Background Effective, long-acting prevention approaches are needed to reduce human immunodeficien... more 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 μ...
IntroductionYoung African women bear a disproportionately high risk for HIV acquisition. HIV tech... more IntroductionYoung African women bear a disproportionately high risk for HIV acquisition. HIV technologies that empower women to protect themselves are needed. Safe, potent antiretroviral agents such as tenofovir alafenamide (TAF), formulated as long-acting subdermal implants, offer an innovative solution.Methods and analysisCAPRISA 018 is a phase I/II trial to evaluate the safety, acceptability, tolerability and pharmacokinetics (PKs) of a TAF free base subdermal silicone implant containing 110 mg of TAF with an anticipated 0.25 mg/day release rate.The phase I trial (n=60) will assess the safety of one implant inserted in six participants (Group 1), followed by dose escalation components (Groups 2 and 3) assessing the safety, tolerability and PK of one to four TAF 110 mg implants releasing between 0.25 mg and 1 mg daily in 54 healthy women at low risk for HIV infection. Data from this phase I trial will be used to determine the dosing, implant location and implant replacement interv...
Introduction New HIV prevention strategies are urgently required. The discovery of broadly neutra... more Introduction New HIV prevention strategies are urgently required. The discovery of broadly neutralising antibodies (bNAbs) has provided the opportunity to evaluate passive immunisation as a potential prevention strategy and facilitate vaccine development. Since 2014, several bNAbs have been isolated from a clade C-infected South African donor, CAPRISA 256. One particular bNAb, CAP256-VRC26.25, was found to be extremely potent, with good coverage against clade C viruses, the dominant HIV clade in sub-Saharan Africa. Challenge studies in non-human primates demonstrated that this antibody was fully protective even at extremely low doses. This bNAb was subsequently structurally engineered and the clinical variant is now referred to as CAP256V2LS. Methods and analysis CAPRISA 012B is the second of three trials in the CAPRISA 012 bNAb trial programme. It is a first-in-human, phase I study to assess the safety and pharmacokinetics of CAP256V2LS. The study is divided into four groups. Group...
Introduction: Tenofovir-containing oral pre-exposure prophylaxis (PrEP) is recommended for those ... more 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 À0.47 (CI: À1.16 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 À0.25 (CI: À0.98 to 0.48), meeting the non-inferiority criteria. Adherence, based on proportion of reported sex acts covered by two gel doses, was 79.9%
IntroductionDespite extensive prevention campaigns and scale-up of antiretroviral therapy, HIV in... more IntroductionDespite extensive prevention campaigns and scale-up of antiretroviral therapy, HIV incidence among young women in southern Africa remains high. While the development of an efficacious vaccine remains a challenge, the discovery of broadly neutralising monoclonal antibodies (mAbs) has created the opportunity to explore passive immunisation as a long-acting injectable HIV prevention strategy. The purpose of this trial is to provide safety, pharmacokinetic (PK) and functional activity data of VRC07-523LS and PGT121 when administered subcutaneously (SC) to young South African women. Going forward, the aim is to select the ideal dose and/or monoclonal antibody for co-formulation and testing with CAP256-VRC26.25LS, a potent monoclonal antibody against subtype C virus, in an efficacy trial.Methods and analysisCAPRISA 012A is a randomised, double blinded, placebo-controlled phase I trial to assess the safety and PK profile of two mAbs, VRC07-523LS and PGT121 administered SC to 35...
Achieving optimal adherence to ARV's in a rural paediatric population is challenging. Monitoring ... more 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 six, 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 six, 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 six months-13 years. Viral load assessment remains the gold standard for assessing treatment success in this age group.
JAIDS Journal of Acquired Immune Deficiency Syndromes, 2015
In our cover story we summarise findings from the CAPRISA 004 trial that indicate that consistent... more In our cover story we summarise findings from the CAPRISA 004 trial that indicate that consistently high tenofovir concentrations during sexual exposure may be necessary to achieve high levels of protection against HIV. On page 2 we provide highlights from the MRC SHIP TB Biomarker meeting and report on a new initiative, "Tea talks" with the Director.
The Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004 trial demonstrated a ... more The Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004 trial demonstrated a 39% reduction in HIV infection, with a 54% HIV reduction in women who used tenofovir gel consistently. A confirmatory trial is expected to report results in early 2015. In the interim, we have a unique window of opportunity to prepare for and devise effective strategies for the future policy and programmatic scale-up of tenofovir gel provision. One approach is to integrate tenofovir gel provision into family planning (FP) services. The CAPRISA 008 implementation trial provides an opportunity to provide post-trial access to tenofovir gel while generating empiric evidence to assess whether integrating tenofovir gel provision into routine FP services can achieve similar levels of adherence as the CAPRISA 004 trial. This is a two-arm, open-label, randomized controlled non-inferiority trial. A maximum of 700 sexually active, HIV-uninfected women aged 18 years and older who previously particip...
Taken as prescribed, that is, with high adherence, combination antiretroviral therapy (ART) has c... more 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.
The Journal of Infection in Developing Countries, 2014
Introduction: The efficacy of tuberculosis (TB) treatment in Human Immunodeficiency Syndrome (HIV... more Introduction: The efficacy of tuberculosis (TB) treatment in Human Immunodeficiency Syndrome (HIV) co-infected patients may be compromised by genetic and pharmacokinetic variation in drug disposition. Rifampicin is a critical component of TB treatment. We investigated the influence of drug transporter gene polymorphisms on rifampicin concentrations in TB-HIV co-infected patients in Durban, South Africa. Methodology: Rifampicin concentrations were measured 2.5 hours post-dose (approximated peak, C2.5hr) in patients receiving either 450mg or 600mg rifampicin, randomized to either integrated or sequential antiretroviral treatment. Patients were genotyped for SLCO1B1 (rs4149032) polymorphisms. A mixed effects regression model was fitted to assess the influence of various factors on rifampicin concentrations. TB recurrence rates were also estimated. Results: In 57 patients, median (IQR) C2.5hr was 3.6 (2.8-5.0) µg/mL. Polymorphism frequency in the SLCO1B1 (rs4149032) drug transporter gen...
Background Frequency of drug changes in combination antiretroviral therapy among patients startin... more Background Frequency of drug changes in combination antiretroviral therapy among patients starting both tuberculosis (TB) and HIV therapy, as a result of treatment-limiting toxicity or virological failure, is not well established. Methods Patients in the Starting Antiretroviral Therapy at Three Points in Tuberculosis (SAPiT) trial were randomized to initiate antiretroviral therapy (ART) either early or late during TB treatment or after completion of TB treatment. Drug changes due to toxicity (defined as due to grade 3 or 4 adverse events) or virological failure (defined as viral load >1,000 copies/ml on two occasions, taken ≥4 weeks apart) were assessed in these patients. Results A total of 501 TB–HIV-coinfected patients were followed for a mean of 16.0 months (95% CI 15.5, 16.6) after ART initiation. The standard first-line antiretrovirals used were efavirenz, lamivudine and didanosine. Individual drug switches for toxicity occurred in 14 patients (incidence rate 2.1 per 100 per...
Background Rifampicin-based tuberculosis (TB) treatment alters efavirenz (EFV) clearance. Polymor... more 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 (C were measured min) 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 C. min Results During TB treatment, median EFV C was 3.2 min (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 C was 2.0 (1.4-3.5) μg/ml. Minor allele min 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% an...
Background Young women in sub-Saharan Africa bear a disproportionate burden of HIV infection comp... more Background Young women in sub-Saharan Africa bear a disproportionate burden of HIV infection compared to men but have limited options to reduce their HIV risk. Microbicides could fill an important HIV prevention gap for sexually active women who are unable to successfully negotiate mutual monogamy or condom use. Purpose This paper describes the baseline sample characteristics in the CAPRISA 004 trial which assessed the safety and effectiveness of the vaginal microbicide, 1% tenofovir gel for HIV prevention in South Africa. Methods This analysis assessed the baseline demographic, clinical and sexual behavior data of women screened and enrolled into the trial. The characteristics were summarized using descriptive summary measures; expressed as means and percent for categorical variables. Results HIV prevalence at screening was 25.8% [95% Confidence Interval (CI):23.9-27.7). Of the 889 eligibly enrolled women who contributed follow-up data, rural participants recruited from a family pl...
