Computer-aided X-ray screening for tuberculosis and HIV testing among adults with cough in Malawi (the PROSPECT study): A randomised trial and cost-effectiveness analysis.

BACKGROUND: Suboptimal tuberculosis (TB) diagnostics and HIV contribute to the high global burden of TB. We investigated costs and yield from systematic HIV-TB screening, including computer-aided digital chest X-ray (DCXR-CAD). METHODS AND FINDINGS: In this open, three-arm randomised trial, adults (≥18 years) with cough attending acute primary services in Malawi were randomised (1:1:1) to standard of care (SOC); oral HIV testing (HIV screening) and linkage to care; or HIV testing and linkage to care plus DCXR-CAD with sputum Xpert for high CAD4TBv5 scores (HIV-TB screening). Participants and study staff were not blinded to intervention allocation, but investigator blinding was maintained until final analysis. The primary outcome was time to TB treatment. Secondary outcomes included proportion with same-day TB treatment; prevalence of undiagnosed/untreated bacteriologically confirmed TB on day 56; and undiagnosed/untreated HIV. Analysis was done on an intention-to-treat basis. Cost-effectiveness analysis used a health-provider perspective. Between 15 November 2018 and 27 November 2019, 8,236 were screened for eligibility, with 473, 492, and 497 randomly allocated to SOC, HIV, and HIV-TB screening arms; 53 (11%), 52 (9%), and 47 (9%) were lost to follow-up, respectively. At 56 days, TB treatment had been started in 5 (1.1%) SOC, 8 (1.6%) HIV screening, and 15 (3.0%) HIV-TB screening participants. Median (IQR) time to TB treatment was 11 (6.5 to 38), 6 (1 to 22), and 1 (0 to 3) days (hazard ratio for HIV-TB versus SOC: 2.86, 1.04 to 7.87), with same-day treatment of 0/5 (0%) SOC, 1/8 (12.5%) HIV, and 6/15 (40.0%) HIV-TB screening arm TB patients (p = 0.03). At day 56, 2 SOC (0.5%), 4 HIV (1.0%), and 2 HIV-TB (0.5%) participants had undiagnosed microbiologically confirmed TB. HIV screening reduced the proportion with undiagnosed or untreated HIV from 10 (2.7%) in the SOC arm to 2 (0.5%) in the HIV screening arm (risk ratio [RR]: 0.18, 0.04 to 0.83), and 1 (0.2%) in the HIV-TB screening arm (RR: 0.09, 0.01 to 0.71). Incremental costs were US$3.58 and US$19.92 per participant screened for HIV and HIV-TB; the probability of cost-effectiveness at a US$1,200/quality-adjusted life year (QALY) threshold was 83.9% and 0%. Main limitations were the lower than anticipated prevalence of TB and short participant follow-up period; cost and quality of life benefits of this screening approach may accrue over a longer time horizon. CONCLUSIONS: DCXR-CAD with universal HIV screening significantly increased the timeliness and completeness of HIV and TB diagnosis. If implemented at scale, this has potential to rapidly and efficiently improve TB and HIV diagnosis and treatment. TRIAL REGISTRATION: clinicaltrials.gov NCT03519425.

Tuberculosis diagnosis cascade in Blantyre, Malawi: a prospective cohort study.

BACKGROUND: Tuberculosis (TB) control relies on early diagnosis and treatment. International guidelines recommend systematic TB screening at health facilities, but implementation is challenging. We investigated completion of recommended TB screening steps in Blantyre, Malawi. METHODS: A prospective cohort recruited adult outpatients attending Bangwe primary clinic. Entry interviews were linked to exit interviews. The proportion of participants progressing through each step of the diagnostic pathway were estimated. Factors associated with request for sputum were investigated using multivariable logistic regression. RESULTS: Of 5442 clinic attendances 2397 (44%) had exit interviews. In clinically indicated participants (n = 445) 256 (57.5%) were asked about cough, 36 (8.1%) were asked for sputum, 21 (4.7%) gave sputum and 1 (0.2%) received same-day results. Significant associations with request for sputum were: any TB symptom (aOR:3.20, 95%CI:2.02-5.06), increasing age (aOR:1.02, 95%CI:1.01-1.04 per year) and for HIV-negative participants only, a history of previous TB (aOR:3.37, 95%CI:1.45-7.81). Numbers requiring sputum tests (26/day) outnumbered diagnostic capacity (8-12/day). CONCLUSIONS: Patients were lost at every stage of the TB care cascade, with same day sputum submission following all steps of the diagnosis cascade achieved in only 4.7% if clinically indicated. Infection control strategies should be implemented, with reporting on early steps of the TB care cascade formalised. High-throughput screening interventions, such as digital CXR, that can achieve same-day TB diagnosis are urgently needed to meet WHO End TB goals.

