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

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

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

The MONARCH intervention to enhance the quality of antenatal and postnatal primary health services in rural South Africa: protocol for a stepped-wedge cluster-randomised controlled trial

Background: Gaps in maternal and child health services can slow progress towards achieving the Sustainable Development Goals. The Management and Optimization of Nutrition, Antenatal, Reproductive, Child Health &amp; HIV Care (MONARCH) study will evaluate a Continuous Quality Improvement (CQI) intervention targeted at improving antenatal and postnatal health service outcomes in rural South Africa where HIV prevalence among pregnant women is extremely high. Specifically, it will establish the effectiveness of CQI on viral load (VL) testing in pregnant women who are HIV-positive and repeat HIV testing in pregnant women who are HIV-negative. Methods: This is a stepped-wedge cluster-randomised controlled trial (RCT) of 7 nurse-led primary healthcare clinics to establish the effect of CQI on selected routine antenatal and postnatal services. Each clinic was a cluster, with the exception of the two smallest clinics, which jointly formed one cluster. The intervention was applied at the cluster level, where staff received training on CQI methodology and additional mentoring as required. In the control exposure state, the clusters received the South African Department of Health standard of care. After a baseline data collection period of 2 months, the first cluster crossed over from control to intervention exposure state; subsequently, one additional cluster crossed over every 2 months. The six clusters were divided into 3 groups by patient volume (low, medium and high). We randomised the six clusters to the sequences of crossing over, such that both the first three and the last three sequences included one cluster with low, one with medium, and one with high patient volume. The primary outcome measures were (i) viral load testing among pregnant women who were HIV-positive, and (ii) repeat HIV testing among pregnant women who were HIV-negative. Consenting women ≥18 years attending antenatal and postnatal care during the data collection period completed outcome measures at delivery, and postpartum at three to 6 days, and 6 weeks. Data collection started on 15 July 2015. The total study duration, including pre- and post-exposure phases, was 19 months. Data will be analyzed by intention-to-treat based on first booked clinic of study participants. Discussion: The results of the MONARCH trial will establish the effectiveness of CQI in improving antenatal and postnatal clinic processes in primary care in sub-Saharan Africa. More generally, the results will contribute to our knowledge on quality improvement interventions in resource-poor settings. Trial registration: This trial was registered on 10 December 2015: www.clinicaltrials.gov, identifier NCT02626351

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

BACKGROUND: Antiretroviral 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. METHODS: An 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. RESULTS: A 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. CONCLUSIONS: Genotypic 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

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

Change of treatment guidelines and evolution of ART initiation in rural South Africa: data of a large HIV care and treatment programme

International audienceBackground: While WHO recommendations are to treat people earlier and earlier, it will considerably increase the number of HIV infected people eligible for antiretroviral therapy (ART). In South Africa, a country which carries one of the highest HIV burden worldwide, very few studies are available on the impact of the ART guidelines on time to ART initiation in both individuals with low CD4 count and those newly eligible for ART. We thus aimed to describe ART initiation percentages in a large HIV programme in rural KwaZulu-Natal, South Africa, according to the temporal changes of national ART eligibility guidelines from 2007 to 2012. Methods: Adults who accessed the decentralized Hlabisa HIV treatment programme in 2007–2012 were included. Three periods following the temporal change of ART eligibility guidelines were defined (Period 1: until). Percentages of ART initiation within three months of programme entry were estimated in men, in women of childbearing age (<40 years old) and in older women, and stratifying by CD4 count. Trend tests and logistic regression models were used to study the effects of change of guidelines on ART initiation percentages. Results: In individuals with CD4 count ≤200 cells/μL (N = 5709 men, N = 6743 women <40 years old and N = 2017 older women), percentages of ART initiation did not differ over time (p trend = 0.25; 0.28; and 0.14, respectively). In individuals with CD4 count = 201–350 cells/μL (N = 2680 men, N = 6086 women <40 years old and N = 1415 older women), percentages of ART initiation significantly increased over time (p trend <0.01 for the three groups): from 6 % in Period 1 to 20 % in Period 2 to 40 % in Period 3 in women of childbearing age, and from 7 % to 8-10 % to 42 % in men and in older women.Conclusions : As temporal changes of guidelines, percentages of ART initiation significantly increased in newly ART eligible people and did not decrease in individuals with very low CD4 counts. It will be crucial to continue verifying the evolution of these percentages of ART initiation with future recommendations reaching near-to-universal access to ART, to ensure that individuals most in need of ART receive it

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 ISRCTN7146840

NRTI mutations, including summary of proportion with thymidine analogue mutations (TAMs).

<p>NRTI mutations, including summary of proportion with thymidine analogue mutations (TAMs).</p

Flow chart showing patients excluded from analysis.

<p>Of the 20 excluded patients, 17 were initiated on TDF-based first-line therapy, dual NRTI therapy or were already receiving a second-line regimen at time of genotype. The three protocol violations were: two patients on treatment for less than a year, and one with viral load <1000 copies/ml at the time of genotyping.</p

Demographic and clinical characteristics.

<p>IQR, interquartile range; d4T, stavudine; 3TC, lamivudine; EFV, efavirenz; NVP, nevirapine; AZT, zidovudine; TDF, tenofovir; NRTI, nucleoside/nucleotide reverse-transcriptase inhibitor; NNRTI, non-nucleoside reverse-transcriptase inhibitor.</p>a<p>Baseline CD4+ cell count was measurement closest to but prior to ART initiation; 28 missing baseline CD4+ cell count.</p>b<p>Immunological failure was defined according to WHO guidelines: fall of CD4+ cell count to baseline or below; 50% fall from on-treatment peak value; or persistent CD4+ cell count <100 cells/µl.</p>c<p>Duration of antiretroviral failure was estimated from the date of the first viral load >1000 copies/ml to date of genotype, unless there was a viral load <50 copies/ml in-between, in which case the time was estimated from the next viral load >1,000 copies/ml. If there was no viral load ≤1,000 copies/ml then time was calculated from date of ART initiation.</p