Measles Vaccine Coverage and Disease Outbreaks: A Systematic Review of the Early Impact of COVID-19 in Low and Lower-Middle Income Countries.

Objectives: We aimed to evaluate changes to measles-containing vaccine (MCV) provision and subsequent measles disease cases in low- and lower-middle income countries (LICs, LMICs) in relation to the COVID-19 pandemic. Methods: A systematic search was conducted of MEDLINE, OVID EMBASE and PubMed records. Primary quantitative and qualitative research studies published from January 2020 were included if they reported on COVID-19 impact on MCV provision and/or measles outbreak rates within LICs and LMICs. Results: 45 studies were included. The change in MCV1 vaccination coverage in national and international regions ranged -13% to +44.4% from pre-COVID time periods. In local regions, the median MCV1 and overall EPI rate changed by -23.3% and -28.5% respectively. Median MCV2 rate was disproportionally impacted in local areas during COVID-interruption time-periods (-48.2%) with ongoing disruption in early-recovery time-periods (-17.7%). 8.9% of studies reported on vaccination status of confirmed measles cases; from these, 71%-91% had received no MCV dose. Conclusion: MCV vaccination coverage experienced ongoing disruption during the recovery periods after initial COVID-19 disruption. Vaccination in local area datasets notably experienced longer-term disruption compared to nationally reported figures.

Expansion of artemisinin partial resistance mutations and lack of histidine rich protein-2 and -3 deletions in Plasmodium falciparum infections from Rukara, Rwanda.

BACKGROUND: Emerging artemisinin partial resistance and diagnostic resistance are a threat to malaria control in Africa. Plasmodium falciparum kelch13 (k13) propeller-domain mutations that confer artemisinin partial resistance have emerged in Africa. k13-561H was initially described at a frequency of 7.4% from Masaka in 2014-2015, but not present in nearby Rukara. By 2018, 19.6% of isolates in Masaka and 22% of isolates in Rukara contained the mutation. Longitudinal monitoring is essential to inform control efforts. In Rukara, an assessment was conducted to evaluate recent k13-561H prevalence changes, as well as other key mutations. Prevalence of hrp2/3 deletions was also assessed. METHODS: Samples collected in Rukara in 2021 were genotyped for key artemisinin and partner drug resistance mutations using molecular inversion probe assays and for hrp2/3 deletions using qPCR. RESULTS: Clinically validated k13 artemisinin partial resistance mutations continue to increase in prevalence with the overall level of mutant infections reaching 32% in Rwanda. The increase appears to be due to the rapid emergence of k13-675V (6.4%, 6/94 infections), previously not observed, rather than continued expansion of 561H (23.5% 20/85). Mutations to partner drugs and other anti-malarials were variable, with high levels of multidrug resistance 1 (mdr1) N86 (95.5%) associated with lumefantrine decreased susceptibility and dihydrofolate reductase (dhfr) 164L (24.7%) associated with a high level of antifolate resistance, but low levels of amodiaquine resistance polymorphisms with chloroquine resistance transporter (crt) 76T: at 6.1% prevalence. No hrp2 or hrp3 gene deletions associated with diagnostic resistance were found. CONCLUSIONS: Increasing prevalence of artemisinin partial resistance due to k13-561H and the rapid expansion of k13-675V is concerning for the longevity of artemisinin effectiveness in the region. False negative RDT results do not appear to be an issue with no hrp2 or hpr3 deletions detected. Continued molecular surveillance in this region and surrounding areas is needed to follow artemisinin partial resistance and provide early detection of partner drug resistance, which would likely compromise control and increase malaria morbidity and mortality in East Africa.

Prevalence of Falciparum and non-Falciparum Malaria in the 2014-15 Rwanda Demographic Health Survey.

Background: Malaria remains a major cause of morbidity in sub-Saharan Africa. Undetected asymptomatic falciparum malaria results in a large transmission reservoir and there is evidence of increasing non-falciparum malaria as malaria is controlled in Africa, both resulting in challenges for malaria control programs. Methods: We performed quantitative real time PCR for 4 malaria species in 4,596 individuals from the 2014-2015 Rwanda Demographic Health Survey. Bivariate models were used to determine species-specific associations with risk factors. Results: Asymptomatic falciparum malaria, P. ovale spp., and P. malariae infection had broad spatial distribution across Rwanda. P. vivax infection was rare. Overall infection prevalence was 23.6% (95%CI [21.7%, 26.0%]), with falciparum and non-falciparum at 17.6% [15.9%, 19.0%] and 8.3% [7.0%, 10.0%], respectively. Parasitemias tended to be low and mixed species infections were common, especially where malaria transmission was the highest. Falciparum infection was associated with socio-econiomic status, rural residence and low altitude. Few risk factors were associated with non-falciparum malaria. Conclusions: Asymptomatic falciparum malaria and non-falciparum malaria are common and widely distributed across Rwanda. Continued molecular monitoring of Plasmodium spp. is needed to monitor these threats to malaria control in Africa.

