Browsing by Author "Gengiah, Tanuja Narayansamy."

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Adherence challenges with drugs for pre-exposure prophylaxis to prevent HIV infection.
(Springer Verlag., 2013) Gengiah, Tanuja Narayansamy.; Moosa, Atika.; Naidoo, Anushka.; Mansoor, Leila Essop.
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.
Adherence to ARVs in a rural paediatric cohort.
(2015) Smith, Chanelle.; Gengiah, Tanuja Narayansamy.
Abstract available in PDF file.
Assessing adherence to antiretroviral therapy in a rural paediatric cohort in KwaZulu-Natal, South Africa.
(Springer., 2016) Smith, Chanelle.; Gengiah, Tanuja Narayansamy.; Yende-Zuma, Fortunate Nonhlanhla.; Upfold, Michele.; Naidoo, Kogieleum.
Abstract available in pdf.
Assessing the implementation effectiveness and safety of 1% tenofovir gel provision through family planning services in KwaZulu-Natal, South Africa: study protocol for an open-label randomized controlled trial.
(BioMed Central., 2014) Mansoor, Leila Essop.; Abdool Karim, Quarraisha.; Mngadi, Kathryn Therese.; Dlamini, Sarah Alexandra.; Montague, Carl.; Nkomonde, Nelisiwe.; Mvandaba, Nomzamo.; Baxter, Cheryl.; Gengiah, Tanuja Narayansamy.; Samsunder, Natasha.; Dawood, Halima.; Grobler, Anna Christina.; Fröhlich, Janet Ann.; Abdool Karim, Salim Safurdeen.
Background: 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. Methods/design: 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 participated in an antiretroviral prevention study will be enrolled from an urban and rural site in KwaZulu-Natal, South Africa. The anticipated study duration is 30 months, with active accrual requiring approximately 12 months (following which an open cohort will be maintained) and follow-up continuing for approximately 18 months. At each of the two sites, eligible participants will be randomly assigned to receive tenofovir gel through either FP services (intervention arm) or through the CAPRISA research clinics (control arm). As part of the study intervention, a quality improvement approach will be used to assist the FP services to expand their current services to include tenofovir gel provision. Discussion: This protocol aims to address an important implementation question on whether FP services are able to effectively incorporate tenofovir gel provision for this at-risk group of women in South Africa. Provision of tenofovir gel to the women from the CAPRISA 004 trial meets the ethical obligation for post-trial access, and helps identify a potential avenue for future scale-up of microbicides within the public health system of South Africa. Trial registration: This trial was registered with the South Africa Department of Health (reference: DOH-27-0812-4129) and ClinicalTrials.gov (reference: NCT01691768) on 05 July 2012.
Changes to antiretroviral drug regimens during integrated TB-HIV treatment: results of the SAPiT trial.
(International Medical Press., 2014) Naidoo, Anushka.; Naidoo, Kogieleum.; Yende-Zuma, Fortunate Nonhlanhla.; Gengiah, Tanuja Narayansamy.; Padayatchi, Nesri.; Gray, Andrew Lofts.; Bamber, Sheila.; Nair, Gonasagrie.; Abdool Karim, Salim Safurdeen.
Background—Frequency of drug changes in combination antiretroviral therapy among patients starting both tuberculosis (TB) and human immunodeficiency virus (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 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 > 1000 copies/ml on two occasions, taken at least 4 weeks apart) were assessed in these patients. Results—A total of 501 TB-HIV co-infected patients were followed for a mean of 16.0 (95% confidence interval (CI): 15.5 to 16.6) months after antiretroviral therapy (ART) initiation. The standard first-line ARVs used, were efavirenz, lamivudine and didanosine. Individual drug switches for toxicity occurred in 14 patients (incidence rate: 2.1 per 100 person-years; 95% (CI): 1.1 to 3.5), and complete regimen changes due to virological failure in 25 patients (incidence rate: 3.7 per 100 person-years; CI: 2.4 to 5.5). The most common treatment limiting toxicities were neuropsychiatric effects (n=4; 0.8%), elevated transaminase levels and hyperlactatemia (n= 3; 0.6%), and peripheral neuropathy (n=2; 0.4%). Complete regimen change due to treatment failure was more common in patients with CD4+ cell count <50cells/mm3 (p<0.001) at ART initiation and body mass index greater than 25 kg/m2 (p=0.01) at entry into the study. Conclusion—Both drug switches and complete regimen change were uncommon in patients cotreated for TB-HIV with the chosen regimen. Patients with severe immunosuppression need to be monitored carefully, as they were most at risk for treatment failure requiring regimen change.