A costing analysis of B-GAP: index-linked HIV testing for children and adolescents in Zimbabwe.

BACKGROUND: By testing children and adolescents of HIV positive caretakers, index-linked HIV testing, a targeted HIV testing strategy, has the ability to identify high risk children and adolescents earlier and more efficiently, compared to blanket testing. We evaluated the incremental cost of integrating index-linked HIV testing via three modalities into HIV services in Zimbabwe. METHODS: A mixture of bottom-up and top-down costing was employed to estimate the provider cost per test and per HIV diagnosis for 2-18 year olds, through standard of care testing, and the incremental cost of index-linked HIV testing via three modalities: facility-based testing, home-based testing by a healthcare worker, and testing at home by the caregiver using an oral mucosal transudate test. In addition to interviews, direct observation and study process data, facility registries were abstracted to extract outcome data and resource use. Costs were converted to 2019 constant US$. RESULTS: The average cost per standard of care test in urban facilities was US$5.91 and US$7.15 at the rural facility. Incremental cost of an index-linked HIV test was driven by the uptake and number of participants tested. The lowest cost approach in the urban setting was home-based testing (US$6.69) and facility-based testing at the rural clinic (US$5.36). Testing by caregivers was almost always the most expensive option (rural US$62.49, urban US$17.49). CONCLUSIONS: This is the first costing analysis of index-linked HIV testing strategies. Unit costs varied across sites and with uptake. When scaling up, alternative testing solutions that increase efficiency such as index-linked HIV testing of the entire household, as opposed to solely targeting children/adolescents, need to be explored.

Sustained Reduction in Third-generation Cephalosporin Usage in Adult Inpatients Following Introduction of an Antimicrobial Stewardship Program in a Large, Urban Hospital in Malawi.

BACKGROUND: Third-generation cephalosporins (3GC) remain the first-choice empiric antibiotic for severe infection in many sub-Saharan African hospitals. In Malawi, the limited availability of alternatives means that strategies to prevent the spread of 3GC resistance are imperative; however, suitable approaches to antimicrobial stewardship (AMS) in low-income settings are not well studied. METHODS: We introduced an AMS intervention to Queen Elizabeth Central Hospital in Blantyre. The intervention consisted of a prescribing application for smartphones and regular point-prevalence surveys with prescriber feedback. We evaluate the effects of the intervention on 3GC usage and on the cost of providing antibiotics. Using a thematic analysis of semi-structured interviews and participant observations, we additionally evaluate the acceptability of the stewardship program. RESULTS: The proportion of antibiotic prescriptions for a 3GC reduced from 193/241 (80.1%) to 177/330 (53.6%; percentage decrease, 26.5%; 95% confidence interval, 18.7-34.1) with no change in the case-fatality rate. The cost analysis estimated an annual savings of US$15 000. Qualitative research revealed trust in the guideline and found that its accessibility through smartphones helpful to guide clinical decisions. Operational health-system barriers and hierarchal clinical relationships lead to continued reliance on 3GC. CONCLUSIONS: We report the successful introduction of an antimicrobial stewardship approach in Malawi. By focusing on pragmatic interventions and simple aims, we demonstrate the feasibility, acceptability, and cost savings of a stewardship program where resources are limited. In doing so, we provide a suitable starting point for expansions of AMS interventions in this and other low-income settings.

Delivery of long-term-injectable agents for TB by lay carers: pragmatic randomised trial.

BACKGROUND: People with recurrent or drug-resistant TB require long courses of intramuscular injections. We evaluate a novel system in which patient-nominated lay carers were trained to deliver intramuscular injections to patients in their own homes. METHODS: A pragmatic, individually randomised non-inferiority trial was conducted at two hospitals in Malawi. Adults starting TB retreatment were recruited. Patients randomised to the intervention received home-based care from patient-nominated lay people trained to deliver intramuscular streptomycin. Patients receiving standard care were admitted to hospital for 2 months of streptomycin. The primary outcome was successful treatment (alive and on treatment) at the end of the intervention. RESULTS: Of 456 patients screened, 204 participants were randomised. The trial was terminated early due to futility. At the end of the intervention, 97/101 (96.0%) in the hospital arm were still alive and on treatment compared with 96/103 (93.2%) in the home-based arm (risk difference -0.03 (95% CI -0.09 to 0.03); p value 0.538). There were no differences in the proportion completing 8 months of anti-TB treatment; or the proportion experiencing 2-month sputum culture conversion. The mean cost of hospital-based management was US$1546.3 per person, compared to US$729.2 for home-based management. Home-based care reduced risk of catastrophic household costs by 84%. CONCLUSIONS: Although this trial failed to meet target recruitment, the available data demonstrate that training patient-nominated lay people has potential to provide a feasible solution to the operational challenges associated with delivering long-term-injectable drugs to people with recurrent or drug-resistant TB in resource-limited settings, and substantially reduce costs. Further data under operational conditions are required. TRIAL REGISTRATION NUMBER: ISRCTN05815615.