An Assessment of the Knowledge and Perceptions of Precision Medicine (PM) in the Rwandan Healthcare Setting.

INTRODUCTION: Precision medicine (PM) or personalized medicine is an innovative approach that aims to tailor disease prevention and treatment to consider the differences in people's genes, environments, and lifestyles. Although many efforts have been made to accelerate the universal adoption of PM, several challenges need to be addressed in order to advance PM in Africa. Therefore, our study aimed to establish baseline data on the knowledge and perceptions of the implementation of PM in the Rwandan healthcare setting. METHOD: A descriptive qualitative study was conducted in five hospitals offering diagnostics and oncology services to cancer patients in Rwanda. To understand the existing policies regarding PM implementation in the country, two additional institutions were surveyed: the Ministry of Health (MOH), which creates and sets policies for the overall vision of the health sector, and the Rwanda Biomedical Center (RBC), which coordinates the implementation of health sector policies in the country. The researchers conducted 32 key informant interviews and assessed the functionality of available PM equipment in the 5 selected health facilities. The data were thematically categorized and analyzed. RESULTS: The study revealed that PM is perceived as a complex and expensive program by most health managers and health providers. The most cited challenges to implementing PM included the following: the lack of policies and guidelines; the lack of supportive infrastructures and limited suppliers of required equipment and laboratory consumables; financial constraints; cultural, behavioral, and religious beliefs; and limited trained, motivated, and specialized healthcare providers. Regarding access to health services for cancer treatment, patients with health insurance pay 10% of their medical costs, which is still too expensive for Rwandans. CONCLUSION: The study participants highlighted the importance of PM to enhance healthcare delivery if the identified barriers are addressed. For instance, Rwandan health sector leadership might consider the creation of specialized oncology centers in all or some referral hospitals with all the necessary genomic equipment and trained staff to serve the needs of the country and implement a PM program.

Salmonella Typhi whole genome sequencing in Rwanda shows a diverse historical population with recent introduction of haplotype H58.

Salmonella enterica serovar Typhi (S. Typhi) is the cause of typhoid fever, presenting high rates of morbidity and mortality in low- and middle-income countries. The H58 haplotype shows high levels of antimicrobial resistance (AMR) and is the dominant S. Typhi haplotype in endemic areas of Asia and East sub-Saharan Africa. The situation in Rwanda is currently unknown and therefore to reveal the genetic diversity and AMR of S. Typhi in Rwanda, 25 historical (1984-1985) and 26 recent (2010-2018) isolates from Rwanda were analysed using whole genome sequencing (WGS). WGS was locally implemented using Illumina MiniSeq and web-based analysis tools, thereafter complemented with bioinformatic approaches for more in-depth analyses. Whereas historical S. Typhi isolates were found to be fully susceptible to antimicrobials and show a diversity of genotypes, i.e 2.2.2, 2.5, 3.3.1 and 4.1; the recent isolates showed high AMR rates and were predominantly associated with genotype 4.3.1.2 (H58, 22/26; 84,6%), possibly resulting from a single introduction in Rwanda from South Asia before 2010. We identified practical challenges for the use of WGS in endemic regions, including a high cost for shipment of molecular reagents and lack of high-end computational infrastructure for the analyses, but also identified WGS to be feasible in the studied setting and giving opportunity for synergy with other programs.

Lessons Learned from Sudan Ebola Virus Disease (SUDV) Preparedness in Rwanda: A Comprehensive Review and Way Forward.

