Graham S. Cooke

Global distribution and prevalence of hepatitis C virus genotypes

Hepatitis C virus (HCV) exhibits high genetic diversity, characterized by regional variations in genotype prevalence. This poses a challenge to the improved development of vaccines and pan‐genotypic treatments, which require the consideration of global trends in HCV genotype prevalence. Here we provide the first comprehensive survey of these trends. To approximate national HCV genotype prevalence, studies published between 1989 and 2013 reporting HCV genotypes are reviewed and combined with overall HCV prevalence estimates from the Global Burden of Disease (GBD) project. We also generate regional and global genotype prevalence estimates, inferring data for countries lacking genotype information. We include 1,217 studies in our analysis, representing 117 countries and 90% of the global population. We calculate that HCV genotype 1 is the most prevalent worldwide, comprising 83.4 million cases (46.2% of all HCV cases), approximately one‐third of which are in East Asia. Genotype 3 is the next most prevalent globally (54.3 million, 30.1%); genotypes 2, 4, and 6 are responsible for a total 22.8% of all cases; genotype 5 comprises the remaining <1%. While genotypes 1 and 3 dominate in most countries irrespective of economic status, the largest proportions of genotypes 4 and 5 are in lower‐income countries. Conclusion: Although genotype 1 is most common worldwide, nongenotype 1 HCV cases—which are less well served by advances in vaccine and drug development—still comprise over half of all HCV cases. Relative genotype proportions are needed to inform healthcare models, which must be geographically tailored to specific countries or regions in order to improve access to new treatments. Genotype surveillance data are needed from many countries to improve estimates of unmet need. (Hepatology 2015;61:77–87)

The global burden of viral hepatitis from 1990 to 2013: findings from the Global Burden of Disease Study 2013

BACKGROUND With recent improvements in vaccines and treatments against viral hepatitis, an improved understanding of the burden of viral hepatitis is needed to inform global intervention strategies. We used data from the Global Burden of Disease (GBD) Study to estimate morbidity and mortality for acute viral hepatitis, and for cirrhosis and liver cancer caused by viral hepatitis, by age, sex, and country from 1990 to 2013. METHODS We estimated mortality using natural history models for acute hepatitis infections and GBDs cause-of-death ensemble model for cirrhosis and liver cancer. We used meta-regression to estimate total cirrhosis and total liver cancer prevalence, as well as the proportion of cirrhosis and liver cancer attributable to each cause. We then estimated cause-specific prevalence as the product of the total prevalence and the proportion attributable to a specific cause. Disability-adjusted life-years (DALYs) were calculated as the sum of years of life lost (YLLs) and years lived with disability (YLDs). FINDINGS Between 1990 and 2013, global viral hepatitis deaths increased from 0·89 million (95% uncertainty interval [UI] 0·86-0·94) to 1·45 million (1·38-1·54); YLLs from 31·0 million (29·6-32·6) to 41·6 million (39·1-44·7); YLDs from 0·65 million (0·45-0·89) to 0·87 million (0·61-1·18); and DALYs from 31·7 million (30·2-33·3) to 42·5 million (39·9-45·6). In 2013, viral hepatitis was the seventh (95% UI seventh to eighth) leading cause of death worldwide, compared with tenth (tenth to 12th) in 1990. INTERPRETATION Viral hepatitis is a leading cause of death and disability worldwide. Unlike most communicable diseases, the absolute burden and relative rank of viral hepatitis increased between 1990 and 2013. The enormous health loss attributable to viral hepatitis, and the availability of effective vaccines and treatments, suggests an important opportunity to improve public health. FUNDING Bill & Melinda Gates Foundation.

Technologies for global health

Institute for Global Health Innovation (L Conteh PhD, Prof A Darzi FRCS, P Howitt MA, K Kerr PhD, Prof S Matlin DSc, R Merrifi eld PhD, Prof G-Z Yang PhD), Centre for Environmental Policy (E Wilson MSc), Centre for Health Policy (D King MRCS, M Kulendran MRCS, Prof P C Smith BA), Department of Bioengineering (Prof A M J Bull PhD, Prof R A Malkin PhD, Prof M M Stevens PhD), Department of Civil and Environmental Engineering (M R Templeton PhD), Department of Infectious Diseases (G S Cooke PhD, N Ford PhD, S D Reid PhD), Department of Infectious Disease Epidemiology (S A J Gregson PhD), Department of Materials (Prof M M Stevens), Department of Medicine (A Blakemore PhD), Department of Primary Care & Public Health (Prof A Majeed MD), Department of Surgery and Cancer (H Ashrafi an MRCS, Prof C Vincent PhD), Faculty of Medicine (Prof R Atun FRCP), Global eHealth Unit (J Car PhD), Imperial College Business School (Prof R Atun FRCP, Prof J Barlow PhD), and Imperial Innovations (HA Penfold PhD), Imperial College London, London, UK Technologies for global health

Localized spatial clustering of HIV infections in a widely disseminated rural South African epidemic

