How health systems in sub-Saharan Africa can benefit from tuberculosis and other infectious disease programmes.

Weak and dysfunctional health systems in low-income countries, particularly in sub-Saharan Africa, are recognised as major obstacles to attaining the health-related Millennium Development Goals by 2015. Some progress is being made towards achieving the targets of Millennium Development Goal 6 for tuberculosis (TB), HIV/AIDS and malaria, with the achievements largely resulting from clearly defined strategies and intervention delivery systems combined with large amounts of external funding. This article is divided into four main sections. The first highlights the crucial elements that are needed in low-income countries in sub-Saharan Africa to deliver good quality health care through general health systems. The second discusses the main characteristics of infectious disease and TB control programmes. The third illustrates how TB control and other infectious disease programmes can help to strengthen these components, particularly in human resources; infrastructure; procurement and distribution; monitoring, evaluation and supervision; leadership and stewardship. The fourth and final section looks at progress made to date at the international level in terms of policy and guidelines, with some specific suggestions about this might be moved forward at the national level. For TB and other infectious disease programmes to drive broad improvements in health care systems and patient care, the lessons that have been learnt must be consciously applied to the broader health system, and sufficient financial input and the engagement of all players are essential

The Union and Médecins Sans Frontières approach to operational research.

Operational research (OR) has become a hot topic at national meetings, international conferences and donor fora. The International Union Against Tuberculosis and Lung Disease (The Union) and Médecins Sans Frontières (MSF) Operational Centre Brussels strongly promote and implement OR with colleagues in low- and middle-income countries. Here we describe how the two organisations define OR, and explain the guiding principles and methodology that underpin the strategy for developing and expanding OR in those countries. We articulate The Union's and MSF's approach to supporting OR, highlighting the main synergies and differences. Then, using the Malawi National Tuberculosis Control Programme as an example, we show how OR can be embedded within tuberculosis control activities, leading to changes in policy and practice at the national level. We discuss the difficult, yet vitally important, issue of capacity building, and share our vision of a new paradigm of product-related training and performance-based OR fellowships as two ways of developing the necessary skills at country level to ensure research is actually performed. Finally, we highlight the need to consider and incorporate into practice the ethical components of OR. This is a key moment to be involved in OR. We are confident that in partnership with interested stakeholders, including the World Health Organization, we can stimulate the implementation of quality, relevant OR as an integral part of health service delivery that in turn will lead to better health for people, particularly for those living in the poorer parts of the world

Routine programmatic delivery of isoniazid preventive therapy to children in Cape Town, South Africa

Setting: Fourteen primary health care facilities in Cape Town, South Africa. Objective: To determine the proportion and characteristics of infectious adult tuberculosis (TB) cases that identify children aged <5 years who qualify for isoniazid preventive therapy (IPT), and to determine the proportion of children who initiate and complete IPT. Design: A retrospective clinical record review conducted as a stratified cluster survey. Results: Of 1179 records of infectious adult cases, 33.3% had no documentation of contacts. Of the remaining 786 records, 525 contacts aged <5 years were identified, representing 0.7 child contacts per infectious adult case. Older age, male, human immunodeficiency virus (HIV) positive, smear-negative and retreatment TB cases were all associated with no documentation of contacts. Of the 525 child contacts identified, less than half were screened for TB, 141 initiated IPT and 19 completed it. Conclusion: Less than 67% of infectious TB case records had documentation of contacts. Younger, female, HIVnegative and new smear-positive TB cases were more likely to have had contacts identified. Less than 14% of children already initiated on IPT completed 6 months of treatment

Assessing the Real-Time Impact of COVID-19 on TB and HIV Services: The Experience and Response from Selected Health Facilities in Nairobi, Kenya

There was concern that the COVID-19 pandemic would adversely affect TB and HIV programme services in Kenya. We set up real-time monthly surveillance of TB and HIV activities in 18 health facilities in Nairobi so that interventions could be implemented to counteract anticipated declining trends. Aggregate data were collected and reported monthly to programme heads during the COVID-19 period (March 2020–February 2021) using EpiCollect5 and compared with monthly data collected during the pre-COVID period (March 2019–February 2020). During the COVID-19 period, there was an overall decrease in people with presumptive pulmonary TB (31.2%), diagnosed and registered with TB (28.0%) and in those tested for HIV (50.5%). Interventions to improve TB case detection and HIV testing were implemented from August 2020 and were associated with improvements in all parameters during the second six months of the COVID-19 period. During the COVID-19 period, there were small increases in TB treatment success (65.0% to 67.0%) and referral of HIV-positive persons to antiretroviral therapy (91.2% to 92.9%): this was more apparent in the second six months after interventions were implemented. Programmatic interventions were associated with improved case detection and treatment outcomes during the COVID-19 period, suggesting that monthly real-time surveillance is useful during unprecedented events

Evaluation of two short standardised regimens for the treatment of rifampicin-resistant tuberculosis (STREAM stage 2): an open-label, multicentre, randomised, non-inferiority trial.

