Summary Background In 2010 a new diagnostic test for tuberculosis, Xpert MTB/RIF, received a conditional programmatic recommendation from WHO. Several model-based economic evaluations predicted that ...Xpert would be cost-effective across sub-Saharan Africa. We investigated the cost-effectiveness of Xpert in the real world during national roll-out in South Africa. Methods For this real-world cost analysis and economic evaluation, we applied extensive primary cost and patient event data from the XTEND study, a pragmatic trial examining Xpert introduction for people investigated for tuberculosis in 40 primary health facilities (20 clusters) in South Africa enrolled between June 8, and Nov 16, 2012, to estimate the costs and cost per disability-adjusted life-year averted of introducing Xpert as the initial diagnostic test for tuberculosis, compared with sputum smear microscopy (the standard of care). Findings The mean total cost per study participant for tuberculosis investigation and treatment was US$312·58 (95% CI 252·46–372·70) in the Xpert group and $298·58 (246·35–350·82) in the microscopy group. The mean health service (provider) cost per study participant was $168·79 (149·16–188·42) for the Xpert group and $160·46 (143·24–177·68) for the microscopy group of the study. Considering uncertainty in both cost and effect using a wide range of willingness to pay thresholds, we found less than 3% probability that Xpert introduction improved the cost-effectiveness of tuberculosis diagnostics. Interpretation After analysing extensive primary data collection during roll-out, we found that Xpert introduction in South Africa was cost-neutral, but found no evidence that Xpert improved the cost-effectiveness of tuberculosis diagnosis. Our study highlights the importance of considering implementation constraints, when predicting and evaluating the cost-effectiveness of new tuberculosis diagnostics in South Africa. Funding Bill & Melinda Gates Foundation.
Summary Tuberculosis is the leading infectious cause of death worldwide, with 9·6 million cases and 1·5 million deaths reported in 2014. WHO estimates 480 000 cases of these were multidrug resistant ...(MDR). Less than half of patients who entered into treatment for MDR tuberculosis successfully completed that treatment, mainly due to high mortality and loss to follow-up. These in turn illustrate weaknesses in current treatment regimens and national tuberculosis programmes, coupled with operational treatment challenges. In this Review we provide an update on recent developments in the tuberculosis drug-development pipeline (including new and repurposed antimicrobials and host-directed drugs) as they are applied to new regimens to shorten and improve outcomes of tuberculosis treatment. Several new or repurposed antimicrobial drugs are in advanced trial stages for MDR tuberculosis, and two new antimicrobial drug candidates are in early-stage trials. Several trials to reduce the duration of therapy in MDR and drug-susceptible tuberculosis are ongoing. A wide range of candidate host-directed therapies are being developed to accelerate eradication of infection, prevent new drug resistance, and prevent permanent lung injury. As these drugs have been approved for other clinical indications, they are now ready for repurposing for tuberculosis in phase 2 clinical trials. We assess risks associated with evaluation of new treatment regimens, and highlight opportunities to advance tuberculosis research generally through regulatory innovation in MDR tuberculosis. Progress in tuberculosis-specific biomarkers (including culture conversion, PET and CT imaging, and gene expression profiles) can support this innovation. Several global initiatives now provide unique opportunities to tackle the tuberculosis epidemic through collaborative partnerships between high-income countries and middle-income and low-income countries for clinical trials training and research, allowing funders to coordinate several national and regional programmes for greatest overall effect.
