Acquired HIV drug resistance among adults living with HIV receiving first-line antiretroviral therapy in Rwanda: A cross-sectional nationally representative survey.

BACKGROUND: We assessed the prevalence of acquired HIV drug resistance (HIVDR) and associated factors among patients receiving first-line antiretroviral therapy (ART) in Rwanda. METHODS: This cross-sectional study included 702 patients receiving first-line ART for at least 6 months with last viral load (VL) results ≥1000 copies/mL. Blood plasma samples were subjected to VL testing; specimens with unsuppressed VL were genotyped to identify HIVDR-associated mutations. Data were analysed using STATA/SE. RESULTS: Median time on ART was 86.4 months (interquartile range [IQR], 44.8-130.2 months), and median CD4 count at ART initiation was 311 cells/mm3 (IQR, 197-484 cells/mm3). Of 414 (68.2%) samples with unsuppressed VL, 378 (88.3%) were genotyped. HIVDR included 347 (90.4%) non-nucleoside reverse transcriptase inhibitor- (NNRTI), 291 (75.5%) nucleoside reverse transcriptase inhibitor- (NRTI) and 13 (3.5%) protease inhibitor (PI) resistance-associated mutations. The most common HIVDR mutations were K65R (22.7%), M184V (15.4%) and D67N (9.8%) for NRTIs and K103N (34.4%) and Y181C/I/V/YC (7%) for NNRTIs. Independent predictors of acquired HIVDR included current ART regimen of zidovudine + lamivudine + nevirapine (adjusted odds ratio [aOR], 3.333 [95% confidence interval (CI): 1.022-10.870]; p = 0.046) for NRTI resistance and current ART regimen of tenofovir + emtricitabine + nevirapine (aOR, 0.148 [95% CI: 0.028-0.779]; p = 0.025), zidovudine + lamivudine + efavirenz (aOR, 0.105 [95% CI: 0.016-0.693]; p = 0.020) and zidovudine + lamivudine + nevirapine (aOR, 0.259 [95% CI: 0.084-0.793]; p = 0.019) for NNRTI resistance. History of ever switching ART regimen was associated with NRTI resistance (aOR, 2.53 [95% CI: 1.198-5.356]; p = 0.016) and NNRTI resistance (aOR, 3.23 [95% CI: 1.435-7.278], p = 0.005). CONCLUSION: The prevalence of acquired HIV drug resistance (HIVDR) was high among patient failing to re-suppress VL and was associated with current ART regimen and ever switching ART regimen. The findings of this study support the current WHO guidelines recommending that patients on an NNRTI-based regimen should be switched based on a single viral load test and suggests that national HIV VL monitoring of patients receiving ART has prevented long-term treatment failure that would result in the accumulation of TAMs and potential loss of efficacy of all NRTI used in second-line ART as the backbone in combination with either dolutegravir or boosted PIs.

High levels of viral load monitoring and viral suppression under Treat All in Rwanda - a cross-sectional study.

INTRODUCTION: Aiming to reach UNAIDS 90-90-90 targets, nearly all sub-Saharan African countries have expanded antiretroviral therapy (ART) to all people living with HIV (PLWH) (Treat All). Few published data exist on viral load testing and viral suppression under Treat All in this region. We assessed proportions of patients with available viral load test results and who were virally suppressed, as well as factors associated with viral suppression, among PLWH in 10 Rwandan health centres after Treat All implementation. METHODS: Cross-sectional study during 2018 of adults (≥15 years) engaged in HIV care at 10 Rwandan health centres. Outcomes were being on ART (available ART initiation date in the study database, with no ART discontinuation prior to 1 January 2018), retained on ART (≥2 post-ART health centre visits ≥90 days apart during 2018), available viral load test results (viral load measured in 2018 and available in study database) and virally suppressed (most recent 2018 viral load <200 copies/mL). We used modified Poisson regression models accounting for clustering by health centre to determine factors associated with being virally suppressed. RESULTS: Of 12,238 patients, 7050 (58%) were female and 1028 (8%) were aged 15 to 24 years. Nearly all patients (11,933; 97%) were on ART, of whom 11,198 (94%) were retained on ART. Among patients retained on ART, 10,200 (91%) had available viral load results; of these 9331 (91%) were virally suppressed. Viral suppression was less likely among patients aged 15 to 24 compared to >49 years (adjusted prevalence ratio (aPR): 0.83, 95% CI 0.76 to 0.90 and those with pre-ART CD4 counts of <200 compared to ≥500 cells/mm3 (aPR: 0.92, 95% CI 0.90 to 0.93). There was no statistically significant difference in viral suppression among patients who entered after Treat All implementation compared to those who enrolled before 2010 (aPR 0.98, 95% CI 0.94 to 1.03). CONCLUSIONS: In this large cohort of Rwandan PLWH receiving HIV care after Treat All implementation, patients in study health centres have surpassed the third UNAIDS 90-90-90 target. To ensure all PLWH fully benefit from ART, additional efforts should focus on improving ART adherence among younger persons.

