Kevindra Naidu

High-Levels of Acquired Drug Resistance in Adult Patients Failing First-Line Antiretroviral Therapy in a Rural HIV Treatment Programme in KwaZulu-Natal, South Africa

Objective To determine the frequency and patterns of acquired antiretroviral drug resistance in a rural primary health care programme in South Africa. Design Cross-sectional study nested within HIV treatment programme. Methods Adult (≥18 years) HIV-infected individuals initially treated with a first-line stavudine- or zidovudine-based antiretroviral therapy (ART) regimen and with evidence of virological failure (one viral load >1000 copies/ml) were enrolled from 17 rural primary health care clinics. Genotypic resistance testing was performed using the in-house SATuRN/Life Technologies system. Sequences were analysed and genotypic susceptibility scores (GSS) for standard second-line regimens were calculated using the Stanford HIVDB 6.0.5 algorithms. Results A total of 222 adults were successfully genotyped for HIV drug resistance between December 2010 and March 2012. The most common regimens at time of genotype were stavudine, lamivudine and efavirenz (51%); and stavudine, lamivudine and nevirapine (24%). Median duration of ART was 42 months (interquartile range (IQR) 32–53) and median duration of antiretroviral failure was 27 months (IQR 17–40). One hundred and ninety one (86%) had at least one drug resistance mutation. For 34 individuals (15%), the GSS for the standard second-line regimen was <2, suggesting a significantly compromised regimen. In univariate analysis, individuals with a prior nucleoside reverse-transcriptase inhibitor (NRTI) substitution were more likely to have a GSS <2 than those on the same NRTIs throughout (odds ratio (OR) 5.70, 95% confidence interval (CI) 2.60–12.49). Conclusions There are high levels of drug resistance in adults with failure of first-line antiretroviral therapy in this rural primary health care programme. Standard second-line regimens could potentially have had reduced efficacy in about one in seven adults involved.

Morbidity in relation to feeding mode in African HIV-exposed, uninfected infants during the first 6 mo of life: the Kesho Bora study

BACKGROUND Refraining from breastfeeding to prevent HIV transmission has been associated with increased morbidity and mortality in HIV-exposed African infants. OBJECTIVE The objective was to assess risks of common and serious infectious morbidity by feeding mode in HIV-exposed, uninfected infants ≤6 mo of age with special attention to the issue of reverse causality. DESIGN HIV-infected pregnant women from 5 sites in Burkina Faso, Kenya, and South Africa were enrolled in the prevention of mother-to-child transmission Kesho Bora trial and counseled to either breastfeed exclusively and cease by 6 mo postpartum or formula feed exclusively. Maternal-reported morbidity (fever, diarrhea, and vomiting) and serious infectious events (SIEs) (gastroenteritis and lower respiratory tract infections) were investigated for 751 infants for 2 age periods (0-2.9 and 3-6 mo) by using generalized linear mixed models with breastfeeding as a time-dependent variable and adjustment for study site, maternal education, economic level, and cotrimoxazole prophylaxis. RESULTS Reported morbidity was not significantly higher in nonbreastfed compared with breastfed infants [OR: 1.31 (95% CI: 0.97, 1.75) and 1.21 (0.90, 1.62) at 0-2.9 and 3-6 mo of age, respectively]. Between 0 and 2.9 mo of age, never-breastfed infants had increased risks of morbidity compared with those of infants who were exclusively breastfed (OR: 1.49; 95% CI: 1.01, 2.2; P = 0.042). The adjusted excess risk of SIEs in nonbreastfed infants was large between 0 and 2.9 mo (OR: 6.0; 95% CI: 2.2, 16.4; P = 0.001). Between 3 and 6 mo, the OR for SIEs was sensitive to the timing of breastfeeding status, i.e., 4.3 (95% CI: 1.2, 15.3; P = 0.02) when defined at end of monthly intervals and 2.0 (95% CI: 0.8, 5.0; P = 0.13) when defined at the beginning of intervals. Of 52 SIEs, 3 mothers reported changes in feeding mode during the SIE although none of the mothers ceased breastfeeding completely. CONCLUSIONS Not breastfeeding was associated with increased risk of serious infections especially between 0 and 2.9 mo of age. The randomized controlled trial component of the Kesho Bora study was registered at Current Controlled Trials (www.controlled-trials.com) as ISRCTN71468401.