The STREAM stage 1 trial showed that a 9-month regimen for the treatment of rifampicin-resistant tuberculosis was non-inferior to the 20-month 2011 WHO-recommended regimen. In STREAM stage 2, we aimed to compare two bedaquiline-containing regimens with the 9-month STREAM stage 1 regimen. We did a randomised, phase 3, non-inferiority trial in 13 hospital clinics in seven countries, in individuals aged 15 years or older with rifampicin-resistant tuberculosis without fluoroquinolone or aminoglycoside resistance. Participants were randomly assigned 1:2:2:2 to the 2011 WHO regimen (terminated early), a 9-month control regimen, a 9-month oral regimen with bedaquiline (primary comparison), or a 6-month regimen with bedaquiline and 8 weeks of second-line injectable. Randomisations were stratified by site, HIV status, and CD4 count. Participants and clinicians were aware of treatment-group assignments, but laboratory staff were masked. The primary outcome was favourable status (negative cultures for Mycobacterium tuberculosis without a preceding unfavourable outcome) at 76 weeks; any death, bacteriological failure or recurrence, and major treatment change were considered unfavourable outcomes. All comparisons used groups of participants randomly assigned concurrently. For non-inferiority to be shown, the upper boundary of the 95% CI should be less than 10% in both modified intention-to-treat (mITT) and per-protocol analyses, with prespecified tests for superiority done if non-inferiority was shown. This trial is registered with ISRCTN, ISRCTN18148631. Between March 28, 2016, and Jan 28, 2020, 1436 participants were screened and 588 were randomly assigned. Of 517 participants in the mITT population, 133 (71%) of 187 on the control regimen and 162 (83%) of 196 on the oral regimen had a favourable outcome: a difference of 11·0% (95% CI 2·9-19·0), adjusted for HIV status and randomisation protocol (p<0·0001 for non-inferiority). By 76 weeks, 108 (53%) of 202 participants on the control regimen and 106 (50%) of 211 allocated to the oral regimen had an adverse event of grade 3 or 4; five (2%) participants on the control regimen and seven (3%) on the oral regimen had died. Hearing loss (Brock grade 3 or 4) was more frequent in participants on the control regimen than in those on the oral regimen (18 [9%] vs four [2%], p=0·0015). Of 134 participants in the mITT population who were allocated to the 6-month regimen, 122 (91%) had a favourable outcome compared with 87 (69%) of 127 participants randomly assigned concurrently to the control regimen (adjusted difference 22·2%, 95% CI 13·1-31·2); six (4%) of 143 participants on the 6-month regimen had grade 3 or 4 hearing loss. Both bedaquiline-containing regimens, a 9-month oral regimen and a 6-month regimen with 8 weeks of second-line injectable, had superior efficacy compared with a 9-month injectable-containing regimen, with fewer cases of hearing loss. USAID and Janssen Research & Development

Economic evaluation of shortened, bedaquiline-containing treatment regimens for rifampicin-resistant tuberculosis (STREAM stage 2) : a within-trial analysis of a randomised controlled trial

Background: The STREAM stage 2 trial assessed two bedaquiline-containing regimens for rifampicin-resistant tuberculosis: a 9-month all-oral regimen and a 6-month regimen containing an injectable drug for the first 2 months. We did a within-trial economic evaluation of these regimens. Methods: STREAM stage 2 was an international, phase 3, non-inferiority randomised trial in which participants with rifampicin-resistant tuberculosis were randomly assigned (1:2:2:2) to the 2011 WHO regimen (terminated early), a 9-month injectable-containing regimen (control regimen), a 9-month all-oral regimen with bedaquiline (oral regimen), or a 6-month regimen with bedaquiline and an injectable for the first 2 months (6-month regimen). We prospectively collected direct and indirect costs and health-related quality of life data from trial participants until week 76 of follow-up. Cost-effectiveness of the oral and 6-month regimens versus control was estimated in four countries (oral regimen) and two countries (6-month regimen), using health-related quality of life for cost-utility analysis and trial efficacy for cost-effectiveness analysis. This trial is registered with ISRCTN, ISRCTN18148631. Findings: 300 participants were included in the economic analyses (Ethiopia, 61; India, 142; Moldova, 51; Uganda, 46). In the cost-utility analysis, the oral regimen was not cost-effective in Ethiopia, India, Moldova, and Uganda from either a provider or societal perspective. In Moldova, the oral regimen was dominant from a societal perspective. In the cost-effectiveness analysis, the oral regimen was likely to be cost-effective from a provider perspective at willingness-to-pay thresholds per additional favourable outcome of more than US$4500 in Ethiopia,$1900 in India, $3950 in Moldova, and$7900 in Uganda, and from a societal perspective at thresholds of more than $15 900 in Ethiopia,$3150 in India, and $4350 in Uganda, while in Moldova the oral regimen was dominant. In Ethiopia and India, the 6-month regimen would cost tuberculosis programmes and participants less than the control regimen and was highly likely to be cost-effective in both cost-utility analysis and cost-effectiveness analysis. Reducing the bedaquiline price from$1·81 to $1·00 per tablet made the oral regimen cost-effective in the provider-perspective cost-utility analysis in India and Moldova and dominate over the control regimen in the provider-perspective cost-effectiveness analysis in India. Interpretation: At current costs, the oral bedaquiline-containing regimen for rifampicin-resistant tuberculosis is unlikely to be cost-effective in many low-income and middle-income countries. The 6-month regimen represents a cost-effective alternative if injectable use for 2 months is acceptable. Funding: USAID and Janssen Research & Development