BACKGROUND: Ebola Virus Disease (EVD) is a severe and often fatal illness that affects humans and has significant public health implications, including high mortality rates, strain on healthcare systems, and social and economic disruption. On 20 September 2022, Uganda declared an Ebola disease outbreak caused by the Sudan ebolavirus species. The neighboring countries of Uganda were classified by World Health Organization (WHO) as being at high risk of Sudan Ebola Virus Disease (SUDV) importation. The country of Rwanda implemented different sustainable strategies and activities to prepare and ensure a timely and effective response to SUDV outbreaks once it has arrived in the country. We aimed to highlight the sustainable strategies and activities implemented for SUDV preparedness and the subsequent lessons learnt in Rwanda. METHODS: This paper reviewed the documentation on activities implemented for SUDV preparedness, with a focus on lessons learned from different countries. The paper analyzed the common themes and highlighted the key components of EVD preparedness in Rwanda after declaration of SUDV outbreak in Uganda. RESULTS: The key components of SUDV preparedness include its readiness assessment in Rwanda, effective coordination, collaboration and leadership mechanisms, enhancing the early detection and surveillance system, effective risk communication and community engagement, capacity building of healthcare providers on case management and infection prevention and control (IPC), and continual preparedness. These components were essential to ensure timely and effective preparation and response to SUDV related outbreaks. CONCLUSION: A multi-sectoral approach involving all stakeholders was necessary to ensure timely and effective preparation and response. Continuous investment in preparedness, strengthening of health systems, and the review of preparedness components provided insights into the best practices for SUDV preparedness, which were essential to prevent future outbreaks and minimize their impact. This will inform other countries about the role of timely development of preparedness plans.

The use of innovative approaches to strengthen health system resilience during the COVID-19 pandemic: case studies from selected Commonwealth countries.

This article is part of the Research Topic 'Health Systems Recovery in the Context of COVID-19 and Protracted Conflict'. The COVID-19 pandemic has exposed the vulnerabilities and limitations of many health systems and underscored the need for strengthening health system resilience to make and sustain progress toward Universal Health Coverage (UHC), global health security and healthier populations in tandem. In response to the COVID-19 pandemic, Commonwealth countries have been practicing a combination of innovative integrated approaches and actions to build health systems resilience. This includes utilizing digital tools, improvements in all-hazard emergency risk management, developing multisectoral partnerships, strengthening surveillance and community engagement. These interventions have been instrumental in strengthening national COVID-19 responses and can contribute to the evidence-base for increasing country investment into health systems resilience, particularly as we look toward COVID-19 recovery. This paper gives perspectives of five Commonwealth countries and their overall responses to the pandemic, highlighting practical firsthand experiences in the field. The countries included in this paper are Guyana, Malawi, Rwanda, Sri Lanka, and Tanzania. Given the diversity within the Commonwealth both in terms of geographical location and state of development, this publication can serve as a useful reference for countries as they prepare their health systems to better absorb the shocks that may emerge in future emergencies.

Prevalence of Human Papillomavirus in Different Mucous Membranes in HIV Concordant Couples in Rwanda.

BACKGROUND: The prevalence of human papillomavirus (HPV) infections in other anatomical sites besides the uterine cervix is unknown in East Africa. Here, we assessed the prevalence and concordance of HPVs in different anatomical sites in HIV concordant couples in Rwanda. METHODS: Fifty HIV-positive concordant male-female couples at the HIV clinic at the University Teaching Hospital of Kigali in Rwanda were interviewed, swabbed from the oral cavity (OC), oropharynx (OP), anal canal (AC), vagina (V), uterine cervix (UC) and penis. A pap smear test and a self-collected vaginal swab (Vself) were taken. Twelve high-risk (HR)-HPVs were analyzed. RESULTS: HR-HPVs occurred in 10%/12% in OC, 10%/0% in OP and 2%/24% in AC (p = 0.002) in men and women, respectively. HR-HPVs occurred in 24% of UC, 32% of Vself, 30% of V and 24% of P samples. Only 22.2% of all HR-HPV infections were shared by both partners (κ -0.34 ± 0.11; p = 0.004). The type-specific HR-HPV concordance was significant between male to female OC-OC (κ 0.56 ± 0.17), V-VSelf (κ 0.70 ± 0.10), UC-V (κ 0.54 ± 0.13), UC-Vself (κ 0.51 ± 0.13) and UC-female AC (κ 0.42 ± 0.15). CONCLUSIONS: HPV infections are prevalent in HIV-positive couples in Rwanda but concordance within couples is low. Vaginal self-sampling for HPV is representative of cervical HPV status.