Summary Background Tuberculosis is the world's leading infectious disease killer. We aimed to identify shorter, safer drug regimens for the treatment of tuberculosis. Methods We did a randomised ...controlled, open-label trial with a multi-arm, multi-stage design. The trial was done in seven sites in South Africa and Tanzania, including hospitals, health centres, and clinical trial centres. Patients with newly diagnosed, rifampicin-sensitive, previously untreated pulmonary tuberculosis were randomly assigned in a 1:1:1:1:2 ratio to receive (all orally) either 35 mg/kg rifampicin per day with 15–20 mg/kg ethambutol, 20 mg/kg rifampicin per day with 400 mg moxifloxacin, 20 mg/kg rifampicin per day with 300 mg SQ109, 10 mg/kg rifampicin per day with 300 mg SQ109, or a daily standard control regimen (10 mg/kg rifampicin, 5 mg/kg isoniazid, 25 mg/kg pyrazinamide, and 15–20 mg/kg ethambutol). Experimental treatments were given with oral 5 mg/kg isoniazid and 25 mg/kg pyrazinamide per day for 12 weeks, followed by 14 weeks of 5 mg/kg isoniazid and 10 mg/kg rifampicin per day. Because of the orange discoloration of body fluids with higher doses of rifampicin it was not possible to mask patients and clinicians to treatment allocation. The primary endpoint was time to culture conversion in liquid media within 12 weeks. Patients without evidence of rifampicin resistance on phenotypic test who took at least one dose of study treatment and had one positive culture on liquid or solid media before or within the first 2 weeks of treatment were included in the primary analysis (modified intention to treat). Time-to-event data were analysed using a Cox proportional-hazards regression model and adjusted for minimisation variables. The proportional hazard assumption was tested using Schoelfeld residuals, with threshold p<0·05 for non-proportionality. The trial is registered with ClinicalTrials.gov ( NCT01785186 ). Findings Between May 7, 2013, and March 25, 2014, we enrolled and randomly assigned 365 patients to different treatment arms (63 to rifampicin 35 mg/kg, isoniazid, pyrazinamide, and ethambutol; 59 to rifampicin 10 mg/kg, isoniazid, pyrazinamide, SQ109; 57 to rifampicin 20 mg/kg, isoniazid, pyrazinamide, and SQ109; 63 to rifampicin 10 mg/kg, isoniazid, pyrazinamide, and moxifloxacin; and 123 to the control arm). Recruitment was stopped early in the arms containing SQ109 since prespecified efficacy thresholds were not met at the planned interim analysis. Time to stable culture conversion in liquid media was faster in the 35 mg/kg rifampicin group than in the control group (median 48 days vs 62 days, adjusted hazard ratio 1·78; 95% CI 1·22–2·58, p=0·003), but not in other experimental arms. There was no difference in any of the groups in time to culture conversion on solid media. 11 patients had treatment failure or recurrent disease during post-treatment follow-up: one in the 35 mg/kg rifampicin arm and none in the moxifloxacin arm. 45 (12%) of 365 patients reported grade 3–5 adverse events, with similar proportions in each arm. Interpretation A dose of 35 mg/kg rifampicin was safe, reduced the time to culture conversion in liquid media, and could be a promising component of future, shorter regimens. Our adaptive trial design was successfully implemented in a multi-centre, high tuberculosis burden setting, and could speed regimen development at reduced cost. Funding The study was funded by the European and Developing Countries Clinical Trials partnership (EDCTP), the German Ministry for Education and Research (BmBF), and the Medical Research Council UK (MRC).
Summary Background The post-2015 End TB Strategy proposes targets of 50% reduction in tuberculosis incidence and 75% reduction in mortality from tuberculosis by 2025. We aimed to assess whether these ...targets are feasible in three high-burden countries with contrasting epidemiology and previous programmatic achievements. Methods 11 independently developed mathematical models of tuberculosis transmission projected the epidemiological impact of currently available tuberculosis interventions for prevention, diagnosis, and treatment in China, India, and South Africa. Models were calibrated with data on tuberculosis incidence and mortality in 2012. Representatives from national tuberculosis programmes and the advocacy community provided distinct country-specific intervention scenarios, which included screening for symptoms, active case finding, and preventive therapy. Findings Aggressive scale-up of any single intervention scenario could not achieve the post-2015 End TB Strategy targets in any country. However, the models projected that, in the South Africa national tuberculosis programme scenario, a combination of continuous isoniazid preventive therapy for individuals on antiretroviral therapy, expanded facility-based screening for symptoms of tuberculosis at health centres, and improved tuberculosis care could achieve a 55% reduction in incidence (range 31–62%) and a 72% reduction in mortality (range 64–82%) compared with 2015 levels. For India, and particularly for China, full scale-up of all interventions in tuberculosis-programme performance fell short of the 2025 targets, despite preventing a cumulative 3·4 million cases. The advocacy scenarios illustrated the high impact of detecting and treating latent tuberculosis. Interpretation Major reductions in tuberculosis burden seem possible with current interventions. However, additional interventions, adapted to country-specific tuberculosis epidemiology and health systems, are needed to reach the post-2015 End TB Strategy targets at country level. Funding Bill and Melinda Gates Foundation
Summary The Millennium Development Goal target for tuberculosis control is to halt the spread of tuberculosis by 2015, and begin to reverse the worldwide incidence. After the introduction of standard ...control practices in 1995, 36 million people were cured and about 6 million deaths were averted. However, substantial scientific advances and innovative solutions are urgently needed together with creative new strategies. Strong international and national political commitment is essential. Urgent action is needed by national governments to fund their own programmes, and for the G8 countries and other donor governments and organisations to support governmental and non-governmental efforts. To foster the global need for urgent action to control the tuberculosis epidemic, The Lancet , in collaboration with the Stop TB Partnership, WHO, Global Fund to Fight AIDS, Tuberculosis and Malaria, and the experts participating in this Series, is launching The Lancet TB Observatory, which will assess and monitor progress in tuberculosis control and research, assess domestic and global financing, regularly disseminate information, and advocate for intensified efforts with stakeholders at all levels.