Background-There are 34 million people living with HIV worldwide and each year this number increa... more Background-There are 34 million people living with 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 preexposure 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 to 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 HAART 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.
Vaginal Gel Versus HIV HIV prevention technologies for women are urgently needed, especially in s... more Vaginal Gel Versus HIV HIV prevention technologies for women are urgently needed, especially in sub-Saharan Africa where young women bear the greatest burden of the HIV epidemic. Abdool Karim et al. (p. 1168 ; published online 19 July) present the results of the CAPRISA 004 randomized control trial. The nearly 3-year-long trial, conducted in urban and rural South African women, tested the efficacy of a vaginal gel containing the antiretroviral drug tenofovir in preventing HIV infection. The dosing strategy required application of the gel both before and after coitus, and with this regime HIV infection was reduced by approximately 39% overall, by 54% in women with high adherence to the protocol, and with no increase in overall adverse event rates.
Background We previously reported that integrating antiretroviral therapy (ART) with tuberculosis... more Background We previously reported that integrating antiretroviral therapy (ART) with tuberculosis treatment reduces mortality. However, the timing for the initiation of ART during tuberculosis treatment remains unresolved. Methods We conducted a three-group, open-label, randomized, controlled trial in South Africa involving 642 ambulatory patients, all with tuberculosis (confirmed by a positive sputum smear for acid-fast bacilli), human immunodeficiency virus infection, and a CD4+ T-cell count of less than 500 per cubic millimeter. Findings in the earlier-ART group (ART initiated within 4 weeks after the start of tuberculosis treatment, 214 patients) and later-ART group (ART initiated during the first 4 weeks of the continuation phase of tuberculosis treatment, 215 patients) are presented here. Results At baseline, the median CD4+ T-cell count was 150 per cubic millimeter, and the median viral load was 161,000 copies per milliliter, with no significant differences between the two groups. The incidence rate of the acquired immunodeficiency syndrome (AIDS) or death was 6.9 cases per 100 person-years in the earlier-ART group (18 cases) as compared with 7.8 per 100 person-years in the later-ART group (19 cases) (incidence-rate ratio, 0.89; 95% confidence interval [CI], 0.44 to 1.79; P = 0.73). However, among patients with CD4+ T-cell counts of less than 50 per cubic millimeter, the incidence rates of AIDS or death were 8.5 and 26.3 cases per 100 person-years, respectively (incidence-rate ratio, 0.32; 95% CI, 0.07 to 1.13; P = 0.06). The incidence rates of the immune reconstitution inflammatory syndrome (IRIS) were 20.1 and 7.7 cases per 100 person-years, respectively (incidence-rate ratio, 2.62; 95% CI, 1.48 to 4.82; P<0.001). Adverse events requiring a switching of antiretroviral drugs occurred in 10 patients in the earlier-ART group and 1 patient in the later-ART group (P = 0.006). Conclusions Early initiation of ART in patients with CD4+ T-cell counts of less than 50 per cubic millimeter increased AIDS-free survival. Deferral of the initiation of ART to the first 4 weeks of the continuation phase of tuberculosis therapy in those with higher CD4+ T-cell counts reduced the risks of IRIS and other adverse events related to ART without increasing the risk of AIDS or death.
Background The rates of death are high among patients with coinfection with tuberculosis and the ... more Background The rates of death are high among patients with coinfection with tuberculosis and the human immunodeficiency virus (HIV). The optimal timing for the initiation of antiretroviral therapy in relation to tuberculosis therapy remains controversial. Methods In an open-label, randomized, controlled trial in Durban, South Africa, we assigned 642 patients with both tuberculosis and HIV infection to start antiretroviral therapy either during tuberculosis therapy (in two integrated-therapy groups) or after the completion of such treatment (in one sequential-therapy group). The diagnosis of tuberculosis was based on a positive sputum smear for acid-fast bacilli. Only patients with HIV infection and a CD4+ cell count of less than 500 per cubic millimeter were included. All patients received standard tuberculosis therapy, prophylaxis with trimethoprim-sulfamethoxazole, and a once-daily antiretroviral regimen of didanosine, lamivudine, and efavirenz. The primary end point was death from any cause. Results This analysis compares data from the sequential-therapy group and the combined integrated-therapy groups up to September 1, 2008, when the data and safety monitoring committee recommended that all patients receive integrated antiretroviral therapy. There was a reduction in the rate of death among the 429 patients in the combined integrated-therapy groups (5.4 deaths per 100 person-years, or 25 deaths), as compared with the 213 patients in the sequential-therapy group (12.1 per 100 person-years, or 27 deaths); a relative reduction of 56% (hazard ratio in the combined integrated-therapy groups, 0.44; 95% confidence interval, 0.25 to 0.79; P = 0.003). Mortality was lower in the combined integrated-therapy groups in all CD4+ count strata. Rates of adverse events during follow-up were similar in the two study groups. Conclusions The initiation of antiretroviral therapy during tuberculosis therapy significantly improved survival and provides further impetus for the integration of tuberculosis and HIV services. (ClinicalTrials.gov number, NCT00398996.