Infant Feeding Modes And Determinants Among Hiv-1-infected African Women In The Kesho Bora Study

Objective:To assess breastfeeding modes and determinants in a prevention of mother-to-child transmission study. Design:HIV-1–infected pregnant women from 5 sites in Burkina Faso, Kenya, and South Africa were enrolled in the study that comprised 2 prospective cohorts and 1 randomized controlled trial. Women were counseled to either breastfeed exclusively up to 6 months or formula feed from birth. Methods:Determinants of breastfeeding initiation and continuation by 3 months postpartum were investigated using multiple logistic regression analysis. Neonatal morbidity was defined as mother-reported fever, diarrhea, or vomiting during the first month of life. Results:Among 1028, 781 women (76%) initiated breastfeeding and 565 of 995 (56%) were still breastfeeding at 3 months postpartum (30% exclusively, 18% predominantly, and 8% partially). Study site (Durban, Mombasa, and Nairobi compared with Bobo-Dioulasso), CD4 cell count (<200 cells/mm3), secondary schooling (compared with none), and emergency cesarean delivery (compared with vaginal delivery) were independently associated with a lower probability of ever breastfeeding. The odds of still breastfeeding by 3 months postpartum (among those breastfeeding by 1 month) were lower in Mombasa, Nairobi, and Somkhele (compared with Bobo-Dioulasso) and among infants with neonatal morbidity [0.60 (0.37–0.976)]. The odds of exclusive breastfeeding (EBF) by 3 months (if EBF by 1 month) were lower in Mombasa and Nairobi, in ill neonates [0.54 (0.31–0.93)] and boys [0.51 (0.34–0.77)]. Conclusions:EBF was of short duration, particularly for boys. The importance of neonatal morbidity for breastfeeding cessation requires further investigation. Infant feeding counseling might need adaptation to better support mothers of boys and ill neonates.

Southern African Treatment Resistance Network (SATuRN) RegaDB HIV drug resistance and clinical management database: supporting patient management, surveillance and research in southern Africa

Abstract Substantial amounts of data have been generated from patient management and academic exercises designed to better understand the human immunodeficiency virus (HIV) epidemic and design interventions to control it. A number of specialized databases have been designed to manage huge data sets from HIV cohort, vaccine, host genomic and drug resistance studies. Besides databases from cohort studies, most of the online databases contain limited curated data and are thus sequence repositories. HIV drug resistance has been shown to have a great potential to derail the progress made thus far through antiretroviral therapy. Thus, a lot of resources have been invested in generating drug resistance data for patient management and surveillance purposes. Unfortunately, most of the data currently available relate to subtype B even though >60% of the epidemic is caused by HIV-1 subtype C. A consortium of clinicians, scientists, public health experts and policy markers working in southern Africa came together and formed a network, the Southern African Treatment and Resistance Network (SATuRN), with the aim of increasing curated HIV-1 subtype C and tuberculosis drug resistance data. This article describes the HIV-1 data curation process using the SATuRN Rega database. The data curation is a manual and time-consuming process done by clinical, laboratory and data curation specialists. Access to the highly curated data sets is through applications that are reviewed by the SATuRN executive committee. Examples of research outputs from the analysis of the curated data include trends in the level of transmitted drug resistance in South Africa, analysis of the levels of acquired resistance among patients failing therapy and factors associated with the absence of genotypic evidence of drug resistance among patients failing therapy. All these studies have been important for informing first- and second-line therapy. This database is a free password-protected open source database available on www.bioafrica.net. Database URL: http://www.bioafrica.net/regadb/

Postpartum weight change among HIV-infected mothers by antiretroviral prophylaxis and infant feeding modality in a research setting.

Objective:To assess the relationship between infant feeding, triple-antiretroviral prophylaxis and weight from 2 weeks (baseline) to 6 months postpartum among HIV-infected mothers in a mother-to-child transmission (MTCT) of HIV-prevention trial in five sub-Saharan African sites. Methods:HIV-infected pregnant women with CD4+ cell counts of 200–500 cells/&mgr;l were counselled to choose breastfeeding to 6 months or replacement feeding from delivery. They were randomized to receive perinatal zidovudine and single-dose nevirapine or triple-antiretroviral MTCT prophylaxis until breastfeeding cessation. Mixed-effect linear models were used to compare maternal weight trajectories over time by infant feeding mode. Antiretroviral prophylaxis and BMI at baseline were examined as potential effect modifiers. Results:Among 797 mothers, 620 (78%) initiated breastfeeding. Wasting (BMI <18.5) was rare at baseline (2%), whereas overweight/obesity (BMI ≥ 25) was common (40%). In the model including all women, breastfeeding was not associated with weight loss up to 6 months, irrespective of baseline BMI and antiretroviral prophylaxis. Triple-antiretroviral prophylaxis was associated with weight gain among replacement-feeding mothers with baseline BMI at least 25 (+0.54 kg/month; P < 0.0001). In the model including breastfeeding mothers only, triple-antiretroviral prophylaxis was associated with weight gain among mothers with baseline BMI at least 25 who ceased breastfeeding before 3 months postpartum (+0.33 kg/month; P = 0.03). Conclusion:The results suggest that breastfeeding up to 6 months postpartum is not detrimental for postpartum weight among well nourished HIV-infected mothers at intermediate-disease stage. In the absence of breastfeeding or after weaning, triple-antiretroviral prophylaxis is associated with weight gain among women with high BMI, even after cessation of prophylaxis.

