Controlling hepatitis C in Rwanda: a framework for a national response.

With the introduction of direct-acting antiviral drugs, treatment of hepatitis C is both highly effective and tolerable. Access to treatment for patients, however, remains limited in low- and middle-income countries due to the lack of supportive health infrastructure and the high cost of treatment. Poorer countries are being encouraged by international bodies to organize public health responses that would facilitate the roll-out of care and treatment on a national scale. Yet few countries have documented formal plans and policies. Here, we outline the approach taken in Rwanda to a public health framework for hepatitis C control and care within the World Health Organization hepatitis health sector strategy. This includes the development and implementation of policies and programmes, prevention efforts, screening capacity, treatment services and strategic information systems. We highlight key successes by the national programme for the control and management of hepatitis C: establishment of national governance and planning; development of diagnostic capacity; approval and introduction of direct-acting antiviral treatments; training of key personnel; generation of political will and leadership; and fostering of key strategic partnerships. Existing challenges and next steps for the programme include developing a detailed monitoring and evaluation framework and tools for monitoring of viral hepatitis. The government needs to further decentralize care and integrate hepatitis C management into routine clinical services to provide better access to diagnosis and treatment for patients. Introducing rapid diagnostic tests to public health-care facilities would help to increase case-finding. Increased public and private financing is essential to support care and treatment services.

Grâce à l'introduction d'antiviraux à action directe, le traitement de l'hépatite C est à la fois très efficace et bien toléré. Néanmoins, l'accès des patients au traitement demeure limité dans les pays à revenu faible et intermédiaire en raison du manque d'infrastructures sanitaires de soutien et du coût élevé du traitement. Les pays pauvres sont encouragés par des organismes internationaux à élaborer des mesures de santé publique qui faciliteraient la mise en place de soins et de traitements à l'échelle nationale. Peu de pays ont cependant établi des politiques et des plans officiels. Dans cet article, nous présentons l'approche adoptée au Rwanda à l'égard d'un cadre de santé publique pour le contrôle de l'hépatite C et les soins qui lui sont associés dans le contexte de la stratégie du secteur de la santé contre l'hépatite de l'Organisation mondiale de la Santé. Cela inclut le développement et la mise en œuvre de politiques et de programmes, d'efforts de prévention, de capacités de dépistage, de services de traitement et de systèmes d'information stratégiques. Nous mettons en avant les principaux succès du programme national pour le contrôle et la gestion de l'hépatite C: l'établissement d'une gouvernance et d'une planification nationales; le renforcement des capacités de diagnostic; l'approbation et l'introduction de traitements antiviraux à action directe; la formation de personnel d'encadrement; le développement d'une volonté et d'un leadership politiques; et la promotion de partenariats stratégiques clés. Les enjeux actuels et les prochaines étapes du programme incluent l'élaboration d'un cadre détaillé de suivi et d'évaluation, ainsi que des outils pour le suivi de l'hépatite virale. Le gouvernement doit favoriser la décentralisation des soins et intégrer la gestion de l'hépatite C aux services cliniques courants afin de fournir aux patients un meilleur accès au diagnostic et au traitement. L'utilisation de tests de diagnostic rapide dans les établissements publics de santé permettrait d'améliorer le dépistage. Il est essentiel d'augmenter les financements publics et privés pour soutenir les services de soins et de traitement.

Con la introducción de los fármacos antivíricos de acción directa, el tratamiento de la hepatitis C es altamente eficaz y tolerable. Sin embargo, el acceso al tratamiento por parte de los pacientes sigue siendo limitado en los países de ingresos medios y bajos, debido a la falta de infraestructuras sanitarias de apoyo y a los altos costos del tratamiento. Los organismos internacionales alientan a los países más pobres a organizar respuestas de salud pública que podrían facilitar la puesta en marcha de atención y tratamiento a escala nacional. Sin embargo, son pocos los países que han documentado planes y políticas formales. En el presente estudio, esbozamos el enfoque adoptado en Rwanda para un marco de salud pública para el control y la atención de la hepatitis C dentro de la estrategia del sector de la salud contra la hepatitis de la Organización Mundial de la Salud. Este incluye la elaboración y aplicación de políticas y programas, medidas preventivas, capacidad de cribado, servicios de tratamiento y sistemas de información estratégica. Destacamos los éxitos clave del programa nacional para el control y tratamiento de la hepatitis C: establecimiento de la gobernanza y planificación nacional; desarrollo de capacidad diagnóstica; aprobación e introducción de tratamientos antivíricos de acción directa; formación de personal clave; generación de voluntad política y liderazgo; y promoción de asociaciones estratégicas clave. Los desafíos actuales y los próximos pasos del programa incluyen el desarrollo de un marco de seguimiento y evaluación detallado, así como herramientas para el seguimiento de la hepatitis viral. El gobierno necesita descentralizar todavía más la atención e integrar la gestión de la hepatitis C en los servicios clínicos corrientes para proporcionar un mejor acceso al diagnóstico y tratamiento de los pacientes. La introducción de pruebas diagnósticas rápidas en los centros de atención de salud pública ayudaría a aumentar la búsqueda de casos. El aumento de la financiación pública y privada es esencial para apoyar los servicios de atención y tratamiento.

