Novel point-of-care cytokine biomarker lateral flow test for the screening for sexually transmitted infections and bacterial vaginosis: study protocol of a multicentre multidisciplinary prospective observational clinical study to evaluate the performance and feasibility of the Genital InFlammation Test (GIFT).

INTRODUCTION: A prototype lateral flow device detecting cytokine biomarkers interleukin (IL)-1α and IL-1ß has been developed as a point-of-care test-called the Genital InFlammation Test (GIFT)-for detecting genital inflammation associated with sexually transmitted infections (STIs) and/or bacterial vaginosis (BV) in women. In this paper, we describe the rationale and design for studies that will be conducted in South Africa, Zimbabwe and Madagascar to evaluate the performance of GIFT and how it could be integrated into routine care. METHODS AND ANALYSIS: We will conduct a prospective, multidisciplinary, multicentre, cross-sectional and observational clinical study comprising two distinct components: a biomedical ('diagnostic study') and a qualitative, modelling and economic ('an integration into care study') part. The diagnostic study aims to evaluate GIFT's performance in identifying asymptomatic women with discharge-causing STIs (Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG), Trichomonas vaginalis (TV) and Mycoplasma genitalium (MG)) and BV. Study participants will be recruited from women attending research sites and family planning services. Several vaginal swabs will be collected for the evaluation of cytokine concentrations (ELISA), STIs (nucleic acid amplification tests), BV (Nugent score) and vaginal microbiome characteristics (16S rRNA gene sequencing). The first collected vaginal swab will be used for the GIFT assay which will be performed in parallel by a healthcare worker in the clinic near the participant, and by a technician in the laboratory. The integration into care study aims to explore how GIFT could be integrated into routine care. Four activities will be conducted: user experiences and/or perceptions of the GIFT device involving qualitative focus group discussions and in-depth interviews with key stakeholders; discrete choice experiments; development of a decision tree classification algorithm; and economic evaluation of defined management algorithms. ETHICS AND DISSEMINATION: Findings will be reported to participants, collaborators and local government for the three sites, presented at national and international conferences, and disseminated in peer-reviewed publications.The protocol and all study documents such as informed consent forms were reviewed and approved by the University of Cape Town Human Research Ethics Committee (HREC reference 366/2022), Medical Research Council of Zimbabwe (MRCZ/A/2966), Comité d'Ethique pour la Recherche Biomédicale de Madagascar (N° 143 MNSAP/SG/AMM/CERBM) and the London School of Hygiene and Tropical Medicine ethics committee (LSHTM reference 28046).Before the start, this study was submitted to the Clinicaltrials.gov public registry (NCT05723484). TRIAL REGISTRATION NUMBER: NCT05723484.

Cost-effectiveness analysis of different screening and diagnostic strategies for sexually transmitted infections and bacterial vaginosis in women attending primary health care facilities in Cape Town.

Background: Genital inflammation associated with sexually transmitted infections (STIs) and bacterial vaginosis (BV) is considered a key driver in the HIV epidemic. A new rapid point-of-care test (POC) that detects genital inflammation in women-Genital InFlammation Test (GIFT)-was recently developed by researchers at the University of Cape Town. The objective of this study was to establish the cost-effectiveness of this novel intervention relative to other relevant screening and diagnostic strategies for the management of STIs and BV in women seeking care in the public health sector in South Africa. Methods: A decision analysis model was developed for five different screening and diagnostic strategies for women incorporating syndromic management, screening with GIFT and using etiological diagnosis. A decision tree was constructed using Microsoft Excel Office 365, and cost and effectiveness parameters were obtained from published literature and market prices. The model incorporated all clinic-level and treatment costs associated with diagnosing and treating a single episode of disease. The effectiveness of each approach was proxied by its sensitivity. One-way and threshold sensitivity analyses were conducted to test key uncertainties and assumptions in the model. Results: Screening with GIFT, and following with antibiotic treatment according to syndromic management guidelines for GIFT-positive cases, was the most cost-effective strategy with an incremental cost-effectiveness ratio (ICER) of USD 11.08 per women diagnosed with an STI(s) and/or BV and provided treatment. This strategy resulted in lower rates of overtreatment compared to syndromic management, but higher rates compared to etiological diagnosis using nucleic acid amplification tests and microscopy. However, following a GIFT positive test with etiological diagnosis prior to treatment did not increase the effectiveness, but dramatically increased the cost. Conclusion: Screening with GIFT and treating positive cases according to syndromic management guidelines is the most cost-effective strategy for the management of STIs and BV. GIFT has a potential to significantly improve the management of STIs and BV in women by identifying asymptomatic women and reducing their risk of HIV infection. This analysis presents a first step in establishing the cost-effectiveness of these interventions and paves the way for further research to develop optimal context-specific implementation strategies.

A comparative cost analysis of two screening strategies for colorectal cancer in Lynch Syndrome in a South African tertiary hospital.