Implementing antiretroviral resistance testing in a primary health care HIV treatment programme in rural KwaZulu-Natal, South Africa: early experiences, achievements and challenges

BackgroundAntiretroviral drug resistance is becoming increasingly common with the expansion of human immunodeficiency virus (HIV) treatment programmes in high prevalence settings. Genotypic resistance testing could have benefit in guiding individual-level treatment decisions but successful models for delivering resistance testing in low- and middle-income countries have not been reported.MethodsAn HIV Treatment Failure Clinic model was implemented within a large primary health care HIV treatment programme in northern KwaZulu-Natal, South Africa. Genotypic resistance testing was offered to adults (≥16 years) with virological failure on first-line antiretroviral therapy (one viral load >1000 copies/ml after at least 12 months on a standard first-line regimen). A genotypic resistance test report was generated with treatment recommendations from a specialist HIV clinician and sent to medical officers at the clinics who were responsible for patient management. A quantitative process evaluation was conducted to determine how the model was implemented and to provide feedback regarding barriers and challenges to delivery.ResultsA total of 508 specimens were submitted for genotyping between 8 April 2011 and 31 January 2013; in 438 cases (86.2%) a complete genotype report with recommendations from the specialist clinician was sent to the medical officer. The median turnaround time from specimen collection to receipt of final report was 18 days (interquartile range (IQR) 13–29). In 114 (26.0%) cases the recommended treatment differed from what would be given in the absence of drug resistance testing. In the majority of cases (n = 315, 71.9%), the subsequent treatment prescribed was in line with the recommendations of the report.ConclusionsGenotypic resistance testing was successfully implemented in this large primary health care HIV programme and the system functioned well enough for the results to influence clinical management decisions in real time. Further research will explore the impact and cost-effectiveness of different implementation models in different settings.

The Effect of Antiretroviral Treatment on Health Care Utilization in Rural South Africa: A Population-Based Cohort Study

Background The effect of the rapid scale-up of vertical antiretroviral treatment (ART) programs for HIV in sub-Saharan Africa on the overall health system is under intense debate. Some have argued that these programs have reduced access for people suffering from diseases unrelated to HIV because ART programs have drained human and physical resources from other parts of the health system; others have claimed that the investments through ART programs have strengthened the general health system and the population health impacts of ART have freed up health care capacity for the treatment of diseases that are not related to HIV. To establish the population-level impact of ART programs on health care utilization in the public-sector health system, we compared trends in health care utilization among HIV-infected people receiving and not receiving ART with HIV-uninfected people during a period of rapid ART scale-up. Methods and Findings We used data from the Wellcome Trust Africa Centre for Population Health, which annually elicited information on health care utilization from all surveillance participants over the period 2009–2012 (N = 32,319). We determined trends in hospitalization, and public-sector and private-sector primary health care (PHC) clinic visits for HIV-infected and -uninfected people over a time period of rapid ART scale-up (2009–2012) in this community. We regressed health care utilization on HIV status and ART status in different calendar years, controlling for sex, age, and area of residence. The proportion of people who reported to have visited a public-sector primary health care (PHC) clinic in the last 6 months increased significantly over the period 2009–2012, for both HIV-infected people (from 59% to 67%; p<0.001), and HIV-uninfected people (from 41% to 47%; p<0.001). In contrast, the proportion of HIV-infected people visiting a private-sector PHC clinic declined from 22% to 12% (p<0.001) and hospitalization rates declined from 128 to 82 per 1000 PY (p<0.001). For HIV-uninfected people, the proportion visiting a private-sector PHC clinic declined from 16% to 9%, and hospitalization rates declined from 78 to 44 per 1000 PY (p<0.001). After controlling for potential confounding factors, all trends remained of similar magnitude and significance. Conclusions Our results indicate that the ART scale-up in this high HIV prevalence community has shifted health care utilization from hospitals and private-sector primary care to public-sector primary care. Remarkably, this shift is observed for both HIV-infected and -uninfected populations, supporting and extending hypotheses of ‘therapeutic citizenship’ whereby HIV-infected patients receiving ART facilitate primary care access for family and community members. One explanation of our findings is that ART has improved the capacity or quality of primary care in this community and, as a consequence, increasingly met overall health care needs at the primary care level rather than at the secondary level. Future research needs to confirm this causal interpretation of our findings using qualitative work to understand causal mechanisms or quasi-experimental quantitative studies to increase the strength of causal inference.

Barriers to antiretroviral treatment initiation in rural KwaZulu‐Natal, South Africa

Although antiretroviral therapy (ART) has been freely available since 2004 in South Africa, not all those who are eligible initiate ART. We aimed to investigate individual and household characteristics as barriers to ART initiation in men and women in rural KwaZulu‐Natal.