Expansion of Artemisinin Partial Resistance Mutations and Lack of Histidine Rich Protein-2 and -3 Deletions in Plasmodium falciparum infections from Rukara, Rwanda.

Background: Emerging artemisinin resistance and diagnostic resistance are a threat to malaria control in Africa. Plasmodium falciparum kelch13 (K13) propeller-domain mutations that confer artemisinin partial resistance have emerged in Africa. K13-561H was initially described at a frequency of 7.4% from Masaka in 2014-2015 but not present in nearby Rukara. By 2018, 19.6% of isolates in Masaka and 22% of isolates in Rukara contained the mutation. Longitudinal monitoring is essential to inform control efforts. In Rukara, we sought to assess recent K13-561H prevalence changes, as well as for other key mutations. Prevalence of hrp2/3 deletions was also assessed. Methods: We genotyped samples collected in Rukara in 2021 for key artemisinin and partner drug resistance mutations using molecular inversion probe assays and for hrp2/3 deletions using qPCR. Results: Clinically validated K13 artemisinin partial resistance mutations continue to increase in prevalence with the overall level of artemisinin resistance mutant infections reaching 32% in Rwanda. The increase appears to be due to the rapid emergence of K13-675V (6.4%, 6/94 infections), previously not observed, rather than continued expansion of 561H (23.5% 20/85). Mutations to partner drugs and other antimalarials were variable, with high levels of multidrug resistance 1 (MDR1) N86 (95.5%) associated with lumefantrine resistance and dihydrofolate reductase (DHFR) 164L (24.7%) associated with antifolate resistance, but low levels of amodiaquine resistance polymorphisms with chloroquine resistance transporter (CRT ) 76T: at 6.1% prevalence. No hrp2 or hrp3 gene deletions associated with diagnostic resistance were found. Conclusions: Increasing prevalence of artemisinin partial resistance due to K13-561H and the rapid expansion of K13-675V is concerning for the longevity of artemisinin effectiveness in the region. False negative mRDT results do not appear to be an issue with no hrp2 or hpr3 deletions detected. Continued molecular surveillance in this region and surrounding areas is needed to follow artemisinin resistance and provide early detection of partner drug resistance, which would likely compromise control and increase malaria morbidity and mortality in East Africa.

Use of trained scent dogs for detection of COVID-19 and evidence of cost-saving.

Background: One of the lessons learned from the coronavirus disease 2019 (COVID-19) pandemic is the importance of early, flexible, and rapidly deployable disease detection methods. Currently, diagnosis of COVID-19 requires the collection of oro/nasopharyngal swabs, nasal turbinate, anterior nares and saliva but as the pandemic continues, disease detection methods that can identify infected individuals earlier and more quickly will be crucial for slowing the spread of the virus. Previous studies have indicated that dogs can be trained to identify volatile organic compounds (VOCs) produced during respiratory infections. We sought to determine whether this approach could be applied for detection of COVID-19 in Rwanda and measured its cost-saving. Methods: Over a period of 5 months, four dogs were trained to detect VOCs in sweat samples collected from human subjects confirmed positive or negative for COVID-19 by reverse transcription polymerase chain reaction (RT-PCR) testing. Dogs were trained using a detection dog training system (DDTS) and in vivo diagnosis. Samples were collected from 5,253 participants using a cotton pad swiped in the underarm to collect sweat samples. Statistical analysis was conducted using R statistical software. Findings: From August to September 2021 during the Delta wave, the sensitivity of the dogs' COVID-19 detection ranged from 75.0 to 89.9% for the lowest- and highest-performing dogs, respectively. Specificity ranged from 96.1 to 98.4%, respectively. In the second phase coinciding with the Omicron wave (January-March 2022), the sensitivity decreased substantially from 36.6 to 41.5%, while specificity remained above 95% for all four dogs. The sensitivity and specificity by any positive sample detected by at least one dog was 83.9, 95% CI: 75.8-90.2 and 94.9%; 95% CI: 93.9-95.8, respectively. The use of scent detection dogs was also found to be cost-saving compared to antigen rapid diagnostic tests, based on a marginal cost of approximately $14,000 USD for testing of the 5,253 samples which makes 2.67 USD per sample. Testing turnaround time was also faster with the scent detection dogs, at 3 h compared to 11 h with routine diagnostic testing. Conclusion: The findings from this study indicate that trained dogs can accurately identify respiratory secretion samples from asymptomatic and symptomatic COVID-19 patients timely and cost-effectively. Our findings recommend further uptake of this approach for COVID-19 detection.