AIM: Lynch Syndrome (LS) individuals have a 25-75% lifetime risk of developing colorectal cancer. Colonoscopy screening decreases this risk. This study compared the cost of Strategy 1: screening colonoscopy for 1st degree relatives of patients that met the Revised Bethesda Criteria (i.e., probands) to Strategy 2: screening colonoscopy for 1st degree relatives of probands with genetic mutations for Lynch Syndrome based in a resource-constrained health care system. METHOD: A comparative, health care provider perspective, cost analysis was conducted at a tertiary hospital, using a micro-costing, ingredient approach. Forty probands that underwent genetic testing between November 01, 2014 and October 30, 2015 and their first-degree relatives were costed according to Strategy 1 and Strategy 2. Unit costs of colonoscopy and genetic testing were estimated and used to calculate and compare the total costs per strategy in South African rand (R) converted to UK pounds (£). Sensitivity analyses were performed on colonoscopy adherence, relatives' positivity, and variable discount rates. RESULTS: The cost for Strategy 1 amounted to £653 344/R6 161 035 compared to £49 327/R 465 155 for Strategy 2 (Discount rate 3%; Adherence 75%; and Positivity rate of relatives 45%). Base case analysis indicated a difference of 92% less in the total cost for Strategy 2 compared to Strategy 1. Sensitivity analyses showed that the difference in cost between the two strategies was not sensitive to variations in adherence, positivity or discount rates. CONCLUSION: Colonoscopy screening for LS and at-risk family members was tenfold less costly when combined with genetic analysis. The logistics of rolling out this strategy nationally should be investigated.

National tuberculosis spending efficiency and its associated factors in 121 low-income and middle-income countries, 2010-19: a data envelopment and stochastic frontier analysis.

BACKGROUND: Maximising the efficiency of national tuberculosis programmes is key to improving service coverage, outcomes, and progress towards End TB targets. We aimed to determine the overall efficiency of tuberculosis spending and investigate associated factors in 121 low-income and middle-income countries between 2010 and 2019. METHODS: In this data envelopment and stochastic frontier analysis, we used data from the WHO Global TB report series on tuberculosis spending as the input and treatment coverage as the output to estimate tuberculosis spending efficiency. We investigated associations between 25 independent variables and overall efficiency. FINDINGS: We estimated global tuberculosis spending efficiency to be between 73·8% (95% CI 71·2-76·3) and 87·7% (84·9-90·6) in 2019, depending on the analytical method used. This estimate suggests that existing global tuberculosis treatment coverage could be increased by between 12·3% (95% CI 9·4-15·1) and 26·2% (23·7-28·8) for the same amount of spending. Efficiency has improved over the study period, mainly since 2015, but a substantial difference of 70·7-72·1 percentage points between the most and least efficient countries still exists. We found a consistent significant association between efficiency and current health expenditure as a share of gross domestic product, out-of-pocket spending on health, and some Sustainable Development Goal (SDG) indicators such as universal health coverage. INTERPRETATION: To improve efficiency, treatment coverage will need to be increased, particularly in the least efficient contexts where this might require additional spending. However, progress towards global End TB targets is slow even in the most efficient countries. Variables associated with TB spending efficiency suggest efficiency is complimented by commitments to improving health-care access that is free at the point of use and wider progress towards the SDGs. These findings support calls for additional investment in tuberculosis care. FUNDING: None.

Rapid Point-of-Care Testing for Genital Tract Inflammatory Cytokine Biomarkers to Diagnose Asymptomatic Sexually Transmitted Infections and Bacterial Vaginosis in Women: Cost Estimation and Budget Impact Analysis.

BACKGROUND: Screening for genital inflammation can reveal asymptomatic cases of sexually transmitted infections (STIs) and bacterial vaginosis (BV), useful in settings where only syndromic management is available. This study aimed to estimate the incremental cost of screening using a new cytokine biomarker rapid test and determine the budget impact of providing this service in primary health facilities in South Africa. METHODS: Costs of adding genital inflammation screening to existing family planning services were estimated for women (15-49 years) attending 3 different family planning clinics in US $2016. The predicted unit cost per patient screened from a provider's perspective was calculated using bottom-up and top-down approaches and was used to analyze the budget impact of scaling up and providing this service in primary health facilities countrywide. Univariate sensitivity analyses tested the robustness of the findings. RESULTS: The incremental cost per woman screened for genital inflammation ranged between US $3.19 and US $4.79. The scaled-up costs ranged between US $7,245,775 and US $22,212,636 countrywide, annually. This was based on the number of women of reproductive age currently seeking contraceptive care at all primary health care facilities, as a proxy for those most susceptible to asymptomatic STIs/BV. The cost estimates were sensitive to changes in personnel costs, utilization rate, and population coverage rates. CONCLUSIONS: This screening tool is likely to increase case detection, contributing to better STI/BV management and control, in addition to reducing women's risk of HIV acquisition. The incremental cost estimates could make implementation affordable.