Co-enrollment in multiple HIV prevention trials - experiences from the CAPRISA 004 Tenofovir gel trial.
(Elsevier., 2011) Abdool Karim, Quarraisha.; Kharsany, Ayesha Bibi Mahomed.; Naidoo, Kasavan.; Yende Zuma, Nonhlanhla.; Gengiah, Tanuja Narayansamy.; Omar, Zaheen.; Arulappan, Natasha.; Mlisana, Koleka Patience.; Luthuli, Londiwe R.; Abdool Karim, Salim Safurdeen.
Background—In settings where multiple HIV prevention trials are conducted in close proximity, trial participants may attempt to enroll in more than one trial simultaneously. Co-enrollment impacts on participant’s safety and validity of trial results. We describe our experience, remedial action taken, inter-organizational collaboration and lessons learnt following the identification of co-enrolled participants. Experiences—Between February and April 2008, we identified 185 of the 398 enrolled participants as ineligible. In violation of the study protocol exclusion criteria, there was simultaneous enrollment in another HIV prevention trial (ineligible co-enrolled, n=135), and enrollment of women who had participated in a microbicide trial within the past 12 months (ineligible not co-enrolled, n=50). Following a complete audit of all enrolled participants, ineligible participants were discontinued via study exit visits from trial follow-up. Custom-designed education program on co-enrollment impacting on participants’ safety and validity of the trial results were implemented. Shared electronic database between research units were established to enable verification of each volunteer’s trial participation and to prevent future co-enrollments. Lessons Learnt—Interviews with ineligible enrolled women revealed that high-quality care; financial incentives; altruistic motives; preference for sex with gel; wanting to increase their likelihood of receiving active gel; perceived low risk of discovery and peer pressure as the reasons for their enrolment in the CAPRISA 004 trial. Conclusion—Instituting education programs based on the reasons reported by women for seeking enrolment in more than one trial and using a shared central database system to identify co-enrollments have effectively prevented further co-enrollments.
A drug evaluation of 1% tenofovir gel and tenofovir disoproxil fumarate tablets for the prevention of HIV infection.
(Informa Healthcare., 2011) Gengiah, Tanuja Narayansamy.; Baxter, Cheryl.; Mansoor, Leila Essop.; Kharsany, Ayesha Bibi Mahomed.; Abdool Karim, Salim Safurdeen.
Introduction: More than a million people acquire HIV infection annually. Pre-exposure 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.
Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women.
(American Association for the Advancement of Science., 2010) Abdool Karim, Salim Safurdeen.; Abdool Karim, Quarraisha.; Fröhlich, Janet Ann.; Grobler, Anna Christina.; Baxter, Cheryl.; Mansoor, Leila Essop.; Kharsany, Ayesha Bibi Mahomed.; Sibeko, Sengeziwe.; Mlisana, Koleka Patience.; Omar, Zaheen.; Gengiah, Tanuja Narayansamy.; Maarschalk, Silvia.; Arulappan, Natasha.; Mlotshwa, Mukelisiwe.; Morris, Lynn.; Taylor, Douglas.