Early outcomes after implementation of treat all in Rwanda: an interrupted time series study.

INTRODUCTION: Nearly all countries in sub-Saharan Africa have adopted policies to provide antiretroviral therapy (ART) to all persons living with HIV (Treat All), though HIV care outcomes of these programmes are not well-described. We estimated changes in ART initiation and retention in care following Treat All implementation in Rwanda in July 2016. METHODS: We conducted an interrupted time series analysis of adults enrolling in HIV care at ten Rwandan health centres from July 2014 to September 2017. Using segmented linear regression, we assessed changes in levels and trends of 30-day ART initiation and six-month retention in care before and after Treat All implementation. We compared modelled outcomes with counterfactual estimates calculated by extrapolating baseline trends. Modified Poisson regression models identified predictors of outcomes among patients enrolling after Treat All implementation. RESULTS: Among 2885 patients, 1803 (62.5%) enrolled in care before and 1082 (37.5%) after Treat All implementation. Immediately after Treat All implementation, there was a 31.3 percentage point increase in the predicted probability of 30-day ART initiation (95% CI 15.5, 47.2), with a subsequent increase of 1.1 percentage points per month (95% CI 0.1, 2.1). At the end of the study period, 30-day ART initiation was 47.8 percentage points (95% CI 8.1, 87.8) above what would have been expected under the pre-Treat All trend. For six-month retention, neither the immediate change nor monthly trend after Treat All were statistically significant. While 30-day ART initiation and six-month retention were less likely among patients 15 to 24 versus >24 years, the predicted probability of both outcomes increased significantly for younger patients in each month after Treat All implementation. CONCLUSIONS: Implementation of Treat All in Rwanda was associated with a substantial increase in timely ART initiation without negatively impacting care retention. These early findings support Treat All as a strategy to help achieve global HIV targets.

Viral load detection and management on first line ART in rural Rwanda.

BACKGROUND: To achieve the ambitious 90-90-90 UNAIDS targets, access to routine viral load (VL) is critical. To measure VL, Rwanda has relied on a national reference laboratory for years. In 2014, a VL testing platform was implemented in a rural District in the Northern Province. Here we analyze the uptake of VL testing, identification of risks for detectable VL (≥1000 copies/ml), and the management of patients with a detectable VL. METHODS: A retrospective cohort study of patients who started ART between July 2012 and June 2015 and followed until end December 2016. Using descriptive statistics, we describe the VL cascade, from VL uptake to the start of second-line ART in patients diagnosed with virological failure. We estimate predictors of having a detectable VL using logistic regression. RESULTS: The uptake of VL testing increased progressively between 2013 and 2016, raising from 25.6% (39/152) in 2013 up to 93.2% (510/547) in 2016.In 2016, 88.5% (n = 451) of patients tested, had a suppressed VL. Predictors of having a detectable VL included being male (aOR 2.1; 95%CI 1.12-4.02; p = 0.02), being a sex worker (aOR 6.4; 95%CI 1.1-36.0; p = 0.04), having a WHO clinical stage IV when starting ART (aOR 8.8; 95%CI 1.8-43.0; p < 0.001), having had a previous detectable VL (aOR 7.2; 95%CI 3.5-14.5; p < 0.001), and having had no VL before 2016 (aOR 3.1; 95%CI 1.2-8.1; p = 0.02). Among patients with initial detectable VL between 2013 and 2016, 88% (n = 103) had a follow-up VL, of whom 60.2% (n = 62) suppressed their VL below 1000 copies/ml. The median time between the initial and follow-up VL was of 12.5 months (IQR: 8.7-19.0). Among patients with confirmed treatment failure, 63.4% (n = 26) started second-line ART within the study period. CONCLUSION: VL uptake increased after decentralizing VL testing in rural Rwanda. Virological suppression was high. An individualized follow up of patients at risk of non-suppression and a prompt management of patients with detectable VL may help to achieve and sustain the third global UNAIDS target: virological suppression in 90% of patients on ART.