Strengthening health systems to improve the value of tuberculosis diagnostics in South Africa: A cost and cost-effectiveness analysis.

BACKGROUND: In South Africa, replacing smear microscopy with Xpert-MTB/RIF (Xpert) for tuberculosis diagnosis did not reduce mortality and was cost-neutral. The unchanged mortality has been attributed to suboptimal Xpert implementation. We developed a mathematical model to explore how complementary investments may improve cost-effectiveness of the tuberculosis diagnostic algorithm. METHODS: Complementary investments in the tuberculosis diagnostic pathway were compared to the status quo. Investment scenarios following an initial Xpert test included actions to reduce pre-treatment loss-to-follow-up; supporting same-day clinical diagnosis of tuberculosis after a negative result; and improving access to further tuberculosis diagnostic tests following a negative result. We estimated costs, deaths and disability-adjusted-life-years (DALYs) averted from provider and societal perspectives. Sensitivity analyses explored the mediating influence of behavioural, disease- and organisational characteristics on investment effectiveness. FINDINGS: Among a cohort of symptomatic patients tested for tuberculosis, with an estimated active tuberculosis prevalence of 13%, reducing pre-treatment loss-to-follow-up from ~20% to ~0% led to a 4% (uncertainty interval [UI] 3; 4%) reduction in mortality compared to the Xpert scenario. Improving access to further tuberculosis diagnostic tests from ~4% to 90% among those with an initial negative Xpert result reduced overall mortality by 28% (UI 27; 28) at $39.70/ DALY averted. Effectiveness of investment scenarios to improve access to further diagnostic tests was dependent on a high return rate for follow-up visits. INTERPRETATION: Investing in direct and indirect costs to support the TB diagnostic pathway is potentially highly cost-effective.

Provider- and patient-level costs associated with providing antiretroviral therapy during the postpartum phase to women living with HIV in South Africa: A cost comparison of three postpartum models of care.

OBJECTIVE: To compare the unit and total costs of three models of ART care for mother-infant pairs during the postpartum phase from provider and patient's perspectives: (i) local standard of care with women in general ART services and infants at well-baby clinics; (ii) women and infants continue to receive care through an integrated maternal and child care approach during the postpartum breastfeeding period; and (iii) referral of women directly to community adherence clubs with their infants receiving care at well-baby clinics. METHODS: Capital and recurrent cost data (relating to buildings, furniture, equipment, personnel, overheads, maintenance, medication, diagnostic tests and immunisations) were collected from a provider's perspective at six sites in Cape Town, South Africa. Patient time, collected via time-and-motion observation and questionnaires, was used to estimate patient perspective costs and is comprised of lost productivity time, time spent travelling and the direct cost of travelling. RESULTS: The cost of postpartum ART visits under models I, II and III was US $13, US $10 and US $7 per visit for a mother-infant pair, respectively, in 2018 US$. The annual costs for the mother-infant pair utilising the average visit frequencies (a mean of 4.5, 6.9 and 6.7 visits postpartum for models I, II and III, respectively) including costs for infant immunisations, visits, medication and diagnostic tests for both mothers and infants were: I - US $222, II - US $335 and III - US $249. Sensitivity analysis to assess the impact of visit frequency on visit cost showed that Model I annual costs would be most costly if visit frequency was equalised. CONCLUSION: This comparative analysis of three models of care provides novel data on unit costs and insight into the costs to provide ART and care to mother-infant pairs during the delicate postpartum phase. These costs may be used to help make decisions around integrated services models and differentiated service delivery for postpartum WLH and their children.