The Centre for the AIDS Program of Research in South Africa (CAPRISA) 004 trial assessed the effectiveness and safety of a 1% vaginal gel formulation of tenofovir, a nucleotide reverse transcriptase inhibitor, for the prevention of HIV acquisition in women. A double-blind, randomized controlled trial was conducted comparing tenofovir gel (n = 445 women) with placebo gel (n = 444 women) in sexually active, HIV-uninfected 18- to 40-year-old women in urban and rural KwaZulu-Natal, South Africa. HIV serostatus, safety, sexual behavior, and gel and condom use were assessed at monthly follow-up visits for 30 months. HIV incidence in the tenofovir gel arm was 5.6 per 100 women-years (person time of study observation) (38 out of 680.6 women-years) compared with 9.1 per 100 women-years (60 out of 660.7 women-years) in the placebo gel arm (incidence rate ratio = 0.61; P = 0.017). In high adherers (gel adherence > 80%), HIV incidence was 54% lower (P = 0.025) in the tenofovir gel arm. In intermediate adherers (gel adherence 50 to 80%) and low adherers (gel adherence < 50%), the HIV incidence reduction was 38 and 28%, respectively. Tenofovir gel reduced HIV acquisition by an estimated 39% overall, and by 54% in women with high gel adherence. No increase in the overall adverse event rates was observed. There were no changes in viral load and no tenofovir resistance in HIV seroconverters. Tenofovir gel could potentially fill an important HIV prevention gap, especially for women unable to successfully negotiate mutual monogamy or condom use.
Genital tenofovir concentrations correlate with protection against HIV infection in the CAPRISA 004 trial: importance of adherence for microbicide effectiveness.
(Wolters Kluwer., 2015) Kashuba, Angela D. M.; Gengiah, Tanuja Narayansamy.; Werner, Lise.; Yang, Kuo-Hsiung.; White, Nicole R.; Abdool Karim, Quarraisha.; Abdool Karim, Salim Safurdeen.
Abstract available in pdf.
Implementing isoniazid preventive therapy in a tuberculosis treatment-experienced cohort on ART.
(International Union against Tuberculosis and Lung Disease., 2017) Maharaj, Bhavna.; Gengiah, Tanuja Narayansamy.; Yende-Zuma, Fortunate Nonhlanhla.; Gengiah, Santhanalakshmi.; Naidoo, Anushka.; Naidoo, Kogieleum.
Abstract available in pdf.
Implementing microbicides in low-income countries.
(Elsevier., 2012) Gengiah, Tanuja Narayansamy.; Abdool Karim, Quarraisha.
The magnitude of the global human immunodeficiency virus (HIV) epidemic is determined by women from lower income countries, specifically sub-Saharan Africa. Microbicides offer women who are unable to negotiate safe sex practices a self-initiated HIV prevention method. Of note, is its potential to yield significant public health benefits even with relatively conservative efficacy, coverage and user adherence estimates, making microbicides an effective intervention to invest scarce healthcare resources. Existing healthcare delivery systems provide an excellent opportunity to identify women at highest risk for infection and to also provide an access point to initiate microbicide use. Innovative quality improvement approaches, which strengthen existing sexual reproductive health services and include HIV testing, and linkages to care and treatment services, provide an opportunity to lay the foundations for wide-scale provision of microbicides. The potential to enhance health outcomes in women and infants and potentially affect rates of new HIV infection may soon be realised.
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.
(Springer., 2015) van Loggerenberg, Francois.; Grant, Alison D.; Naidoo, Kogieleum.; Murrman, Marita.; Gengiah, Santhanalakshmi.; Gengiah, Tanuja Narayansamy.; Fielding, Katherine L.; Abdool Karim, Salim Safurdeen.
Abstract available in pdf.
The influence of tuberculosis treatment on efavirenz clearance in patients co-infected with HIV and tuberculosis.
(Springer-Verlag., 2011) Gengiah, Tanuja Narayansamy.; Holford, Nicholas H. G.; Botha, Julia Hilary.; Gray, Andrew Lofts.; Naidoo, Kogieleum.; Abdool Karim, Salim Safurdeen.
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.
Initiating antiretrovirals during tuberculosis treatment: a drug safety review.