Introduction: More than a million people acquire HIV infection annually. Preexposure prophylaxis ... more Introduction: More than a million people acquire HIV infection annually. Preexposure prophylaxis (PrEP) using antiretrovirals is currently being investigated for HIV prevention. Oral and topical formulations of tenofovir have undergone preclinical and clinical testing to assess acceptability, safety and effectiveness in preventing HIV infection. Areas covered: The tenofovir drug development pathway from compound discovery, preclinical animal model testing and human testing were reviewed for safety, tolerability and efficacy. Tenofovir is well tolerated and safe when used both systemically or applied topically for HIV prevention. High drug concentrations at the site of HIV transmission and concomitant low systemic drug concentrations are achieved with vaginal application. Coitally applied gel may be the favored prevention option for women compared with the tablets, which may be more suitable for prevention in men and sero-discordant couples. However, recent contradictory effectiveness outcomes in women need to be better understood. Expert opinion: Emerging evidence has brought new hope that antiretrovirals can potentially change the course of the HIV epidemic when used as early treatment for prevention, as topical or oral PrEP. Although some trial results appear conflicting, behavioral factors, adherence to dosing and pharmacokinetic properties of the different tenofovir formulations and dosing approaches offer plausible explanations for most of the variations in effectiveness observed in different trials.
Background Effective, long-acting prevention approaches are needed to reduce human immunodeficien... more 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 μ...
IntroductionYoung African women bear a disproportionately high risk for HIV acquisition. HIV tech... more IntroductionYoung African women bear a disproportionately high risk for HIV acquisition. HIV technologies that empower women to protect themselves are needed. Safe, potent antiretroviral agents such as tenofovir alafenamide (TAF), formulated as long-acting subdermal implants, offer an innovative solution.Methods and analysisCAPRISA 018 is a phase I/II trial to evaluate the safety, acceptability, tolerability and pharmacokinetics (PKs) of a TAF free base subdermal silicone implant containing 110 mg of TAF with an anticipated 0.25 mg/day release rate.The phase I trial (n=60) will assess the safety of one implant inserted in six participants (Group 1), followed by dose escalation components (Groups 2 and 3) assessing the safety, tolerability and PK of one to four TAF 110 mg implants releasing between 0.25 mg and 1 mg daily in 54 healthy women at low risk for HIV infection. Data from this phase I trial will be used to determine the dosing, implant location and implant replacement interv...
Introduction New HIV prevention strategies are urgently required. The discovery of broadly neutra... more Introduction New HIV prevention strategies are urgently required. The discovery of broadly neutralising antibodies (bNAbs) has provided the opportunity to evaluate passive immunisation as a potential prevention strategy and facilitate vaccine development. Since 2014, several bNAbs have been isolated from a clade C-infected South African donor, CAPRISA 256. One particular bNAb, CAP256-VRC26.25, was found to be extremely potent, with good coverage against clade C viruses, the dominant HIV clade in sub-Saharan Africa. Challenge studies in non-human primates demonstrated that this antibody was fully protective even at extremely low doses. This bNAb was subsequently structurally engineered and the clinical variant is now referred to as CAP256V2LS. Methods and analysis CAPRISA 012B is the second of three trials in the CAPRISA 012 bNAb trial programme. It is a first-in-human, phase I study to assess the safety and pharmacokinetics of CAP256V2LS. The study is divided into four groups. Group...
