, with a mean difference of -0.25 (CI: -0.98 to 0.48), meeting the non-inferiority criteria. Adherence, based on proportion of reported sex acts covered by two gel doses, was 79.9% (CI: 76.7 to 83.2) in intervention compared with 73.9% (CI: 70.7 to 77.1) in control clinics; mean difference:6.0% (CI: 1.5 to 10.6) (p = 0.009). HIV incidence rates were 3.5 (CI: 1.8 to 6.0) and 3.6 (CI: 1.9 to 6.3) per 100 women-years in intervention and control clinics respectively. Both these incidence rates were lower than the age-standardized rate of 6.2 per 100 women-years (n = 444) in the placebo arm of the parent trial (p = 0.019). CONCLUSIONS: 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.

Efavirenz dosing: influence of drug metabolizing enzyme polymorphisms and concurrent tuberculosis treatment.

BACKGROUND: Rifampicin-based tuberculosis (TB) treatment alters efavirenz (EFV) clearance. Polymorphisms in important drug metabolizing enzymes and the implications for EFV dosing were investigated. METHODS: Trough EFV concentrations (Cmin) were measured in 54 South African black patients. During TB treatment, EFV dose was 600 mg in patients <50 kg or 800 mg if ≥50 kg. Off TB treatment it was 600 mg. Polymorphisms in CYP2B6, CYP2A6 and UGT2B7 enzymes were sequenced. A multivariate generalized estimating equations model was fitted to assess predictors of high median EFV Cmin. RESULTS: During TB treatment, median EFV Cmin was 3.2 (IQR 2.6-6.3) µg/ml and 3.3 (2.4-9.5) µg/ml in the 800 mg and 600 mg groups, respectively. After TB treatment EFV Cmin was 2.0 (1.4-3.5) µg/ml. Minor allele frequencies for CYP2B6 516G→T, 785A→G, 983T→C, UGT2B7-372G→A, CYP2A6*9B and CYP2A6*17 were 0.31, 0.33, 0.23, 0.29, 0.10 and 0.02, respectively. Haplotypes CYP2B6*6 and CYP2B6*18 were found in 38.9% and 25.9% of patients, respectively. Polymorphisms in all three CYP2B6 genes studied (516T-785G-983C) were present in 11.1% of patients and in this group median EFV Cmin was 19.2 (IQR 9.5-20) µg/ml during and 4.7 (IQR 3.5-5.6) µg/ml after TB treatment. The presence of TB treatment and composite genotypes CYP2B6 516 GT/TT, CYP2B6 983 TC/CC and CYP2A6*9B carrier status predicted median EFV Cmin>4 µg/ml. Adverse events due to high EFV concentrations were rare. CONCLUSIONS: Because polymorphisms of EFV metabolizing enzymes are frequent and are associated with elevated EFV concentrations in this population, EFV dose increases are unnecessary when concomitant rifampicin-containing TB treatment is prescribed.

Genital Tenofovir Concentrations Correlate With Protection Against HIV Infection in the CAPRISA 004 Trial: Importance of Adherence for Microbicide Effectiveness.

OBJECTIVE: The CAPRISA 004 trial showed that coitally dosed tenofovir 1% gel reduced HIV acquisition by 39% overall and 54% when used consistently. The objective of this analysis was to ascertain its pharmacokinetic-pharmacodynamic relationship to protect against HIV acquisition. DESIGN: Genital and systemic tenofovir concentrations in 34 women who acquired HIV (cases) were compared with 302 randomly selected women who remained HIV uninfected (controls) during the CAPRISA 004 trial. In total, 336 cervicovaginal fluid (CVF), 55 plasma, and 23 paired cervical and vaginal tissue samples were assayed by validated methods for tenofovir and tenofovir diphosphate (tenofovir-DP) detection. RESULTS: Tenofovir was detected in the genital tract in 8 (23.5%) cases and 119 (39.4%) controls (P = 0.076). Among those with detectable genital tract tenofovir, the median CVF concentrations were 97% lower in cases compared with controls, 476 versus 13,821 ng/mL (P = 0.107). A total of 14.7% (5/34) of cases and 32.8% (99/302) of controls were found to have tenofovir CVF concentrations above 100 ng/mL [odds ratio (OR): 0.35, P = 0.037]. At a higher threshold, 8.8% (3/34) of cases and 26.2% (79/302) of controls were found to have tenofovir CVF concentrations above 1000 ng/mL (OR: 0.27, P = 0.036). Plasma tenofovir concentrations were <1 ng/mL in all women and were detected only in controls (16.7%) and not in cases (0%), (P = 0.031). Returned used tenofovir gel applicators and CVF concentrations were correlated (Spearman r = 0.22, P = 0.001). CONCLUSIONS: A tenofovir concentration of ≥100 ng/mL in CVF was associated with 65% (95% CI: 6% to 87%) protection against HIV, whereas a ≥1000 ng/mL concentration correlated with 76% (95% CI: 8% to 92%) protection against HIV infection.