OBJECTIF: Comparer le coût et unitaire et total de trois modèles de soins ART pour les paires mère-enfant pendant la phase post-partum selon les perspectives du fournisseur et du patient: (I) - normes locales des soins avec les femmes dans les services généraux de l'ART et les nourrissons dans les cliniques de bien-être pour bébés; (II) - les femmes et les nourrissons continuent de recevoir des soins via une approche intégrée de soins maternels et infantiles pendant la période d'allaitement post-partum; et (III) - orientation des femmes directement vers les clubs d'adhésion communautaires, leurs nourrissons recevant des soins dans les cliniques de bien-être pour bébés pour bébés. MÉTHODES: Les données sur les coûts d'investissement et les coûts récurrents (relatifs aux bâtiments, au mobilier, à l'équipement, au personnel, aux frais généraux, à l'entretien, aux médicaments, aux tests de diagnostic et aux vaccinations) ont été recueillies selon le point de vue du prestataire sur six sites à Cape Town, en Afrique du Sud. Le temps du patient, recueilli via l'observation du temps et des mouvements et des questionnaires, a été utilisé pour estimer les coûts selon le point de vue du patient, et comprend le temps de productivité perdu, le temps passé en déplacement et le coût direct du déplacement. RÉSULTATS: Le coût des visites ART post-partum dans les modèles I, II et III était respectivement de 13 USD, 10 USD et 7 USD par visite pour une paire mère-enfant en USD de 2018. Les coûts annuels pour la paire mère-enfant en utilisant la fréquence moyenne des visites (une moyenne de 4,5 ; 6,9 et 6,7 visites post-partum pour les modèles I, II et III respectivement), y compris les coûts des vaccinations infantiles, des visites, des médicaments et des tests diagnostiques pour les mères et les nourrissons étaient: I - 222 USD, II - 335 USD et III - 249 USD. L'analyse de sensibilité pour évaluer l'impact de la fréquence des visites sur le coût des visites a montré que les coûts annuels du modèle I seraient les plus élevés si la fréquence des visites était égalisée. CONCLUSIONS: Cette analyse comparative de trois modèles de soins fournit de nouvelles données sur les coûts unitaires et un aperçu des coûts de fourniture de l'ART et de soins aux paires mère-enfant pendant la phase délicate du post-partum. Ces coûts peuvent être utilisés pour aider à la prise des décisions concernant les modèles de services intégrés et la prestation de services différenciés pour les femmes en période de post-partum et leurs enfants.

A Systematic Review of Methodological Variation in Healthcare Provider Perspective Tuberculosis Costing Papers Conducted in Low- and Middle-Income Settings, Using An Intervention-Standardised Unit Cost Typology.

BACKGROUND: There is a need for easily accessible tuberculosis unit cost data, as well as an understanding of the variability of methods used and reporting standards of that data. OBJECTIVE: The aim of this systematic review was to descriptively review papers reporting tuberculosis unit costs from a healthcare provider perspective looking at methodological variation; to assess quality using a study quality rating system and machine learning to investigate the indicators of reporting quality; and to identify the data gaps to inform standardised tuberculosis unit cost collection and consistent principles for reporting going forward. METHODS: We searched grey and published literature in five sources and eight databases, respectively, using search terms linked to cost, tuberculosis and tuberculosis health services including tuberculosis treatment and prevention. For inclusion, the papers needed to contain empirical unit cost estimates for tuberculosis interventions from low- and middle-income countries, with reference years between 1990 and 2018. A total of 21,691 papers were found and screened in a phased manner. Data were extracted from the eligible papers into a detailed Microsoft Excel tool, extensively cleaned and analysed with R software (R Project, Vienna, Austria) using the user interface of RStudio. A study quality rating was applied to the reviewed papers based on the inclusion or omission of a selection of variables and their relative importance. Following this, machine learning using a recursive partitioning method was utilised to construct a classification tree to assess the reporting quality. RESULTS: This systematic review included 103 provider perspective papers with 627 unit costs (costs not presented here) for tuberculosis interventions among a total of 140 variables. The interventions covered were active, passive and intensified case finding; tuberculosis treatment; above-service costs; and tuberculosis prevention. Passive case finding is the detection of tuberculosis cases where individuals self-identify at health facilities; active case finding is detection of cases of those not in health facilities, such as through outreach; and intensified case finding is detection of cases in high-risk populations. There was heterogeneity in some of the reported methods used such cost allocation, amortisation and the use of top-down, bottom-up or mixed approaches to the costing. Uncertainty checking through sensitivity analysis was only reported on by half of the papers (54%), while purposive and convenience sampling was reported by 72% of papers. Machine learning indicated that reporting on 'Intervention' (in particular), 'Urbanicity' and 'Site Sampling', were the most likely indicators of quality of reporting. The largest data gap identified was for tuberculosis vaccination cost data, the Bacillus Calmette-Guérin (BCG) vaccine in particular. There is a gap in available unit costs for 12 of 30 high tuberculosis burden countries, as well as for the interventions of above-service costs, tuberculosis prevention, and active and intensified case finding. CONCLUSION: Variability in the methods and reporting used makes comparison difficult and makes it hard for decision makers to know which unit costs they can trust. The study quality rating system used in this review as well as the classification tree enable focus on specific reporting aspects that should improve variability and increase confidence in unit costs. Researchers should endeavour to be explicit and transparent in how they cost interventions following the principles as laid out in the Global Health Cost Consortium's Reference Case for Estimating the Costs of Global Health Services and Interventions, which in turn will lead to repeatability, comparability and enhanced learning from others.

Correction to: A Systematic Review of Methodological Variation in Healthcare Provider Perspective Tuberculosis Costing Papers Conducted in Low- and Middle-Income Settings, Using An Intervention-Standardised Unit Cost Typology.

In the original version of this article, Fig. 3 was published in an incorrect format. The correct figure is published with this correction.

Developing the Global Health Cost Consortium Unit Cost Study Repository for HIV and TB: methodology and lessons learned.