Introduction: Tenofovir-containing oral pre-exposure prophylaxis (PrEP) is recommended for those ... more 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 À0.47 (CI: À1.16 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 À0.25 (CI: À0.98 to 0.48), meeting the non-inferiority criteria. Adherence, based on proportion of reported sex acts covered by two gel doses, was 79.9%
IntroductionDespite extensive prevention campaigns and scale-up of antiretroviral therapy, HIV in... more IntroductionDespite extensive prevention campaigns and scale-up of antiretroviral therapy, HIV incidence among young women in southern Africa remains high. While the development of an efficacious vaccine remains a challenge, the discovery of broadly neutralising monoclonal antibodies (mAbs) has created the opportunity to explore passive immunisation as a long-acting injectable HIV prevention strategy. The purpose of this trial is to provide safety, pharmacokinetic (PK) and functional activity data of VRC07-523LS and PGT121 when administered subcutaneously (SC) to young South African women. Going forward, the aim is to select the ideal dose and/or monoclonal antibody for co-formulation and testing with CAP256-VRC26.25LS, a potent monoclonal antibody against subtype C virus, in an efficacy trial.Methods and analysisCAPRISA 012A is a randomised, double blinded, placebo-controlled phase I trial to assess the safety and PK profile of two mAbs, VRC07-523LS and PGT121 administered SC to 35...
Achieving optimal adherence to ARV's in a rural paediatric population is challenging. Monitoring ... more 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 six, 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 six, 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 six months-13 years. Viral load assessment remains the gold standard for assessing treatment success in this age group.
JAIDS Journal of Acquired Immune Deficiency Syndromes, 2015
In our cover story we summarise findings from the CAPRISA 004 trial that indicate that consistent... more In our cover story we summarise findings from the CAPRISA 004 trial that indicate that consistently high tenofovir concentrations during sexual exposure may be necessary to achieve high levels of protection against HIV. On page 2 we provide highlights from the MRC SHIP TB Biomarker meeting and report on a new initiative, "Tea talks" with the Director.
The Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004 trial demonstrated a ... more The Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004 trial demonstrated a 39% reduction in HIV infection, with a 54% HIV reduction in women who used tenofovir gel consistently. A confirmatory trial is expected to report results in early 2015. In the interim, we have a unique window of opportunity to prepare for and devise effective strategies for the future policy and programmatic scale-up of tenofovir gel provision. One approach is to integrate tenofovir gel provision into family planning (FP) services. The CAPRISA 008 implementation trial provides an opportunity to provide post-trial access to tenofovir gel while generating empiric evidence to assess whether integrating tenofovir gel provision into routine FP services can achieve similar levels of adherence as the CAPRISA 004 trial. This is a two-arm, open-label, randomized controlled non-inferiority trial. A maximum of 700 sexually active, HIV-uninfected women aged 18 years and older who previously particip...
Taken as prescribed, that is, with high adherence, combination antiretroviral therapy (ART) has c... more 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.
The Journal of Infection in Developing Countries, 2014
Introduction: The efficacy of tuberculosis (TB) treatment in Human Immunodeficiency Syndrome (HIV... more Introduction: The efficacy of tuberculosis (TB) treatment in Human Immunodeficiency Syndrome (HIV) co-infected patients may be compromised by genetic and pharmacokinetic variation in drug disposition. Rifampicin is a critical component of TB treatment. We investigated the influence of drug transporter gene polymorphisms on rifampicin concentrations in TB-HIV co-infected patients in Durban, South Africa. Methodology: Rifampicin concentrations were measured 2.5 hours post-dose (approximated peak, C2.5hr) in patients receiving either 450mg or 600mg rifampicin, randomized to either integrated or sequential antiretroviral treatment. Patients were genotyped for SLCO1B1 (rs4149032) polymorphisms. A mixed effects regression model was fitted to assess the influence of various factors on rifampicin concentrations. TB recurrence rates were also estimated. Results: In 57 patients, median (IQR) C2.5hr was 3.6 (2.8-5.0) µg/mL. Polymorphism frequency in the SLCO1B1 (rs4149032) drug transporter gen...