The Management of Infectious Diseases in Comorbidity with Tuberculosis.

Tuberculosis (TB) infection is instigated by the bacillus Mycobacterium tuberculosis (MTB) [...].

Community-Based Control of Malaria Vectors Using Bacillus thuringiensis var. Israelensis (Bti) in Rwanda.

Larval source management (LSM) programs for control of malaria vectors are often vertically organized, while there is much potential for involving local communities in program implementation. To address this, we evaluated the entomological impact of community-based application of Bacillus thuringiensis var. israelensis (Bti) in a rice irrigation scheme in Ruhuha, Rwanda. A non-randomized trial with control compared a Bti implementation program that was supervised by the project team (ES) with a program that was led and carried out by local rice farming communities (CB). One other area served as a control to assess mosquito populations without Bti application. Entomological surveys were carried out every two weeks and assessed the presence and abundance of the larval, pupal, and adult stages of Anopheles mosquitoes. In ES, the per round reduction in Anopheles larval habitats was estimated at 49%. This reduction was less in CB (28%) and control (22%) although the per round reduction in CB was still significantly higher than in control. Pupal production was almost completely prevented from round 5 (out of 10) onwards in both CB (average habitat occupancy 0.43%) and ES intervention arms (average habitat occupancy 0.27%), whereas pupal occupancy rates were on average 12.8% from round 5 onwards in the control. Emergence of adult mosquitoes from rice fields was thus prevented although this was not directly noticeable in adult An. gambiae populations in houses nearby the rice fields. Together with our earlier work on the willingness to financially contribute to the LSM program and the high perceived safety and acceptance of the Bti product, the current study demonstrates that, in an environment with limited resources, communities could become more engaged in LSM program implementation and contribute directly to malaria vector control in their environment.

In vitro antimycobacterial activity of medicinal plants Lantana camara, Cryptolepis sanguinolenta, and Zanthoxylum leprieurii.

Background: Imperative need exists to search for new anti-TB drugs that are safer, and more effective against drug-resistant strains. Medicinal plants have been the source of active ingredients for drug development. However, the slow growth and biosafety level requirements of M. tuberculosis culture are considerable challenges. M. smegmatis can be used as a surrogate for M. tuberculosis. In the current study, preliminary phytochemical screening and antimycobacterial activity evaluation of crude methanolic extracts of medicinal plants against M. smegmatis, and two M. tuberculosis strains, were conducted. Materials and Methods: Crude methanolic extracts, obtained from the leaves of L. camara, roots of C. sanguinolenta, and stem barks of Z. leprieurii, were tested for antimycobacterial activity against M. smegmatis (mc2155), pan-sensitive (H37Rv), and rifampicin-resistant (TMC-331) M. tuberculosis, using visual Resazurin Microtiter Assay (REMA) on 96 well plates. Preliminary qualitative phytochemical screening tests were performed using standard chemical methods. Results: The three methanolic extracts inhibited mycobacterial growth in vitro. They were more active against rifampicin-resistant strain with MICs of 176, 97, and 45 µg/mL for L. camara, C. sanguinolenta, and Z. leprieurii extracts, respectively. The lowest activity was observed against M. smegmatis with MICs of 574, 325, and 520 µg/mL, respectively. Against H37Rv, activity was intermediate to those of TMC-331 and mc2155. However, L. camara extract showed the same activity against H37Rv and M. smegmatis. Preliminary phytochemical analysis revealed alkaloids, flavonoids, phenolic compounds, saponins, tannins, and terpenoids. Conclusions: Leaves of L. camara, roots of C. sanguinolenta, and stem barks of Z. leprieurii exhibit antimycobacterial activity against M. smegmatis, pan-sensitive, and rifampicin-resistant M. tuberculosis. This offers the possibilities for novel therapeutic opportunities against TB including multidrug-resistant TB. Further investigations on safety and mechanisms of action are required. These studies could be done using M. smegmatis as a surrogate for the highly pathogenic M. tuberculosis.

Safety and efficacy of sofosbuvir-velpatasvir-voxilaprevir for re-treatment of chronic hepatitis C virus infection in patients with previous direct-acting antiviral treatment failure in Rwanda (SHARED-3): a single-arm trial.