Consistently defined, accurate, and easily accessible cost data are a valuable resource to inform efficiency analyses, budget preparation, and sustainability planning in global health. The Global Health Cost Consortium (GHCC) designed the Unit Cost Study Repository (UCSR) to be a resource for standardised HIV and TB intervention cost data displayed by key characteristics such as intervention type, country, and target population. To develop the UCSR, the GHCC defined a typology of interventions for each disease; aligned interventions according to the standardised principles, methods, and cost and activity categories from the GHCC Reference Case for Estimating the Costs of Global Health Services and Interventions; completed a systematic literature review; conducted extensive data extraction; performed quality assurance; grappled with complex methodological issues such as the proper approach to the inflation and conversion of costs; developed and implemented a study quality rating system; and designed a web-based user interface that flexibly displays large amounts of data in a user-friendly way. Key lessons learned from the extraction process include the importance of assessing the multiple uses of extracted data; the critical role of standardising definitions (particularly units of measurement); using appropriate classifications of interventions and components of costs; the efficiency derived from programming data checks; and the necessity of extraction quality monitoring by senior analysts. For the web interface, lessons were: understanding the target audiences, including consulting them regarding critical characteristics; designing the display of data in "levels"; and incorporating alert and unique trait descriptions to further clarify differences in the data.

Cost of managing severe cutaneous adverse drug reactions to first-line tuberculosis therapy in South Africa.

OBJECTIVE: To compare the cost of managing treatment-limiting cutaneous adverse drug reactions (CADRs) to first-line anti-tuberculosis drugs to an alternative strategy of immediate treatment initiation using second-line drugs in a South African setting. METHODS: Clinical and cost data were retrospectively collected from patients presenting with a first-line anti-tuberculosis therapy-associated CADR. Costs (2016 US$) were estimated using an ingredient's approach from a healthcare provider perspective. The per-patient and total cost of drug rechallenge, the current management strategy for severe CADR, was calculated. Alternative strategies involving second-line treatment were derived from literature and expert clinical advice. RESULTS: Drug rechallenge costs US $5831 (95% CI: 5134-6527) per patient. Hospitalisation accounted for 62% of this cost. Alternative CADR management strategies using regimens containing rifabutin, bedaquiline and/or delamanid cost 44%-55% less than drug rechallenge (US $2651-US $3276/patient). In univariate sensitivity analyses, drug rechallenge and alternative strategies were most sensitive to hospitalisation and tuberculosis drug costs, respectively. CONCLUSION: Cutaneous adverse drug reactions to anti-tuberculosis treatment represent a significant economic burden. An alternate strategy of outpatient-initiated second-line therapy is economically feasible but requires clinical validation to assess effectiveness.

OBJECTIF: Comparer le coût de la prise ne charge des effets indésirables cutanés (EIC) limitant le traitement aux antituberculeux de première ligne à celui d'une stratégie alternative d'initiation immédiate du traitement par des médicaments de deuxième ligne dans un contexte sud-africain. MÉTHODES: Les données cliniques et les coûts ont été collectés rétrospectivement chez des patients présentant un EIC associé au traitement antituberculeux de première ligne. Les coûts (USD, 2016) ont été estimés en utilisant une approche d'ingrédient du point de vue d'un prestataire de soins de santé. Le coût par patient et le coût total du nouveau traitement, de la stratégie actuelle de prise en charge des cas d'EIC sévère, ont été calculés. Des stratégies alternatives impliquant un traitement de deuxième ligne ont été dérivées de la littérature et de conseils cliniques d'experts. RÉSULTATS: Le coût du nouveau traitement était de 5.831 USD (IC95%: 5.134 - 6.527) par patient. L'hospitalisation représentait 62% de ce coût. Les stratégies alternatives de prise en charge des EIC utilisant des schémas thérapeutiques contenant de la rifabutine, de la bédaquiline et/ou du delamanide coûtent de 44 % à 55 % moins cher que le nouveau traitement (2.651 USD - 3.276 USD/patient). Dans les analyses de sensibilité univariées, les stratégies de re-traitement et les stratégies alternatives étaient plus sensibles aux coûts d'hospitalisation et de médicaments antituberculeux, respectivement. CONCLUSION: Les EIC des antituberculeux représentent une charge économique importante. Une stratégie alternative de traitement de deuxième ligne mise en place chez des patients ambulatoires est économiquement réalisable mais nécessite une validation clinique pour évaluer l'efficacité.

A cost comparison analysis of paediatric intermediate care in a tertiary hospital and an intermediate care facility in Cape Town, South Africa.