Background Frequency of drug changes in combination antiretroviral therapy among patients startin... more Background Frequency of drug changes in combination antiretroviral therapy among patients starting both tuberculosis (TB) and HIV therapy, as a result of treatment-limiting toxicity or virological failure, is not well established. Methods Patients in the Starting Antiretroviral Therapy at Three Points in Tuberculosis (SAPiT) trial were randomized to initiate antiretroviral therapy (ART) either early or late during TB treatment or after completion of TB treatment. Drug changes due to toxicity (defined as due to grade 3 or 4 adverse events) or virological failure (defined as viral load >1,000 copies/ml on two occasions, taken ≥4 weeks apart) were assessed in these patients. Results A total of 501 TB–HIV-coinfected patients were followed for a mean of 16.0 months (95% CI 15.5, 16.6) after ART initiation. The standard first-line antiretrovirals used were efavirenz, lamivudine and didanosine. Individual drug switches for toxicity occurred in 14 patients (incidence rate 2.1 per 100 per...
Background Rifampicin-based tuberculosis (TB) treatment alters efavirenz (EFV) clearance. Polymor... more 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 (C were measured min) 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 C. min Results During TB treatment, median EFV C was 3.2 min (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 C was 2.0 (1.4-3.5) μg/ml. Minor allele min 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% an...
Background Young women in sub-Saharan Africa bear a disproportionate burden of HIV infection comp... more Background Young women in sub-Saharan Africa bear a disproportionate burden of HIV infection compared to men but have limited options to reduce their HIV risk. Microbicides could fill an important HIV prevention gap for sexually active women who are unable to successfully negotiate mutual monogamy or condom use. Purpose This paper describes the baseline sample characteristics in the CAPRISA 004 trial which assessed the safety and effectiveness of the vaginal microbicide, 1% tenofovir gel for HIV prevention in South Africa. Methods This analysis assessed the baseline demographic, clinical and sexual behavior data of women screened and enrolled into the trial. The characteristics were summarized using descriptive summary measures; expressed as means and percent for categorical variables. Results HIV prevalence at screening was 25.8% [95% Confidence Interval (CI):23.9-27.7). Of the 889 eligibly enrolled women who contributed follow-up data, rural participants recruited from a family pl...
Background-There are 34 million people living with HIV worldwide and each year this number increa... more Background-There are 34 million people living with 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 preexposure 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 to 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 HAART 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.
Vaginal Gel Versus HIV HIV prevention technologies for women are urgently needed, especially in s... more Vaginal Gel Versus HIV HIV prevention technologies for women are urgently needed, especially in sub-Saharan Africa where young women bear the greatest burden of the HIV epidemic. Abdool Karim et al. (p. 1168 ; published online 19 July) present the results of the CAPRISA 004 randomized control trial. The nearly 3-year-long trial, conducted in urban and rural South African women, tested the efficacy of a vaginal gel containing the antiretroviral drug tenofovir in preventing HIV infection. The dosing strategy required application of the gel both before and after coitus, and with this regime HIV infection was reduced by approximately 39% overall, by 54% in women with high adherence to the protocol, and with no increase in overall adverse event rates.
Background We previously reported that integrating antiretroviral therapy (ART) with tuberculosis... more Background We previously reported that integrating antiretroviral therapy (ART) with tuberculosis treatment reduces mortality. However, the timing for the initiation of ART during tuberculosis treatment remains unresolved. Methods We conducted a three-group, open-label, randomized, controlled trial in South Africa involving 642 ambulatory patients, all with tuberculosis (confirmed by a positive sputum smear for acid-fast bacilli), human immunodeficiency virus infection, and a CD4+ T-cell count of less than 500 per cubic millimeter. Findings in the earlier-ART group (ART initiated within 4 weeks after the start of tuberculosis treatment, 214 patients) and later-ART group (ART initiated during the first 4 weeks of the continuation phase of tuberculosis treatment, 215 patients) are presented here. Results At baseline, the median CD4+ T-cell count was 150 per cubic millimeter, and the median viral load was 161,000 copies per milliliter, with no significant differences between the two groups. The incidence rate of the acquired immunodeficiency syndrome (AIDS) or death was 6.9 cases per 100 person-years in the earlier-ART group (18 cases) as compared with 7.8 per 100 person-years in the later-ART group (19 cases) (incidence-rate ratio, 0.89; 95% confidence interval [CI], 0.44 to 1.79; P = 0.73). However, among patients with CD4+ T-cell counts of less than 50 per cubic millimeter, the incidence rates of AIDS or death were 8.5 and 26.3 cases per 100 person-years, respectively (incidence-rate ratio, 0.32; 95% CI, 0.07 to 1.13; P = 0.06). The incidence rates of the immune reconstitution inflammatory syndrome (IRIS) were 20.1 and 7.7 cases per 100 person-years, respectively (incidence-rate ratio, 2.62; 95% CI, 1.48 to 4.82; P<0.001). Adverse events requiring a switching of antiretroviral drugs occurred in 10 patients in the earlier-ART group and 1 patient in the later-ART group (P = 0.006). Conclusions Early initiation of ART in patients with CD4+ T-cell counts of less than 50 per cubic millimeter increased AIDS-free survival. Deferral of the initiation of ART to the first 4 weeks of the continuation phase of tuberculosis therapy in those with higher CD4+ T-cell counts reduced the risks of IRIS and other adverse events related to ART without increasing the risk of AIDS or death.