Viral Suppression in a Nationwide Sample of HIV-Infected Children on Antiretroviral Therapy in Rwanda.

Rwanda has made significant progress in expanding pediatric antiretroviral treatment coverage. This was a nationwide, cross-sectional study of pediatric HIV suppression rates. Of 292 children on antiretroviral treatment ≥12 months, 68.8% achieved viral suppression < 40 copies/ml, respectively. Rwanda achieved good pediatric viral suppression rates, comparable to those from other resource-limited settings, yet more efforts are needed to achieve the UNAIDS 90-90-90 target.

Impact of maternal ART on mother-to-child transmission (MTCT) of HIV at six weeks postpartum in Rwanda.

BACKGROUND: In 2010, Rwanda adopted ART for prevention of mother to child transmission of HIV from pregnant women living with HIV during pregnancy and breasfeeding period. This study examines rates of mother-to-child-transmission of HIV at 6-10 weeks postpartum and risk factors for mother-to-child transmission of HIV (MTCT) among HIV infected women on ART during pregnancy and breastfeeding. METHODS: A cross-sectional survey study was conducted between July 2011-June 2012 among HIV-exposed infants aged 6-10 weeks and their mothers/caregivers. Stratified multi-stage, probability proportional to size and systematic sampling to select a national representative sample of clients. Consenting mothers/caregivers were interviewed on demographic and program interventions. Dry blood spots from HIV-exposed infants were collected for HIV testing using DNA PCR technique. Results are weighted for sample realization. Univariable analysis of socio-demographic and programmatic determinants of early mother-to-child transmission of HIV was conducted. Variables were retained for final multivariable models if they were either at least of marginal significance (p-value < 0.10) or played a confounding role (the variable had a noticeable impact > 10% change on the effect estimate). RESULTS: The study sample was 1639 infants with HIV test results. Twenty-six infants were diagnosed HIV-positive translating to a weighted MTCT estimate of 1.58% (95% CI 1.05-2.37%). Coverage of most elimination of MTCT (EMTCT) program interventions, was above 80, and 90.4% of mother-infant pairs received antiretroviral treatment or prophylaxis. Maternal ART and infant antiretroviral prophylaxis (OR 0.01; 95%CI 0.001-0.17) and maternal age older than 25 years were significantly protective (OR 0.33; 95%CI 0.14-0.78). No disclosure of HIV status, not testing for syphilis during pregnancy and preterm birth were significant risk factors for MTCT. Factors suggesting higher socio-demographic status (flush toilet, mother self-employed) were borderline risk factors for MTCT. CONCLUSION: ART for all women during pregnancy and breastfeeding was associated with the estimated low MTCT rate of 1.58%. Mothers who did not receive a full package of anti-retroviral therapy according to the Rwanda EMTCT protocol, and young and single mothers were at higher risk of MTCT and should be targeted for support in preventing HIV infection.

Phased implementation of spaced clinic visits for stable HIV-positive patients in Rwanda to support Treat All.

INTRODUCTION: In 2016, Rwanda implemented "Treat All," requiring the national HIV programme to increase antiretroviral (ART) treatment coverage to all people living with HIV. Approximately half of the 164,262 patients on ART have been on treatment for more than five years, and long-term retention of patients in care is an increasing concern. To address these challenges, the Ministry of Health has introduced a differentiated service delivery approach to reduce the frequency of clinical visits and medication dispensing for eligible patients. This article draws on key policy documents and the views of technical experts involved in policy development to describe the process of implementation of differentiated service delivery in Rwanda. DISCUSSION: Implementation of differentiated service delivery followed a phased approach to ensure that all steps are clearly defined and agreed by all partners. Key steps included: definition of scope, including defining which patients were eligible for transition to the new model; definition of the key model components; preparation for patient enrolment; considerations for special patient groups; engagement of implementing partners; securing political and financial support; forecasting drug supply; revision, dissemination and implementation of ART guidelines; and monitoring and evaluation. CONCLUSIONS: Based on the outcomes of the evaluation of the new service delivery model, the Ministry of Health will review and strategically reduce costs to the national HIV program and to the patient by exploring and implementing adjustments to the service delivery model.