BACKGROUND: In South Africa, 600-700 new cases of paediatric cancers have been reported every year for the past 25 years, and in the year 2000, HIV/AIDS was responsible for 42,479 deaths in children under five. These children need intermediate care but research in the field is lacking, with the few costing studies conducted in South Africa reporting a range of inpatient day costs. METHODS: A retrospective cost analysis for the period April 2014-March 2015 was undertaken from the provider perspective in the public sector, using a step down costing approach. Costs of paediatric intermediate care were estimated for an intermediate care facility (ICF) and a tertiary hospital in Cape Town. Costs were inflated to 2016 prices and reported in US dollars. RESULTS: Cost per inpatient day was $713.09 at the hospital and $695.17 at the ICF for any child requiring care at these institutions. The cost for a paediatric patient who is HIV/TB co-infected was $7 130.94 and $6 951.67 at the hospital and ICF respectively, assuming an average length of stay of 10 days. For a patient with terminal brain carcinoma the cost was $19 966.63 and $19 464.69 at the hospital and ICF respectively, assuming an average length of stay of 28 days. Personnel costs accounted for 60% and 17% of the total cost at the hospital and ICF respectively. Overhead costs accounted for 12.33% at the ICF and 4.48% at the hospital. CONCLUSIONS: The drivers of cost are not uniform across settings. Providing intermediate care at an ICF could be less costly than providing this care at a hospital, however more in-depth analysis is needed. The costs presented in this study were considerably higher than those found in other studies, however, the paucity of cost data available in this area makes comparisons difficult.

The costs and cost effectiveness of providing second-trimester medical and surgical safe abortion services in Western Cape Province, South Africa.

BACKGROUND: In South Africa, access to second-trimester abortion services, which are generally performed using medical induction with misoprostol alone, is challenging for many women. We aimed to estimate the costs and cost effectiveness of providing three safe second-trimester abortion services (dilation and evacuation (D&E)), medical induction with mifepristone and misoprostol (MI-combined), or medical induction with misoprostol alone (MI-misoprostol)) in Western Cape Province, South Africa to aid policymakers with planning for service provision in South Africa and similar settings. METHODS: We derived clinical outcomes data for this economic evaluation from two previously conducted clinical studies. In 2013-2014, we collected cost data from three public hospitals where the studies took place. We collected cost data from the health service perspective through micro-costing activities, including discussions with site staff. We used decision tree analysis to estimate average costs per patient interaction (e.g. first visit, procedure visit, etc.), the total average cost per procedure, and cost-effectiveness in terms of the cost per complete abortion. We discounted equipment costs at 3%, and present the results in 2015 US dollars. RESULTS: D&E services were the least costly and the most cost-effective at $91.17 per complete abortion. MI-combined was also less costly and more cost-effective (at $298.03 per complete abortion) than MI-misoprostol (at $375.31 per complete abortion), in part due to a shortened inpatient stay. However, an overlap in the plausible cost ranges for the two medical procedures suggests that the two may have equivalent costs in some circumstances. CONCLUSION: D&E was most cost-effective in this analysis. However, due to resistance from health care providers and other barriers, these services are not widely available and scale-up is challenging. Given South Africa's reliance on medical induction, switching to the combined regimen could result in greater access to second-trimester services due to shorter inpatient stays without increasing costs.

Doing more for less: identifying opportunities to expand public sector access to safe abortion in South Africa through budget impact analysis.

OBJECTIVE(S): To estimate the costs of public-sector abortion provision in South Africa and to explore the potential for expanding access at reduced cost by changing the mix of technologies used. STUDY DESIGN: We conducted a budget impact analysis using public sector abortion statistics and published cost data. We estimated the total costs to the public health service over 10 years, starting in South Africa's financial year 2016/17, given four scenarios: (1) holding service provision constant, (2) expanding public sector provision, (3) changing the abortion technologies used (i.e. the method mix), and (4) expansion plus changing the method mix. RESULTS: The public sector performed an estimated 20% of the expected total number of abortions in 2016/17; 26% and 54% of all abortions were performed illegally or in the private sector respectively. Costs were lowest in scenarios where method mix shifting occurred. Holding the proportion of abortions performed in the public-sector constant, shifting to more cost-effective service provision (more first-trimester services with more medication abortion and using the combined regimen for medical induction in the second trimester) could result in savings of $28.1 million in the public health service over the 10-year period. Expanding public sector provision through elimination of unsafe abortions would require an additional $192.5 million. CONCLUSIONS: South Africa can provide more safe abortions for less money in the public sector through shifting the methods provided. More research is needed to understand whether the cost of expanding access could be offset by savings from averting costs of managing unsafe abortions. IMPLICATIONS: South Africa can provide more safe abortions for less money in the public sector through shifting to more first-trimester methods, including more medication abortion, and shifting to a combined mifepristone plus misoprostol regimen for second trimester medical induction. Expanding access in addition to method mix changes would require additional funds.

Incremental Cost Effectiveness of Bedaquiline for the Treatment of Rifampicin-Resistant Tuberculosis in South Africa: Model-Based Analysis.