(Informa UK, Ltd., 2011) Gengiah, Tanuja Narayansamy.; Gray, Andrew Lofts.; Naidoo, Kogieleum.; Abdool Karim, Quarraisha.
Introduction: Integrating HIV and tuberculosis (TB) treatment can reduce mortality substantially. Practical barriers to treatment integration still exist and include safety concerns related to concomitant drug use because of drug interactions and additive toxicities. Altered therapeutic concentrations may influence the chances of treatment success or toxicity. Areas covered: The available data on drug--drug interactions between the rifamycin class of anti-mycobacterials and the non-nucleoside reverse transcriptase inhibitor and the protease inhibitor classes of antiretrovirals are discussed with recommendations for integrated use. Additive drug toxicities, the impact of immune reconstitution inflammatory syndrome (IRIS) and the latest data on survival benefits of integrating treatment are elucidated. Expert opinion: Deferring treatment of HIV to avoid drug interactions with TB treatment or the occurrence of IRIS is not necessary. In the integrated management of TB--HIV co-infection, rational drug combinations aimed at reducing toxicities while effecting TB cure and suppressing HIV viral load are possible.
Integrating human immunodeficiency virus and tuberculosis drug treatment.
(2014) Gengiah, Tanuja Narayansamy.; Botha, Julia Hilary.
The human immunodeficiency virus (HIV) and tuberculosis (TB) epidemics are major global public health challenges. Worldwide, approximately 42% of TB patients are also co-infected with HIV, and sub-Saharan Africa (SSA) is home to the majority of the world’s infections of both HIV and TB. Dual infection has been shown to be associated with a higher risk of death. Integrating drug treatment for both diseases is therefore essential to improve survival. However, drug interactions between antiretroviral therapy (ART) and anti-TB medication remain a challenge to effective treatment integration. Although several drug interactions have been identified, only some are clinically relevant. The impact of significant interactions on public health outcomes is expected to be greatest when large numbers of patients are prescribed interacting drugs. Efavirenz (EFV) is the most commonly prescribed nucleoside reverse transcriptase inhibitor (NNRTI) component of first line ART in sub-Saharan Africa, particularly when rifampicin (RIF) based TB treatment is co-administered. RIF is known to up-regulate cytochrome P450 (CYP450) drug metabolizing enzymes resulting in decreased exposure to concomitantly administered drugs that utilize similar metabolic pathways. Therefore, the concomitant use of EFV with RIF would be expected to increase EFV clearance while absorption of TB drugs may also be compromised by advanced HIV disease. The efficacy of both TB and HIV treatment may thus be compromised by pharmacokinetic interactions, while more recent evidence also implicates genetic variation in drug metabolism as a predictor of drug exposure. To understand the significance of the EFV-RIF interaction better in a South African population, the pharmacokinetics of EFV during and after RIF-based TB treatment were investigated as an ancillary study of the ‘Starting Tuberculosis and Antiretroviral Therapy’ (START) trial (CAPRISA 001: NCT00091936). Participants were randomized to receive both ART and TB treatment simultaneously (integrated arm) or to initiate ART only on completion of TB treatment (sequential arm). In both arms, the ART regimen included once daily enteric-coated didanosine (400 mg for participants >60 kg; 250 mg for participants <60 kg), lamivudine 300mg and efavirenz. Based on the expected drug interactions, when EFV was administered in the presence of TB treatment, participants weighing less than 50kg received 600mg and those weighing 50kg or more received 800mg daily. After TB treatment was successfully completed, all patients received EFV 600mg. Blood samples for trough EFV plasma concentrations were obtained at the end of months 1, 2 and 3 during TB treatment and at the same time points after TB treatment was successfully completed. Additionally, approximated