Background The rates of death are high among patients with coinfection with tuberculosis and the ... more Background The rates of death are high among patients with coinfection with tuberculosis and the human immunodeficiency virus (HIV). The optimal timing for the initiation of antiretroviral therapy in relation to tuberculosis therapy remains controversial. Methods In an open-label, randomized, controlled trial in Durban, South Africa, we assigned 642 patients with both tuberculosis and HIV infection to start antiretroviral therapy either during tuberculosis therapy (in two integrated-therapy groups) or after the completion of such treatment (in one sequential-therapy group). The diagnosis of tuberculosis was based on a positive sputum smear for acid-fast bacilli. Only patients with HIV infection and a CD4+ cell count of less than 500 per cubic millimeter were included. All patients received standard tuberculosis therapy, prophylaxis with trimethoprim-sulfamethoxazole, and a once-daily antiretroviral regimen of didanosine, lamivudine, and efavirenz. The primary end point was death from any cause. Results This analysis compares data from the sequential-therapy group and the combined integrated-therapy groups up to September 1, 2008, when the data and safety monitoring committee recommended that all patients receive integrated antiretroviral therapy. There was a reduction in the rate of death among the 429 patients in the combined integrated-therapy groups (5.4 deaths per 100 person-years, or 25 deaths), as compared with the 213 patients in the sequential-therapy group (12.1 per 100 person-years, or 27 deaths); a relative reduction of 56% (hazard ratio in the combined integrated-therapy groups, 0.44; 95% confidence interval, 0.25 to 0.79; P = 0.003). Mortality was lower in the combined integrated-therapy groups in all CD4+ count strata. Rates of adverse events during follow-up were similar in the two study groups. Conclusions The initiation of antiretroviral therapy during tuberculosis therapy significantly improved survival and provides further impetus for the integration of tuberculosis and HIV services. (ClinicalTrials.gov number, NCT00398996.
Introduction: More than a million people acquire HIV infection annually. Preexposure prophylaxis ... more Introduction: More than a million people acquire HIV infection annually. Preexposure prophylaxis (PrEP) using antiretrovirals is currently being investigated for HIV prevention. Oral and topical formulations of tenofovir have undergone preclinical and clinical testing to assess acceptability, safety and effectiveness in preventing HIV infection. Areas covered: The tenofovir drug development pathway from compound discovery, preclinical animal model testing and human testing were reviewed for safety, tolerability and efficacy. Tenofovir is well tolerated and safe when used both systemically or applied topically for HIV prevention. High drug concentrations at the site of HIV transmission and concomitant low systemic drug concentrations are achieved with vaginal application. Coitally applied gel may be the favored prevention option for women compared with the tablets, which may be more suitable for prevention in men and sero-discordant couples. However, recent contradictory effectiveness outcomes in women need to be better understood. Expert opinion: Emerging evidence has brought new hope that antiretrovirals can potentially change the course of the HIV epidemic when used as early treatment for prevention, as topical or oral PrEP. Although some trial results appear conflicting, behavioral factors, adherence to dosing and pharmacokinetic properties of the different tenofovir formulations and dosing approaches offer plausible explanations for most of the variations in effectiveness observed in different trials.
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Papers by Tanuja Gengiah