BACKGROUND: Nearly 20,000 people were diagnosed with multi-drug and rifampicin-resistant tuberculosis (MDR/RR-TB) in South Africa in 2015, yet only one-half of the patients who start treatment are expected to have a successful outcome. There is increasing evidence of the effectiveness and safety of new drug regimens containing bedaquiline for MDR/RR-TB; however, whether they are affordable for high-burden, limited-resource settings is uncertain. OBJECTIVE: Our objective was to determine the incremental cost effectiveness of a bedaquiline-based regimen for MDR/RR-TB treatment in South Africa compared with the standard kanamycin-based regimen. METHODS: We established a Markov model for ambulatory treatment of MDR/RR-TB in a high-HIV prevalence setting, parameterized using clinical outcomes from the South African National TB Programme (SA NTP) before (2012-2014) and after (2015-2016) bedaquiline roll-out. The effectiveness of treatment was evaluated in disability-adjusted life-years (DALYs). Ingredient costs from the provider's perspective were collected in 2016 South African Rand and converted to $US, including bedaquiline at $US675.23 per 6-month treatment course. Culture conversion rates were derived from the phase IIb trial of bedaquiline, and disability adjustments were adapted from published literature. Costs and effectiveness were discounted at 3%. RESULTS: For non-bedaquiline regimens, the total expected cost over the 10-year time horizon for a patient with MDR/RR-TB was $US4439 with disability-adjusted survival of 5.1 years. Replacing capreomycin with bedaquiline in patients who failed MDR/RR-TB treatment and required treatment for extensively drug-resistant (XDR-TB) resulted in cost savings ($US4356; 1.8% less) and similar effectiveness (0.02 DALYs averted). As a result, the standard regimen (no bedaquiline) was dominated. Replacing kanamycin with bedaquiline to provide all patients with MDR/RR-TB access to bedaquiline cost $US4647 (4.3% more) and averted 0.17 DALYs compared with the no bedaquiline regimen. The incremental cost-effectiveness ratio was $US1242/DALY averted. CONCLUSION: Markov modelling indicates providing bedaquiline for all patients with MDR/RR-TB could increase the 24-month treatment success rate in South Africa from 56.3% using the current regimen to 60.6%, at a cost $US2.6 million over a 10-year horizon, less than 1% of the estimated $US425 million SA NTP annual budget.

The utility of repeat Xpert MTB/RIF testing to diagnose tuberculosis in HIV-positive adults with initial negative result.

Background: Amongst HIV-positive adults in South Africa with initial negative Xpert results, we compared the yield from repeating Xpert MTB/RIF ("Xpert") on sputum to guideline-recommended investigation for tuberculosis (TB). Methods:  A systematic sample of adults attending for HIV care were enrolled in a cohort exploring TB investigation pathways. This substudy was restricted to those at highest risk of TB (CD4<200 cells/mm 3 or unknown) who had a negative initial Xpert result. At attendance for the Xpert result, a repeat sputum sample was stored, and further investigations facilitated per national guidelines. Participants were reviewed monthly, with reinvestigation if indicated, for at least three months, when sputum and blood were cultured for mycobacteria, and the stored sputum tested using Xpert. We defined TB as "confirmed" if Xpert, line probe assay or Mycobacterium tuberculosis culture within six months of enrolment were positive, and "clinical" if TB treatment was started without microbiological confirmation. Results: Amongst 227 participants with an initial negative Xpert result (63% female, median age 37 years, median CD4 count 100 cells/mm 3), 28 (12%) participants had TB diagnosed during study follow-up (16 confirmed, 12 clinical); stored sputum tested positive on Xpert in 5/227 (2%). Amongst 27 participants who started TB treatment, the basis was bacteriological confirmation 11/27 (41%); compatible imaging 11/27 (41%); compatible symptoms 2/27 (7%); and unknown 3/27 (11%).  Conclusions:  Amongst HIV-positive individuals at high risk of active TB with a negative Xpert result, further investigation using appropriate diagnostic modalities is more likely to lead to TB treatment than immediately repeating sputum for Xpert. TB diagnostic tests with improved sensitivity are needed.

The cost and utilisation patterns of a pilot sign language interpreter service for primary health care services in South Africa.