BACKGROUND: Hepatitis C virus (HCV) genotype 4 non-a/d subtypes, which frequently have NS5A resistance-associated substitutions, are highly prevalent in sub-Saharan Africa. These subtypes, particularly genotype 4r, have been associated with higher rates of failure of treatment regimens containing the NS5A inhibitors ledipasvir or daclatasvir, which are the most accessible direct-acting antivirals in low-income countries. Clinical evidence regarding the efficacy of re-treatment options for these subtypes is limited. We aimed to evaluate the safety and efficacy of sofosbuvir-velpatasvir-voxilaprevir for the treatment of adults in Rwanda with chronic HCV infection, predominantly of genotype 4, and a history of direct-acting antiviral treatment failure. METHODS: In this single-arm prospective trial, we enrolled adults (aged ≥18 years) with a HCV RNA titre of at least 1000 IU/mL, and a documented history of direct-acting antiviral failure. Patients were assessed for eligibility at a single study site after referral from hospitals with HCV treatment programmes throughout Rwanda, and participants for whom sofosbuvir-ledipasvir treatment had failed in the previous SHARED trial were also included. Participants with decompensated liver disease or hepatitis B virus co-infection were excluded. Participants were treated once daily with an oral fixed-dose combination tablet containing sofosbuvir (400 mg), velpatasvir (100 mg), and voxilaprevir (100 mg) for 12 weeks. The primary endpoint was the proportion of participants with a sustained virological response 12 weeks after completion of treatment (SVR12) in the intention-to-treat population. Viral sequencing of NS3, NS5A, and NS5B genes was done at baseline in all participants and at end of follow-up (week 24) in participants with treatment failure. The study is registered with ClinicalTrials.gov (NCT03888729) and is completed. FINDINGS: Between Sept 23, 2019, and Jan 10, 2020, 49 individuals were screened and 40 participants were enrolled. 20 (50%) were female, 20 (50%) were male, median age was 63 years (IQR 56-68), and median HCV viral load was 6·2 log10 IU/mL (5·8-6·5) at baseline. The genotype subtypes identified were 4r (18 [45%] participants), 4k (six [15%]), 4b (five [13%]), 4q (four [10%]), 4l (two [5%]), 4a (one [3%]), 4m (one [3%]), and 3h (one [3%]). One (3%) genotype 4 isolate could not be subtyped, and one (3%) isolate was of unknown genotype. All successfully sequenced isolates (33 [83%]) had at least two NS5A resistance-associated substitutions and 25 (63%) had three or more. 39 (98% [95% CI 87-100]) participants had SVR12. Seven (18%) participants had a total of ten grade 3, 4, or 5 adverse events, including three (8%) cases of hypertension, and one (3%) case each of cataract, diabetes, gastrointestinal bleeding, joint pain, low back pain, vaginal cancer, and sudden death. Four of these events were categorised as serious adverse events resulting in hospitalisation. The one sudden death occurred at home from an unknown cause 4 weeks after the completion of treatment. No serious adverse event was determined to be related to the study drug or resulted in treatment discontinuation. INTERPRETATION: A 12 week course of sofosbuvir-velpatasvir-voxilaprevir is safe and efficacious for the re-treatment of individuals infected with HCV genotype 4 non-a/d subtypes with frequent baseline NS5A resistance-associated substitutions, following failure of previous direct-acting antiviral treatment. Improved affordability and access to sofosbuvir-velpatasvir-voxilaprevir in regions with these subtypes is crucial. FUNDING: Gilead Sciences.

Safety and efficacy of sofosbuvir-velpatasvir to treat chronic hepatitis C virus infection in treatment-naive patients in Rwanda (SHARED-3): a single-arm trial.