Summary Background Control of tuberculosis in settings with high HIV prevalence is a pressing public health priority. We tested two active case-finding strategies to target long periods of ...infectiousness before diagnosis, which is typical of HIV-negative tuberculosis and is a key driver of transmission. Methods Clusters of neighbourhoods in the high-density residential suburbs of Harare, Zimbabwe, were randomised to receive six rounds of active case finding at 6-monthly intervals by either mobile van or door-to-door visits. Randomisation was done by selection of discs of two colours from an opaque bag, with one disc to represent every cluster, and one colour allocated to each intervention group before selection began. In both groups, adult (≥16 years) residents volunteering chronic cough (≥2 weeks) had two sputum specimens collected for fluorescence microscopy. Community health workers and cluster residents were not masked to intervention allocation, but investigators and laboratory staff were masked to allocation until final analysis. The primary outcome was the cumulative yield of smear-positive tuberculosis per 1000 adult residents, compared between intervention groups; analysis was by intention to treat. The secondary outcome was change in prevalence of culture-positive tuberculosis from before intervention to before round six of intervention in 12% of randomly selected households from the two intervention groups combined; analysis was based on participants who provided sputum in the two prevalence surveys. This trial is registered, number ISRCTN84352452. Findings 46 study clusters were identified and randomly allocated equally between intervention groups, with 55 741 adults in the mobile van group and 54 691 in the door-to-door group at baseline. HIV prevalence was 21% (1916/9060) and in the 6 months before intervention the smear-positive case notification rate was 2·8 per 1000 adults per year. The trial was completed as planned with no adverse events. The mobile van detected 255 smear-positive patients from 5466 participants submitting sputum compared with 137 of 4711 participants identified through door-to-door visits (adjusted risk ratio 1·48, 95% CI 1·11–1·96, p=0·0087). The overall prevalence of culture-positive tuberculosis declined from 6·5 per 1000 adults (95% CI 5·1–8·3) to 3·7 per 1000 adults (2·6–5·0; adjusted risk ratio 0·59, 95% CI 0·40–0·89, p=0·0112). Interpretation Wide implementation of active case finding, particularly with a mobile van approach, could have rapid effects on tuberculosis transmission and disease. Funding Wellcome Trust.
Summary Background The post-2015 End TB Strategy sets global targets of reducing tuberculosis incidence by 50% and mortality by 75% by 2025. We aimed to assess resource requirements and ...cost-effectiveness of strategies to achieve these targets in China, India, and South Africa. Methods We examined intervention scenarios developed in consultation with country stakeholders, which scaled up existing interventions to high but feasible coverage by 2025. Nine independent modelling groups collaborated to estimate policy outcomes, and we estimated the cost of each scenario by synthesising service use estimates, empirical cost data, and expert opinion on implementation strategies. We estimated health effects (ie, disability-adjusted life-years averted) and resource implications for 2016–35, including patient-incurred costs. To assess resource requirements and cost-effectiveness, we compared scenarios with a base case representing continued current practice. Findings Incremental tuberculosis service costs differed by scenario and country, and in some cases they more than doubled existing funding needs. In general, expansion of tuberculosis services substantially reduced patient-incurred costs and, in India and China, produced net cost savings for most interventions under a societal perspective. In all three countries, expansion of access to care produced substantial health gains. Compared with current practice and conventional cost-effectiveness thresholds, most intervention approaches seemed highly cost-effective. Interpretation Expansion of tuberculosis services seems cost-effective for high-burden countries and could generate substantial health and economic benefits for patients, although substantial new funding would be required. Further work to determine the optimal intervention mix for each country is necessary. Funding Bill & Melinda Gates Foundation.