BACKGROUND South Africa contains more than one in seven of the worlds HIV-positive population. Knowledge of local variation in levels of HIV infection is important for prioritization of areas for intervention. We apply two spatial analytical techniques to investigate the micro-geographical patterns and clustering of HIV infections in a high prevalence, rural population in KwaZulu-Natal, South Africa. METHODS All 12,221 participants who consented to an HIV test in a population under continuous demographical surveillance were linked to their homesteads and geo-located in a geographical information system (accuracy of <2 m). We then used a two-dimensional Gaussian kernel of radius 3 km to produce robust estimates of HIV prevalence that vary across continuous geographical space. We also applied a Kulldorff spatial scan statistic (Bernoulli model) to formally identify clusters of infections (P < 0.05). RESULTS The results reveal considerable geographical variation in local HIV prevalence (range = 6-36%) within this relatively homogenous population and provide clear empirical evidence for the localized clustering of HIV infections. Three high-risk, overlapping spatial clusters [Relative Risk (RR) = 1.34-1.62] were identified by the Kulldorff statistic along the National Road (P < or = 0.01), whereas three low risk clusters (RR = 0.2-0.38) were identified elsewhere in the study area (P < or = 0.017). CONCLUSIONS The findings show the existence of several localized HIV epidemics of varying intensity that are partly contained within geographically defined communities. Despite the overall high prevalence of HIV in many rural South African settings, the results support the need for interventions that target socio-geographic spaces (communities) at greatest risk to supplement measures aimed at the general population.

Long-Term Treatment Outcomes of Patients Infected With Hepatitis C Virus: A Systematic Review and Meta-analysis of the Survival Benefit of Achieving a Sustained Virological Response

The results of this meta-analysis suggest that there is a significant survival benefit of achieving an sustained virologic response compared with unsuccessful treatment in the general hepatitis C virus-infected population. This benefit is held in patients with cirrhosis and those coinfected with human immunodeficiency virus.

Retention in HIV care for individuals not yet eligible for antiretroviral therapy: rural KwaZulu-Natal, South Africa

Objectives: To determine retention in HIV care for individuals not yet eligible for antiretroviral therapy (ART) and to explore factors associated with retention in a rural public health HIV program. Methods: HIV-infected adults (≥16 years) not yet eligible for ART, with CD4 cell count >200 cells per microliter from January 2007 to December 2007 were included in the analysis. Retention was defined by repeat CD4 count within 13 months. Factors associated with retention were assessed using logistic regression with clustering at clinic level. Results: Four thousand two hundred twenty-three were included in the analysis (83.9% female). Overall retention was 44.9% with median time to return 201 days [interquartile range (IQR): 127-274]. Retention by initial CD4 count 201-350, 351-500, and >500 cells per microliter was 51.6% [95% confidence interval (CI): 49.1 to 54.0], 43.2% (95% CI: 40.5 to 45.9), and 34.9% (95% CI: 32.4 to 37.4), respectively. Compared with CD4 201-350 cells per microliter, higher initial CD4 count was significantly associated with lower odds of retention [CD4: 351-500 cells/μL adjusted odds ratio (aOR): 0.72, 95% CI: 0.62 to 0.84; CD4 >500 cells/μL aOR: 0.51, 95% CI: 0.44 to 0.60]. Male sex was independently associated with lower odds (aOR: 0.80, 95% CI: 0.67 to 0.96), and older age with higher odds of retention (for each additional year of age aOR: 1.03, 95% CI: 1.03 to 1.04). Conclusions: Retention in HIV care before eligibility for ART is poor, particularly for younger individuals and those at an earlier stage of infection. Further work to optimize and evaluate care and monitoring strategies is required to realize the full benefits of the rapid expansion of HIV programs in sub-Saharan Africa.

Treatment outcomes for children with multidrug-resistant tuberculosis: a systematic review and meta-analysis.

BACKGROUND Paediatric multidrug-resistant (MDR) tuberculosis is a public health challenge of growing concern, accounting for an estimated 15% of all global cases of MDR tuberculosis. Clinical management is especially challenging, and recommendations are based on restricted evidence. We aimed to assess existing evidence for the treatment of MDR tuberculosis in children. METHODS We did a systematic review and meta-analysis of published and unpublished studies reporting treatment outcomes for children with MDR tuberculosis. We searched PubMed, Ovid, Embase, Cochrane Library, PsychINFO, and BioMedCentral databases up to Oct 31, 2011. Eligible studies included five or more children (aged ≤16 years) with MDR tuberculosis within a defined treatment cohort. The primary outcome was treatment success, defined as a composite of cure and treatment completion. RESULTS We identified eight studies, which reported treatment outcomes for a total of 315 patients. We recorded much variation in the characteristics of patients and programmes. Time to appropriate treatment varied from 2 days to 46 months. Average duration of treatment ranged from 6 months to 34 months, and duration of follow-up ranged from 12 months to 37 months. The pooled estimate for treatment success was 81·67% (95% CI 72·54-90·80). Across all studies, 5·9% (95% CI 1·3-10·5) died, 6·2% (2·3-10·2) defaulted, and 39·1% (28·7-49·4) had an adverse event. The most common drug-related adverse events were nausea and vomiting. Other serious adverse events were hearing loss, psychiatric effects, and hypothyroidism. INTERPRETATION The treatment of paediatric MDR tuberculosis has been neglected, but when children are treated outcomes can be achieved that are at least as good as those reported for adults. Programmes should be encouraged to report outcomes in children to improve the knowledge base for care, especially as new drugs become available. FUNDING None.