Controlling hepatitis C in Rwanda: a framework for a national response

With the introduction of direct-acting antiviral drugs, treatment of hepatitis C is both highly effective and tolerable. Access to treatment for patients, however, remains limited in low- and middle-income countries due to the lack of supportive health infrastructure and the high cost of treatment. Poorer countries are being encouraged by international bodies to organize public health responses that would facilitate the roll-out of care and treatment on a national scale. Yet few countries have documented formal plans and policies. Here, we outline the approach taken in Rwanda to a public health framework for hepatitis C control and care within the World Health Organization hepatitis health sector strategy. This includes the development and implementation of policies and programmes, prevention efforts, screening capacity, treatment services and strategic information systems. We highlight key successes by the national programme for the control and management of hepatitis C: establishment of national governance and planning; development of diagnostic capacity; approval and introduction of direct-acting antiviral treatments; training of key personnel; generation of political will and leadership; and fostering of key strategic partnerships. Existing challenges and next steps for the programme include developing a detailed monitoring and evaluation framework and tools for monitoring of viral hepatitis. The government needs to further decentralize care and integrate hepatitis C management into routine clinical services to provide better access to diagnosis and treatment for patients. Introducing rapid diagnostic tests to public health-care facilities would help to increase case-finding. Increased public and private financing is essential to support care and treatment services

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.

High levels of adherence and viral suppression in a nationally representative sample of HIV-infected adults on antiretroviral therapy for 6, 12 and 18 months in Rwanda.

BACKGROUND: Generalizable data are needed on the magnitude and determinants of adherence and virological suppression among patients on antiretroviral therapy (ART) in Africa. METHODS: We conducted a cross-sectional survey with chart abstraction, patient interviews and site assessments in a nationally representative sample of adults on ART for 6, 12 and 18 months at 20 sites in Rwanda. Adherence was assessed using 3- and 30-day patient recall. A systematically selected sub-sample had viral load (VL) measurements. Multivariable logistic regression examined predictors of non-perfect (<100%) 30-day adherence and detectable VL (>40 copies/ml). RESULTS: Overall, 1,417 adults were interviewed and 837 had VL measures. Ninety-four percent and 78% reported perfect adherence for the last 3 and 30 days, respectively. Eighty-three percent had undetectable VL. In adjusted models, characteristics independently associated with higher odds of non-perfect 30-day adherence were: being on ART for 18 months (vs. 6 months); younger age; reporting severe (vs. no or few) side effects in the prior 30 days; having no documentation of CD4 cell count at ART initiation (vs. having a CD4 cell count of <200 cells/µL); alcohol use; and attending sites which initiated ART services in 2003-2004 and 2005 (vs. 2006-2007); sites with ≥600 (vs. <600 patients) on ART; or sites with peer educators. Participation in an association for people living with HIV/AIDS; and receiving care at sites which regularly conduct home-visits were independently associated with lower odds of non-adherence. Higher odds of having a detectable VL were observed among patients at sites with peer educators. Being female; participating in an association for PLWHA; and using a reminder tool were independently associated with lower odds of having detectable VL. CONCLUSIONS: High levels of adherence and viral suppression were observed in the Rwandan national ART program, and associated with potentially modifiable factors.

Effectiveness of early antiretroviral therapy initiation to improve survival among HIV-infected adults with tuberculosis: a retrospective cohort study.