BACKGROUND: Hepatitis C virus (HCV) genotype 4 is the predominant type of HCV found in sub-Saharan Africa. Various genotype 4 subtypes, such as 4r, frequently have resistance-associated substitutions that can increase rates of treatment failure with common direct-acting antiviral regimens. In-vitro studies suggest that the NS5A inhibitor velpatasvir is effective against viral isolates containing such resistance-associated substitutions, but its clinical efficacy against genotype 4 non-a/d subtypes in sub-Saharan Africa remains to be confirmed. We aimed to evaluate the safety and efficacy of sofosbuvir-velpatasvir among adults chronically infected with HCV and naive to direct-acting antiviral treatment in Rwanda, where genotype 4 non-a/d subtypes predominate. METHODS: In this single-arm prospective trial, we enrolled adults (age ≥18 years) in Rwanda who had chronic HCV infection and a plasma HCV RNA titre of at least 1000 IU/mL. Patients were referred from hospitals with HCV treatment programmes throughout Rwanda and were sequentially enrolled and assessed for eligibility at a single study site. Individuals with decompensated liver disease or hepatitis B virus co-infection were excluded. Participants were given an oral fixed-dose combination tablet of sofosbuvir (400 mg) and velpatasvir (100 mg) once-daily for 12 weeks. The primary endpoint was the proportion of participants with a sustained virological response 12 weeks after completion of treatment (SVR12) in the intention-to-treat population. Viral sequencing of the NS5A and NS5B genes was done at baseline for all participants and end of follow-up (week 24) for participants who did not have SVR12. This study is registered with ClinicalTrials.gov (NCT03888729) and is completed. FINDINGS: Between Sept 23, 2019, and Jan 10, 2020, 73 individuals were screened for eligibility, of whom 12 (16%) were excluded and 61 (84%) were enrolled. 40 (66%) participants were female, 21 (34%) were male, median age was 64 years (IQR 51-74), and median baseline HCV viral load was 5·7 log10 IU/mL (5·2-6·2). The genotypes identified among the participants were 4k (28 [46%] participants), 4r (11 [18%]), 4v (eight [13%]), 4q (five [8%]), 4l (three [5%]), 4b (one [2%]), 4c (one [2%]), and one undetermined genotype 4 subtype. Three isolates could not be sequenced and were of indeterminate genotype. Of the 55 HCV isolates that were successfully sequenced, all had at least two NS5A resistance-associated substitutions. 59 (97% [95% CI 89-99]) participants had SVR12. 18 (30%) participants had grade 3 adverse events (including 12 [20%] with hypertension), and none had grade 4 adverse events. Four (7%) participants had serious adverse events, including one asthma exacerbation, one abscess, one uterine myoma, and one pelvic fracture related to a motor vehicle accident. No serious adverse events were attributed to the study drug and no adverse event resulted in discontinuation of the study drug. INTERPRETATION: A 12-week regimen of sofosbuvir-velpatasvir is safe and efficacious in treating chronic HCV genotype 4 infection in patients in Rwanda. This regimen could be an effective treatment option in regions known to have a high prevalence of HCV genotype 4 of diverse non-a/d subtypes. FUNDING: Gilead Sciences.

Multidrug-resistant tuberculosis control in Rwanda overcomes a successful clone that causes most disease over a quarter century.

SUMMARY BACKGROUND: Multidrug-resistant (MDR) tuberculosis (TB) poses an important challenge in TB management and control. Rifampicin resistance (RR) is a solid surrogate marker of MDR-TB. We investigated the RR-TB clustering rates, bacterial population dynamics to infer transmission dynamics, and the impact of changes to patient management on these dynamics over 27 years in Rwanda. METHODS: We analysed whole genome sequences of a longitudinal collection of nationwide RR-TB isolates. The collection covered three important periods: before programmatic management of MDR-TB (PMDT; 1991-2005), the early PMDT phase (2006-2013), in which rifampicin drug-susceptibility testing (DST) was offered to retreatment patients only, and the consolidated phase (2014-2018), in which all bacteriologically confirmed TB patients had rifampicin DST done mostly via Xpert MTB/RIF assay. We constructed clusters based on a 5 SNP cut-off and resistance conferring SNPs. We used Bayesian modelling for dating and population size estimations, TransPhylo to estimate the number of secondary cases infected by each patient, and multivariable logistic regression to assess predictors of being infected by the dominant clone. RESULTS: Of 308 baseline RR-TB isolates considered for transmission analysis, the clustering analysis grouped 259 (84.1%) isolates into 13 clusters. Within these clusters, a single dominant clone was discovered containing 213 isolates (82.2% of clustered and 69.1% of all RR-TB), which we named the "Rwanda Rifampicin-Resistant clone" (R3clone). R3clone isolates belonged to Ugandan sub-lineage 4.6.1.2 and its rifampicin and isoniazid resistance were conferred by the Ser450Leu mutation in rpoB and Ser315Thr in katG genes, respectively. All R3clone isolates had Pro481Thr, a putative compensatory mutation in the rpoC gene that likely restored its fitness. The R3clone was estimated to first arise in 1987 and its population size increased exponentially through the 1990s', reaching maximum size (∼84%) in early 2000 s', with a declining trend since 2014. Indeed, the highest proportion of R3clone (129/157; 82·2%, 95%CI: 75·3-87·8%) occurred between 2000 and 13, declining to 64·4% (95%CI: 55·1-73·0%) from 2014 onward. We showed that patients with R3clone detected after an unsuccessful category 2 treatment were more likely to generate secondary cases than patients with R3clone detected after an unsuccessful category 1 treatment regimen. CONCLUSIONS: RR-TB in Rwanda is largely transmitted. Xpert MTB/RIF assay as first diagnostic test avoids unnecessary rounds of rifampicin-based TB treatment, thus preventing ongoing transmission of the dominant R3clone. As PMDT was intensified and all TB patients accessed rifampicin-resistance testing, the nationwide R3clone burden declined. To our knowledge, our findings provide the first evidence supporting the impact of universal DST on the transmission of RR-TB.