Summary 15 years after liberation from apartheid, South Africans are facing new challenges for which the highest calibre of leadership, vision, and commitment is needed. The effect of the ...unprecedented HIV/AIDS epidemic has been immense. Substantial increases in mortality and morbidity are threatening to overwhelm the health system and undermine the potential of South Africa to attain the Millennium Development Goals (MDGs). However The Lancet 's Series on South Africa has identified several examples of leadership and innovation that point towards a different future scenario. We discuss the type of vision, leadership, and priority actions needed to achieve such a change. We still have time to change the health trajectory of the country, and even meet the MDGs. The South African Government, installed in April, 2009, has the mandate and potential to address the public health emergencies facing the country—will they do so or will another opportunity and many more lives be lost?
Summary One of the greatest challenges facing post-apartheid South Africa is the control of the concomitant HIV and tuberculosis epidemics. HIV continues to spread relentlessly, and tuberculosis has ...been declared a national emergency. In 2007, South Africa, with 0·7% of the world's population, had 17% of the global burden of HIV infection, and one of the world's worst tuberculosis epidemics, compounded by rising drug resistance and HIV co-infection. Until recently, the South African Government's response to these diseases has been marked by denial, lack of political will, and poor implementation of policies and programmes. Nonetheless, there have been notable achievements in disease management, including substantial improvements in access to condoms, expansion of tuberculosis control efforts, and scale-up of free antiretroviral therapy (ART). Care for acutely ill AIDS patients and long-term provision of ART are two issues that dominate medical practice and the health-care system. Decisive action is needed to implement evidence-based priorities for the control of the HIV and tuberculosis epidemics. By use of the framework of the Strategic Plans for South Africa for tuberculosis and HIV/AIDS, we provide prioritised four-step approaches for tuberculosis control, HIV prevention, and HIV treatment. Strong leadership, political will, social mobilisation, adequate human and financial resources, and sustainable development of health-care services are needed for successful implementation of these approaches.
Summary Background The HVTN 503/Phambili study, which assessed the efficacy of the Merck Ad5 gag/pol/nef subtype B HIV-1 preventive vaccine in South Africa, was stopped when futility criteria in the ...Step study (assessing the same vaccine in the Americas, Caribbean, and Australia) were met. Here we report long-term follow-up data. Methods HVTN 503/Phambili was a double-blind, placebo-controlled, randomised trial that recruited HIV-1 uninfected, sexually active adults aged 18–35 years from five sites in South Africa. Eligible participants were randomly assigned (1:1) by computer-generated random numbers to either vaccine or placebo, stratified by site and sex. Cox proportional hazards models were used to estimate HIV-1 infection in the modified intention-to-treat cohort, all of whom were unmasked early in follow-up. The trial is registered with ClinicalTrials.gov , number NCT00413725 and the South African National Health Research Database, number DOH-27-0207-1539. Findings Between Jan 24, 2007, and Sept 19, 2007, 801 participants (26·7%) of a planned 3000 were randomly assigned (400 to vaccine, 401 to placebo); 216 (27%) received only one injection, 529 (66%) received only two injections, and 56 (7%) received three injections. At a median follow-up of 42 months (IQR 31–42), 63 vaccine recipients (16%) had HIV-1 infection compared with 37 placebo recipients (9%; adjusted HR 1·70, 95% CI 1·13–2·55; p=0·01). Risk for HIV-1 infection did not differ according to the number of vaccinations received, sex, circumcision, or adenovirus type 5 (Ad5) serostatus. Differences in risk behaviour at baseline or during the study, or annualised dropout rate (7·7% 95% CI 6·2–9·5 for vaccine recipients vs 8·8% 7·1–10·7 for placebo recipients; p=0·40) are unlikely explanations for the increased rate of HIV-1 infections seen in vaccine recipients. Interpretation The increased risk of HIV-1 acquisition in vaccine recipients, irrespective of number of doses received, warrants further investigation to understand the biological mechanism. We caution against further use of the Ad5 vector for HIV vaccines. Funding National Institute of Allergy and Infectious Diseases, Merck, and South African Medical Research Council.
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