BACKGROUND: Randomized clinical trials examining the optimal time to initiate combination antiretroviral therapy (cART) in HIV-infected adults with sputum smear-positive tuberculosis (TB) disease have demonstrated improved survival among those who initiate cART earlier during TB treatment. Since these trials incorporated rigorous diagnostic criteria, it is unclear whether these results are generalizable to the vast majority of HIV-infected patients with TB, for whom standard diagnostic tools are unavailable. We aimed to examine whether early cART initiation improved survival among HIV-infected adults who were diagnosed with TB in a clinical setting. METHODS AND FINDINGS: We retrospectively reviewed charts for 308 HIV-infected adults in Rwanda with a CD4 count ≤ 350 cells/µl and a TB diagnosis. We estimated the effect of cART on survival using marginal structural models and simulated 2-y survival curves for the cohort under different cART strategies:start cART 15, 30, 60, or 180 d after TB treatment or never start cART. We conducted secondary analyses with composite endpoints of (1) death, default, or lost to follow-up and (2) death, hospitalization, or serious opportunistic infection. Early cART initiation led to a survival benefit that was most marked for individuals with low CD4 counts. For individuals with CD4 counts of 50 or 100 cells/µl, cART initiation at day 15 yielded 2-y survival probabilities of 0.82 (95% confidence interval: [0.76, 0.89]) and 0.86 (95% confidence interval: [0.80, 0.92]), respectively. These were significantly higher than the probabilities computed under later start times. Results were similar for the endpoint of death, hospitalization, or serious opportunistic infection. cART initiation at day 15 versus later times was protective against death, default, or loss to follow-up, regardless of CD4 count. As with any observational study, the validity of these findings assumes that biases from residual confounding by unmeasured factors and from model misspecification are small. CONCLUSIONS: Early cART reduced mortality among individuals with low CD4 counts and improved retention in care, regardless of CD4 count. Please see later in the article for the Editors' Summary.

Prevalence of kidney disease in HIV-infected and uninfected Rwandan women.

BACKGROUND: In the United States, HIV-related kidney disease disproportionately affects individuals of African descent; however, there are few estimates of kidney disease prevalence in Africa. We evaluated the prevalence of kidney disease among HIV-infected and uninfected Rwandan women. METHODS: The Rwandan Women's Interassociation Study and Assessment prospectively enrolled 936 women. Associations with estimated glomerular filtration rate (eGFR)<60 mL/min/1.73 m(2) and proteinuria were assessed in separate logistic regression models. RESULTS: Among 891 non-pregnant women with available data, 2.4% had an eGFR<60 mL/min/1.73 m(2) (calculated by the Modification of Diet in Renal Disease equation, MDRD eGFR) and 8.7% had proteinuria ≥1+. The prevalence of decreased eGFR varied markedly depending on the estimating method used, with the highest prevalence by Cockcroft-Gault. Regardless of the method used to estimate GFR, the proportion with decreased eGFR or proteinuria did not differ significantly between HIV-infected and -uninfected women in unadjusted analysis. After adjusting for age and blood pressure, HIV infection was associated with significantly higher odds of decreased MDRD eGFR but not proteinuria. CONCLUSION: In a well-characterized cohort of Rwandan women, HIV infection was associated with decreased MDRD eGFR. The prevalence of decreased eGFR among HIV-infected women in our study was lower than that previously reported in African-Americans and in other Central and East African HIV populations, although there was substantial variability depending on the equation used to estimate GFR. Future studies are needed to optimize GFR estimates and to determine the impact of antiretroviral therapy on kidney disease in this population.

When one can infect two: a reflection on the impact of HIV discordance on child HIV infection.

This is an opinion piece based on data and experience from Rwanda. The authors believe this opinion piece may help improve current programs on prevention of HIV transmission from mother to child in Africa taking into account the prevalence of HIV sero-discordance in couples. The authors recommend that if we want to ensure newborns stay HIV negative, PMTCT protocols should offer a series of HIV tests linked with antenatal visits and the lactation period as well as HIV testing of current sexual partners. Moreover, if the male partner is found to be positive and the woman is negative, programs should provide intensive counseling on the use of condoms. The lives of three individuals have the potential to be changed from HIV testing and counseling. Morally, this cannot be ignored.

Weight loss after the first year of stavudine-containing antiretroviral therapy and its association with lipoatrophy, virological failure, adherence and CD4 counts at primary health care level in Kigali, Rwanda.