Evaluation of a health education program for improving uptake of HIV self-testing by men in Rwanda: a pilot pragmatic randomized control trial.

BACKGROUND: Health education interventions tailored to suit men have the potential to improve health outcomes for this underserved population. HIV self-testing (HIVST) is a promising approach to overcoming challenges associated with low HIV testing rates among men. The primary objective of this study is to assess the feasibility of conducting a definitive trial to determine the effectiveness of a locally adapted and optimized health education program (HEP) on the uptake of HIVST among men in Kigali, Rwanda. METHODS: This study employs a pilot pragmatic randomized controlled trial to evaluate an HIVST HEP for men. Participants were randomized to the intervention (HEP) arm or to the control arm. In the intervention group, the adapted HEP was administered in addition to routine health education. In the non-intervention group, only routine health education was offered. Participant data was collected first upon recruitment and then after 3 months' follow-up using interviewer-administered questionnaires. RESULTS: There was a 100% response rate at enrollment and no loss to follow-up at exit. There was significant association between the study arm and knowledge of HIVST. Participants in the control arm had a mean knowledge score of 67% compared to 92% among participants in the intervention arm. There was an association between the study arm and HIVST uptake: 67% of the study participants in the intervention arm self-reported HIVST uptake compared to 23% of the participants in the control arm. DISCUSSION: This pilot study demonstrates the feasibility of a larger trial to assess the effectiveness of an HEP intervention on uptake of HIVST among men. We found preliminary evidence of increased uptake of HIVST in the intervention group. TRIAL REGISTRATION: Pan African Clinical Trial Registry PACTR201908758321490 . Registered on 8 August 2019.

Risk factors for difficult-to-treat hepatitis C virus genotype 4r in Rwanda and implications for elimination in sub-Saharan Africa.

In sub-Saharan Africa, there exist distinct HCV genotype (GT) subtypes harbouring resistance-associated substitutions to commonly used non-structural protein 5A (NS5A) inhibitor-based direct-acting antiviral (DAA) regimens. In particular, GT4r subtype has demonstrated high rates of treatment failure. In the absence of routine viral sequencing in sub-Saharan Africa, it is important to identify sociodemographic, epidemiologic, and clinical characteristics that may be associated with GT4r infection. Methods: A secondary analysis was performed on data from 300 adults with HCV GT4 enrolled in a prospective trial assessing the safety and efficacy of sofosbuvir-ledipasvir in Rwanda in 2017. The association between characteristics at enrolment and GT subtype was assessed by chi-square analysis and logistic regression. In multivariate analysis, there were a higher proportion of participants with GT4r subtype with age <40 years (OR: 3.6, 95% CI: 1.3-10.5, p = 0.02), previous hospitalization (OR: 2.5, 95% CI: 1.3-5.0, p = 0.006), previous surgery (OR: 2.2, 95% CI: 1.1-4.2, p = 0.03), cirrhosis (OR: 3.2, 95% CI: 1.3-7.5, p = 0.008) and baseline HCV RNA >1 million IU/ml (OR: 3.4, 95% CI: 1.6-6.9, p = 0.001). Rwandan adults with GT4r are more likely to be younger, have a history of hospital admissions and surgeries and have more active or advanced liver disease compared to those with other GT4 subtypes. In the absence of advanced diagnostics to assess GT subtype, patients with these characteristics may warrant closer monitoring for treatment failure or alternative DAA regimens. More treatment experience with diverse DAA regimens is urgently needed for GT subtypes particular to this region.