Scale-up of a decentralized HIV treatment programme in rural KwaZulu-Natal, South Africa: does rapid expansion affect patient outcomes?

OBJECTIVE To describe the scale-up of a decentralized HIV treatment programme delivered through the primary health care system in rural KwaZulu-Natal, South Africa, and to assess trends in baseline characteristics and outcomes in the study population. METHODS The programme started delivery of antiretroviral therapy (ART) in October 2004. Information on all patients initiated on ART was captured in the programme database and follow-up status was updated monthly. All adult patients (> or = 16 years) who initiated ART between October 2004 and September 2008 were included and stratified into 6-month groups. Clinical and sociodemographic characteristics were compared between the groups. Retention in care, mortality, loss to follow-up and virological outcomes were assessed at 12 months post-ART initiation. FINDINGS A total of 5719 adults initiated on ART were included (67.9% female). Median baseline CD4+ lymphocyte count was 116 cells/microl (interquartile range, IQR: 53-173). There was an increase in the proportion of women who initiated ART while pregnant but no change in other baseline characteristics over time. Overall retention in care at 12 months was 84.0% (95% confidence interval, CI: 82.6-85.3); 10.9% died (95% CI: 9.8-12.0); 3.7% were lost to follow-up (95% CI: 3.0-4.4). Mortality was highest in the first 3 months after ART initiation: 30.1 deaths per 100 person-years (95% CI: 26.3-34.5). At 12 months 23.0% had a detectable viral load (> 25 copies/ml) (95% CI: 19.5-25.5). CONCLUSION Outcomes were not affected by rapid expansion of this decentralized HIV treatment programme. The relatively high rates of detectable viral load highlight the need for further efforts to improve the quality of services.

Risk of Late Relapse or Reinfection With Hepatitis C Virus After Achieving a Sustained Virological Response: A Systematic Review and Meta-analysis

Sustained virological response is durable in patients treated for hepatitis C virus. Recurrence rates are generally low but increase in patient populations with risk factors for reinfection. The evidence supports the notion that risk of recurrence is driven by reinfection.

Strategies for reducing treatment default in drug-resistant tuberculosis: systematic review and meta-analysis [Review article].

BACKGROUND Scaling up treatment for multidrug-resistant tuberculosis is a global health priority. However, current treatment regimens are long and associated with side effects, and default rates are consequently high. This systematic review aimed to identify strategies for reducing treatment default. METHODS We conducted a systematic search up to May 2012 to identify studies describing interventions to support patients receiving treatment for multidrug-resistant tuberculosis (MDR-TB). The potential influence of study interventions were explored through subgroup analyses. RESULTS A total of 75 studies provided outcomes for 18,294 patients across 31 countries. Default rates ranged from 0.5% to 56%, with a pooled proportion of 14.8% (95%CI 12.4-17.4). Strategies identified to be associated with lower default rates included the engagement of community health workers as directly observed treatment (DOT) providers, the provision of DOT throughout treatment, smaller cohort sizes and the provision of patient education. CONCLUSION Current interventions to support adherence and retention are poorly described and based on weak evidence. This review was able to identify a number of promising, inexpensive interventions feasible for implementation and scale-up in MDR-TB programmes. The high default rates reported from many programmes underscore the pressing need to further refine and evaluate simple intervention packages to support patients.BACKGROUND Scaling up treatment for multidrug-resistant tuberculosis is a global health priority. However, current treatment regimens are long and associated with side effects, and default rates are consequently high. This systematic review aimed to identify strategies for reducing treatment default. METHODS We conducted a systematic search up to May 2012 to identify studies describing interventions to support patients receiving treatment for multidrug-resistant tuberculosis (MDR-TB). The potential influence of study interventions were explored through subgroup analyses. RESULTS A total of 75 studies provided outcomes for 18 294 patients across 31 countries. Default rates ranged from 0.5% to 56%, with a pooled proportion of 14.8% (95%CI 12.4-17.4). Strategies identified to be associated with lower default rates included the engagement of community health workers as directly observed treatment (DOT) providers, the provision of DOT throughout treatment, smaller cohort sizes and the provision of patient education. CONCLUSION Current interventions to support adherence and retention are poorly described and based on weak evidence. This review was able to identify a number of promising, inexpensive interventions feasible for implementation and scale-up in MDR-TB programmes. The high default rates reported from many programmes underscore the pressing need to further refine and evaluate simple intervention packages to support patients.