A qualitative study of patient motivation to adhere to combination antiretroviral therapy in South Africa.

Taken as prescribed, that is, with high adherence, combination antiretroviral therapy (ART) has changed HIV infection and disease from being a sure predictor of death to a manageable chronic illness. Adherence, however, is difficult to achieve and maintain. The CAPRISA 058 study was conducted between 2007 and 2009 to test the efficacy of individualized motivational counselling to enhance ART adherence in South Africa. As part of the overall trial, a qualitative sub-study was conducted, including 30 individual interviews and four focus group discussions with patients in the first 9 months of ART initiation. Data were inductively analyzed, using thematic analysis, to identify themes central to ART adherence in this context. Four themes emerged that characterize the participants' experiences and high motivation to adhere to ART. Participants in this study were highly motivated to adhere, as they acknowledged that ART was 'life-giving', in the face of a large amount of morbidity and mortality. They were further supported by techniques of routine remembering, and highlighted the importance of good social support and access to supportive healthcare workers, to their continued success in negotiating their treatment. Participants in the current study told us that their adherence motivation is enhanced by free accessible care, approachable and supportive healthcare workers, broad social acceptance of ART, and past first-hand experiences with AIDS-related co-morbidity and mortality. Programs that include specific attention to these aspects of care will likely be successful in the long term.

Adherence challenges with drugs for pre-exposure prophylaxis to prevent HIV infection.

BACKGROUND: There are 34 million people living with human immunodeficiency virus (HIV) worldwide and each year this number increases. Until a vaccine is discovered, the prevention of new HIV infections remains an urgent priority. Several trials studying the use of oral and topical agents for the prevention of HIV infection have already been completed. Adherence has proved to be a major challenge in achieving product efficacy. AIM OF THE REVIEW: To provide the clinical pharmacist with an understanding of the oral pre-exposure prophylaxis (PrEP) and topical microbicide product pipeline whilst emphasizing the critical importance of adherence to these drugs to avert HIV infection. METHODS: PubMed/Medline and the web-based clinical trials registry (ClinTrials.gov) were searched using appropriate key words. For the time period 1992-2013--all phase II and phase III safety and effectiveness studies--testing agents for prevention of HIV infection were included in the review. Efficacy estimates, adherence estimates and reported challenges with adherence were extracted. RESULTS: Twenty-four phase II and III clinical trials were found during review. Of these, 20 trials have been completed, and six trials show effectiveness in preventing HIV infection. The majority of the successful trials were to oral PrEP and to date only one microbicide trial of a vaginal antiretroviral microbicide gel has showed effectiveness. Adherence to study product played a major role in trial outcomes and there are several reasons for non-adherence. These include high on-trial pregnancy rates, low trial retention rates, low participant perception of risk, participant characteristics such as age <25 years, single status, migratory partners and trial fatigue. Study product characteristics such as dosage form, dosing interval, as well as associated adverse events may also influence adherence. CONCLUSION: Moderate to high adherence is critical to demonstrate efficacy of drugs for HIV prevention. For topical agents, intermittent use associated with coitus is more effective than daily use, particularly if sex is infrequent or partners migrant. For oral agents, daily use is effective but the motivation to use the drug and high risk perception is important. In serodiscordant couples, early initiation of highly active antiretroviral therapy in the infected partner affords almost complete protection to the negative partner. Drugs need to be tailored to the population at risk and availability of multiple drug options are important.