Five-year Outcomes Among Children Receiving Antiretroviral Therapy in a Community-based Accompaniment Program in Rural Rwanda.

Of 277 HIV-infected children in rural Rwanda enrolled in a community-based accompaniment program, 95.0% were retained in care 5 years after treatment initiation, with only 9 (3.3%) deaths and 3 (1.1%) defaults. Of 235 (84.8%) children with a documented viral load result, 201 (85.5%) demonstrated viral load suppression (<1000 copies/mL).

Retention of mothers and infants in the prevention of mother-to-child transmission of HIV programme is associated with individual and facility-level factors in Rwanda.

OBJECTIVES: Investigate levels of retention at specified time periods along the prevention of mother-to-child transmission (PMTCT) cascade among mother-infant pairs as well as individual- and facility-level factors associated with retention. METHODS: A retrospective cohort of HIV-positive pregnant women and their infants attending five health centres from November 2010 to February 2012 in the Option B programme in Rwanda was established. Data were collected from several health registers and patient follow-up files. Additionally, informant interviews were conducted to ascertain health facility characteristics. Generalized estimating equation methods and modelling were utilized to estimate the number of mothers attending each antenatal care visit and assess factors associated with retention. RESULTS: Data from 457 pregnant women and 462 infants were collected at five different health centres (three urban and two rural facilities). Retention at 30 days after registration and retention at 6 weeks, 3, 6, 9 and 12 months post-delivery were analyzed. Based on an analytical sample of 348, we found that 58% of women and 81% of infants were retained in care within the same health facility at 12 months post-delivery, respectively. However, for mother-infant paired mothers, retention at 12 months was 74% and 79% for their infants. Loss to facility occurred early, with 26% to 33% being lost within 30 days post-registration. In a multivariable model retention was associated with being married, adjusted relative risk (ARR): 1.26, (95% confidence intervals: 1.11, 1.43); antiretroviral therapy eligible, ARR: 1.39, (1.12, 1.73) and CD4 count per 50 mm(3), ARR: 1.02, (1.01, 1.03). CONCLUSIONS: These findings demonstrate varying retention levels among mother-infant pairs along the PMTCT cascade in addition to potential determinants of retention to such programmes. Unmarried, apparently healthy, HIV-positive pregnant women need additional support for programme retention. With the significantly increased workload resulting from lifelong antiretroviral treatment for all HIV-positive pregnant women, strategies need to be developed to identify, provide support and trace these women at risk of loss to follow-up. This study provides further evidence for the need for such a targeted supportive approach.

Drug resistance mutations after the first 12 months on antiretroviral therapy and determinants of virological failure in Rwanda.

OBJECTIVE: To evaluate HIV drug resistance (HIVDR) and determinants of virological failure in a large cohort of patients receiving first-line tenofovir-based antiretroviral therapy (ART) regimens. METHODS: A nationwide retrospective cohort from 42 health facilities was assessed for virological failure and development of HIVDR mutations. Data were collected at ART initiation and at 12 months of ART on patients with available HIV-1 viral load (VL) and ART adherence measurements. HIV resistance genotyping was performed on patients with VL ≥1000 copies/ml. Multiple logistic regression was used to determine factors associated with treatment failure. RESULTS: Of 828 patients, 66% were women, and the median age was 37 years. Of the 597 patients from whom blood samples were collected, 86.9% were virologically suppressed, while 11.9% were not. Virological failure was strongly associated with age <25 years (adjusted odds ratio [aOR]: 6.4; 95% confidence interval [CI]: 3.2-12.9), low adherence (aOR: 2.87; 95% CI: 1.5-5.0) and baseline CD4 counts <200 cells/µl (aOR 3.4; 95% CI: 1.9-6.2). Overall, 9.1% of all patients on ART had drug resistance mutations after 1 year of ART; 27% of the patients who failed treatment had no evidence of HIVDR mutations. HIVDR mutations were not observed in patients on the recommended second-line ART regimen in Rwanda. CONCLUSIONS: The last step of the UNAIDS 90-90-90 target appears within grasp, with some viral failures still due to non-adherence. Nonetheless, youth and late initiators are at higher risk of virological failure. Youth-focused programmes could help prevent further drug HIVDR development.