This study was conducted among 609 adults on stavudine-based antiretroviral treatment (ART) for at least one year at health center level in Kigali, Rwanda to (a) determine the proportion who manifest weight loss after one year of ART (b) examine the association between such weight loss and a number of variables, namely: lipoatrophy, virological failure, adherence and on-treatment CD4 count and (c) assess the validity and predictive values of weight loss to identify patients with lipoatrophy. Weight loss after the first year of ART was seen in 62% of all patients (median weight loss 3.1 kg/year). In multivariate analysis, weight loss was significantly associated with treatment-limiting lipoatrophy (adjusted effect/kg/year -2.0 kg, 95% confidence interval -0.6;-3.4 kg; P<0.01). No significant association was found with virological failure or adherence. Higher on-treatment CD4 cell counts were protective against weight loss. Weight loss that was persistent, progressive and/or chronic was predictive of lipoatrophy, with a sensitivity and specificity of 72% and 77%, and positive and negative predictive values of 30% and 95%. In low-income countries, measuring weight is a routine clinical procedure that could be used to filter out individuals with lipoatrophy on stavudine-based ART, after alternative causes of weight loss have been ruled out.

Stavudine- and nevirapine-related drug toxicity while on generic fixed-dose antiretroviral treatment: incidence, timing and risk factors in a three-year cohort in Kigali, Rwanda.

This cohort study was conducted to report on the incidence, timing and risk factors for stavudine (d4T)- and nevirapine (NVP)-related severe drug toxicity (requiring substitution) with a generic fixed-dose combination under program conditions in Kigali, Rwanda. Probability of 'time to first toxicity-related drug substitution' was estimated using the Kaplan-Meier method and Cox-proportional hazards modeling was used to identify risk factors. Out of 2190 adults (median follow-up: 1.5 years), d4T was replaced in 175 patients (8.0%) for neuropathy, 69 (3.1%) for lactic acidosis and 157 (7.2%) for lipoatrophy, which was the most frequent toxicity by 3 years of antiretroviral treatment (ART). NVP was substituted in 4.9 and 1.3% of patients for skin rash and hepatotoxicity, respectively. Use of d4T 40 mg was associated with increased risk of lipoatrophy and early (<6 months) neuropathy. Significant risk factors associated with lactic acidosis and late neuropathy included higher baseline body weight. Older age and advanced HIV disease increased the risk of neuropathy. Elevated baseline liver tests and older age were identified as risk factors for NVP-related hepatotoxicity. d4T is associated with significant long-term toxicity. d4T-dose reduction, increased access to safer ART in low-income countries and close monitoring for those at risk are all relevant strategies.

Adult clinical and immunologic outcomes of the national antiretroviral treatment program in Rwanda during 2004-2005.

BACKGROUND: By December 2007, over 48,000 persons had initiated antiretroviral treatment (ART) at 171 clinics in Rwanda. Assessing national ART program outcomes is essential to determine whether programs have the desired impact. METHODS: We conducted a retrospective cohort study to assess key 6- and 12-month outcomes among a nationally representative, stratified, random sample of 3194 adults (> or =15 years) who initiated ART from January 1, 2004, through December 31, 2005. FINDINGS: At ART initiation, the median patient age was 37 years and 65% were female. Overall, the baseline median CD4 cell count was 141 cells per microliter. At 6 and 12 months after ART initiation, 92% and 86% of patients, respectively, remained on ART at their original site. By 6 months, 3.6% were dead and 3.4% were lost to follow-up; by 12 months, 4.6% were dead and 4.9% were lost to follow-up. Among patients with available follow-up CD4 cell count data, median CD4 cell counts increased by 98 cells per microliter and 119 cells per microliter at 6 and 12 months after ART initiation, respectively. CONCLUSIONS: Rwanda's national ART program achieved excellent 6- and 12-month retention and immunologic outcomes during the first 2 years of rapid scale-up. Routine supervision is required to improve compliance with clinical guidelines and data quality.

Exceptional genetic variability of hepatitis B virus indicates that Rwanda is east of an emerging African genotype E/A1 divide.

In Western Africa, hepatitis B virus (HBV) genotype E predominates throughout a vast crescent spanning from Senegal to Namibia and at least to the Central African Republic to the East. Although from most of the eastern parts of sub-Saharan Africa only limited sets of strains have been characterized, these belong predominantly to genotype A. To study how far the genotype E crescent extends to the East, a larger number of HBV strains from Rwanda were analyzed. Phylogenetic analysis of 45 S fragment sequences revealed strains of genotypes A (n = 30), D (n = 10), C (n = 4), and B (n = 1). Twelve genotype A sequences formed a new cluster clearly separated from the reference strains of the known sub-genotypes. Thus, with four genotypes and at least six sub-genotypes and a new cluster of genotype A strains, HBV shows an exceptional genetic variability in this small country, unprecedented in sub-Saharan Africa. Despite this exceptional genetic variability, not a single genotype E virus was found indicating that this country does not belong to the genotype E crescent, but is east of an emerging African genotype E/A1 divide.