peak RIF concentrations were measured 2.5 hours post-dose at the end of months 1, 2 and 3 of TB treatment. The influence of single nucleotide polymorphisms, in CYP2B6, CYP2A6, and UGT2B7 on EFV concentrations, and in drug transporter genes (SLCO1B1) on RIF concentrations, was assessed post-trial from stored peripheral blood mononuclear cell (PBMC) samples. EFV concentration-time data were analyzed using a population pharmacokinetic nonlinear mixed effects model (NONMEM) to quantify the impact of RIF-based TB treatment on EFV clearance. Unexpectedly, there was an overall 29.5% reduction in EFV clearance during TB treatment. A bimodal distribution of EFV apparent clearance (CL/F) was evident and indicated that slow EFV metabolisers accounted for 21.9% of the population. EFV clearance after oral administration in fast metabolisers was 11.5 L/h/70kg off TB treatment and 7.6 L/h/70kg when on TB treatment. In slow metabolisers, however, the clearance estimates were 2.9 and 4.3 L/h/70kg in the presence and absence of TB treatment respectively. Building on the findings of the NONMEM analysis and in response to the US FDA prescribing change in 2012, that approved an EFV dose increase from 600mg to 800mg in patients weighing 50kg and more when on concomitant RIF, the presence and influence of pharmacogenetic polymorphisms of the CYP450 enzyme system on NNRTI plasma exposure during and after TB co-treatment and the effect of increasing the EFV dose was investigated. During TB treatment, median (IQR) EFV Cmin was 3.2 (2.6-6.3) μg/mL and 3.3 (2.4-9.5) μg/mL in the EFV 800mg and 600mg groups respectively, while off TB treatment Cmin was 2.0 (1.4 - 3.5) μg/mL. The frequency of the CYP2B6 *1, *6 and *18 haplotypes was 18.5%, 38.9% and 25.9% respectively. Polymorphisms in all three CYP2B6 genes studied (516T-785G-983C) were present in 11.1% of patients. Median (IQR) EFV concentrations in patients with the three mutations were 19.2 (9.5-20) μg/mL and 4.7 (3.5-5.6) μg/mL when on and off TB treatment. TB treatment, composite genotypes CYP2B6 516 GT/TT, CYP2B6 983 TC/CC or being a CYP2A6*9B carrier predicted median EFV Cmin > 4 μg/mL. Therefore, increasing the EFV dose to 800mg during TB treatment is unnecessary in African patients with these polymorphisms. As a critical component of first line TB treatment concerns about sub-optimal TB drug bioavailability were examined for RIF. The influence of drug transporter gene polymorphisms on RIF concentrations was also assessed. Median RIF (IQR) C2.5hr was found to be 3.6 (2.8-5.0) μg/mL while polymorphism frequency of the SLCO1B1 (rs4149032) drug transporter gene was high (0.76) and was associated with low RIF concentrations as was male gender and having a low haemoglobin. Increased RIF dosage warrants urgent consideration in African TB-HIV co-infected patients. In conclusion, concomitant RIF-containing TB treatment unexpectedly reduced EFV CL/F with a corresponding increase in EFV exposure. Polymorphisms of EFV metabolizing enzymes were frequent in this population and contribute to this outcome. While in South Africa where TB-HIV co-treatment is associated with elevated EFV concentrations, peak RIF concentrations were alarmingly low and well below the recommended target range of 8 to 24 μg/mL. Increased RIF dosage may be warranted in African TB-HIV co-infected patients whilst the need for EFV dose increase is not supported by these data. Recommendations for public health benefit, in this generalized epidemic in South Africa, include the consideration of an EFV dose reduction as a cost saving to improve life-long treatment sustainability, and a RIF dose increase to curb TB treatment failure and future development of multiple-drug resistant (MDR) TB.
Integration of antiretroviral therapy with tuberculosis treatment.
(Massachusetts Medical Society., 2011) Abdool Karim, Salim Safurdeen.; Naidoo, Kogieleum.; Grobler, Anna Christina.; Padayatchi, Nesri.; Baxter, Cheryl.; Gray, Andrew Lofts.; Gengiah, Tanuja Narayansamy.; Gengiah, Santhanalakshmi.; Naidoo, Anushka.; Jithoo, Niraksha.; Nair, Gonasagrie.; El-Sadr, Wafaa M.; Friedland, Gerald H.; Abdool Karim, Quarraisha.