BACKGROUND: The World Health Organisation estimates disabling hearing loss to be around 5.3%, while a study of hearing impairment and auditory pathology in Limpopo, South Africa found a prevalence of nearly 9%. Although Sign Language Interpreters (SLIs) improve the communication challenges in health care, they are unaffordable for many signing Deaf people and people with disabling hearing loss. On the other hand, there are no legal provisions in place to ensure the provision of SLIs in the health sector in most countries including South Africa. To advocate for funding of such initiatives, reliable cost estimates are essential and such data is scarce. To bridge this gap, this study estimated the costs of providing such a service within a South African District health service based on estimates obtained from a pilot-project that initiated the first South African Sign Language Interpreter (SASLI) service in health-care. METHODS: The ingredients method was used to calculate the unit cost per SASLI-assisted visit from a provider perspective. The unit costs per SASLI-assisted visit were then used in estimating the costs of scaling up this service to the District Health Services. The average annual SASLI utilisation rate per person was calculated on Stata v.12 using the projects' registry from 2008-2013. Sensitivity analyses were carried out to determine the effect of changing the discount rate and personnel costs. RESULTS: Average Sign Language Interpreter services' utilisation rates increased from 1.66 to 3.58 per person per year, with a median of 2 visits, from 2008-2013. The cost per visit was US$189.38 in 2013 whilst the estimated costs of scaling up this service ranged from US$14.2million to US$76.5million in the Cape Metropole District. These cost estimates represented 2.3%-12.2% of the budget for the Western Cape District Health Services for 2013. CONCLUSIONS: In the presence of Sign Language Interpreters, Deaf Sign language users utilise health care service to a similar extent as the hearing population. However, this service requires significant capital investment by government to enable access to healthcare for the Deaf.

A clinical scoring system to prioritise investigation for tuberculosis among adults attending HIV clinics in South Africa.

BACKGROUND: The World Health Organization (WHO) recommendation for regular tuberculosis (TB) screening of HIV-positive individuals with Xpert MTB/RIF as the first diagnostic test has major resource implications. OBJECTIVE: To develop a diagnostic prediction model for TB, for symptomatic adults attending for routine HIV care, to prioritise TB investigation. DESIGN: Cohort study exploring a TB testing algorithm. SETTING: HIV clinics, South Africa. PARTICIPANTS: Representative sample of adult HIV clinic attendees; data from participants reporting ≥1 symptom on the WHO screening tool were split 50:50 to derive, then internally validate, a prediction model. OUTCOME: TB, defined as "confirmed" if Xpert MTB/RIF, line probe assay or M. tuberculosis culture were positive; and "clinical" if TB treatment started without microbiological confirmation, within six months of enrolment. RESULTS: Overall, 79/2602 (3.0%) participants on ART fulfilled TB case definitions, compared to 65/906 (7.2%) pre-ART. Among 1133/3508 (32.3%) participants screening positive on the WHO tool, 1048 met inclusion criteria for this analysis: 52/515 (10.1%) in the derivation and 58/533 (10.9%) in the validation dataset had TB. Our final model comprised ART status (on ART > 3 months vs. pre-ART or ART < 3 months); body mass index (continuous); CD4 (continuous); number of WHO symptoms (1 vs. >1 symptom). We converted this to a clinical score, using clinically-relevant CD4 and BMI categories. A cut-off score of ≥3 identified those with TB with sensitivity and specificity of 91.8% and 34.3% respectively. If investigation was prioritised for individuals with score of ≥3, 68% (717/1048) symptomatic individuals would be tested, among whom the prevalence of TB would be 14.1% (101/717); 32% (331/1048) of tests would be avoided, but 3% (9/331) with TB would be missed amongst those not tested. CONCLUSION: Our clinical score may help prioritise TB investigation among symptomatic individuals.

Cost-effectiveness of Xpert MTB/RIF for tuberculosis diagnosis in South Africa: a real-world cost analysis and economic evaluation.

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.

Health-related quality of life in South African patients with pulmonary tuberculosis.

BACKGROUND: The evaluation of patient-reported health-related quality of life (HRQOL) in pulmonary tuberculosis (TB) contributes to a comprehensive understanding of the burden associated with this disease. The aim of this study was to assess the overall impact of TB on the health status and on single health domains identified in the WHO definition of health, including physical, mental and social health aspects. METHODS: Four instruments for HRQOL evaluation were applied in a longitudinal multicentre study during six-month standard TB treatment in South Africa. These included the generic SF-12 and EQ-5D-5L, the disease-specific St. George´s Respiratory Questionnaire (SGRQ) and the condition-specific Hospital Anxiety and Depression Scale (HADS). Statistical analysis included significance testing, univariable and multivariable analysis, and repeated measures ANOVA. Change over time in the physical component score (PCS) of SF-12 was defined as primary endpoint. A target sample size of 96 patients was estimated. RESULTS: HRQOL of the study participants was impaired in all physical, mental and psycho-social health domains at treatment start. HRQOL improved significantly and in a clinically meaningful manner during the course of standard TB treatment, over the period of the study. The greatest improvement (95%) was observed in mental health. Younger patients with higher education and who were employed had a better HRQOL. DISCUSSION: This study demonstrates the need for an integrative understanding of TB with HRQOL as core element to inform gaps in current TB management. Improvements in the management of TB following an integrative patient-centred approach will contribute towards meeting the United Nations Sustainable Development Goal 3 (SDG3) target and will support the End TB strategy of the WHO.