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.
Long term adherence to antiretroviral therapy in a South African cohort.
(2018) Moosa, Atika.; Gengiah, Tanuja Narayansamy.
Background Current treatment of HIV requires life-long antiretroviral therapy (ART) to suppress HIV replication. Adherence to medication is a critical component of treatment success, where ≥95% of doses, must be taken to achieve and maintain undetectable viral loads which are essential for successful patient and public health outcomes. Although South Africa recently introduced universal test and treat (UTT) and supports the largest number of people living with HIV (PLWH) on treatment in the world, there is limited data on long term adherence in our population. Objective The aim of this project was to retrospectively assess long term adherence in HIV infected patients on ART for at least five years or longer in order to inform long term care. Methodology Long-term adherence to ART was retrospectively analysed in HIV infected, ART naïve patients, first enrolled in a randomised controlled trial assessing tuberculosis (TB) and HIV treatment integration (N=642) and subsequently followed post-trial in an observational cohort study (N=402) in Durban, South Africa. Adherence was determined by assessing monthly or quarterly (depending on appointment schedule) pharmacy pill counts for patients on ART for five years or longer. Results From the initial randomized control trial cohort of 642 patients, 270 met the inclusion criteria for this 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 ART adherence was maintained at ≥ 95% for each year on ART and 93.9% of patients maintained viral suppression by the end of the follow up period. Pill count based adherence estimates showed high sensitivity (95%; 95%CI: 91-98%) in predicting viral suppression but poor specificity (9%; 95%CI: 0-41%) for predicting detectable viral loads at five years post-ART initiation. However, half of all patients had at least one sub-optimal (<95%) pill count in the first six months after ART initiation and <20% between the first and sixth year. Viral suppression was 87.4% six months after ART initiation and increased thereafter, remaining >92% throughout follow-up. HIV and TB co-treatment or switching to second line regimens with high pill burdens did not worsen adherence. Mean adherence was >99% in stable patients provided with an extended 90-day ART supply. Conclusion Our study found overall high adherence to ART in this South African cohort followed up over a period of more than five years. Treatment outcomes were successful on both first and second line treatment. Pill count was not a good predictor of virologic failure in our study and viral load measurement should be used as the benchmark for monitoring treatment response as required by current guidelines. However, adherence during the initial six months after ART initiation has been shown to impact long term treatment outcomes, therefore, pill count may be used as a quick, simple measure of adherence to identify patients with early adherence challenges and provide the opportunity for timeous adherence interventions. Optimal long-term adherence with successful treatment outcomes are possible within a structured ART programme with close adherence monitoring.This adherence support approach and these findings are relevant in the era of UTT.
Low rifampicin concentrations in tuberculosis patients with HIV infection.
(Open Learning on Enteric Pathogens., 2014) Gengiah, Tanuja Narayansamy.; Botha, Julia Hilary.; Soowamber, Deepak.; Naidoo, Kogieleum.; Abdool Karim, Salim Safurdeen.
Abstract available in pdf.
Measuring adherence by visual inspection of returned empty gel applicators in the CAPRISA 004 microbicide trial.
(Springer., 2014) Gengiah, Tanuja Narayansamy.; Mansoor, Leila Essop.; Upfold, Michele.; Naidoo, Anushka.; Yende-Zuma, Fortunate Nonhlanhla.; Kashuba, Angela D. M.; Abdool Karim, Quarraisha.; Abdool Karim, Salim Safurdeen.
Abstract not available in pdf.
Monitoring microbicide gel use with real-time notification of the container’s opening events : results of the CAPRISA Wisebag study.
(Springer., 2014) Gengiah, Tanuja Narayansamy.; Upfold, Michele.; Naidoo, Anushka.; Mansoor, Leila Essop.; Feldblum, Paul J.; Abdool Karim, Quarraisha.; Abdool Karim, Salim Safurdeen.
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.