HIV self-testing alone or with additional interventions, including financial incentives, and linkage to care or prevention among male partners of antenatal care clinic attendees in Malawi: An adaptive multi-arm, multi-stage cluster randomised trial.

BACKGROUND: Conventional HIV testing services have been less comprehensive in reaching men than in reaching women globally, but HIV self-testing (HIVST) appears to be an acceptable alternative. Measurement of linkage to post-test services following HIVST remains the biggest challenge, yet is the biggest driver of cost-effectiveness. We investigated the impact of HIVST alone or with additional interventions on the uptake of testing and linkage to care or prevention among male partners of antenatal care clinic attendees in a novel adaptive trial. METHODS AND FINDINGS: An adaptive multi-arm, 2-stage cluster randomised trial was conducted between 8 August 2016 and 30 June 2017, with antenatal care clinic (ANC) days (i.e., clusters of women attending on a single day) as the unit of randomisation. Recruitment was from Ndirande, Bangwe, and Zingwangwa primary health clinics in urban Blantyre, Malawi. Women attending an ANC for the first time for their current pregnancy (regardless of trimester), 18 years and older, with a primary male partner not known to be on ART were enrolled in the trial after giving consent. Randomisation was to either the standard of care (SOC; with a clinic invitation letter to the male partner) or 1 of 5 intervention arms: the first arm provided women with 2 HIVST kits for their partners; the second and third arms provided 2 HIVST kits along with a conditional fixed financial incentive of $3 or $10; the fourth arm provided 2 HIVST kits and a 10% chance of receiving $30 in a lottery; and the fifth arm provided 2 HIVST kits and a phone call reminder for the women's partners. The primary outcome was the proportion of male partners who were reported to have tested for HIV and linked into care or prevention within 28 days, with referral for antiretroviral therapy (ART) or circumcision accordingly. Women were interviewed at 28 days about partner testing and adverse events. Cluster-level summaries compared each intervention versus SOC using eligible women as the denominator (intention-to-treat). Risk ratios were adjusted for male partner testing history and recruitment clinic. A total of 2,349/3,137 (74.9%) women participated (71 ANC days), with a mean age of 24.8 years (SD: 5.4). The majority (2,201/2,233; 98.6%) of women were married, 254/2,107 (12.3%) were unable to read and write, and 1,505/2,247 (67.0%) were not employed. The mean age for male partners was 29.6 years (SD: 7.5), only 88/2,200 (4.0%) were unemployed, and 966/2,210 (43.7%) had never tested for HIV before. Women in the SOC arm reported that 17.4% (71/408) of their partners tested for HIV, whereas a much higher proportion of partners were reported to have tested for HIV in all intervention arms (87.0%-95.4%, p < 0.001 in all 5 intervention arms). As compared with those who tested in the SOC arm (geometric mean 13.0%), higher proportions of partners met the primary endpoint in the HIVST + $3 (geometric mean 40.9%, adjusted risk ratio [aRR] 3.01 [95% CI 1.63-5.57], p < 0.001), HIVST + $10 (51.7%, aRR 3.72 [95% CI 1.85-7.48], p < 0.001), and phone reminder (22.3%, aRR 1.58 [95% CI 1.07-2.33], p = 0.021) arms. In contrast, there was no significant increase in partners meeting the primary endpoint in the HIVST alone (geometric mean 17.5%, aRR 1.45 [95% CI 0.99-2.13], p = 0.130) or lottery (18.6%, aRR 1.43 [95% CI 0.96-2.13], p = 0.211) arms. The lottery arm was dropped at interim analysis. Overall, 46 male partners were confirmed to be HIV positive, 42 (91.3%) of whom initiated ART within 28 days; 222 tested HIV negative and were not already circumcised, of whom 135 (60.8%) were circumcised as part of the trial. No serious adverse events were reported. Costs per male partner who attended the clinic with a confirmed HIV test result were $23.73 and $28.08 for the HIVST + $3 and HIVST + $10 arms, respectively. Notable limitations of the trial included the relatively small number of clusters randomised to each arm, proxy reporting of the male partner testing outcome, and being unable to evaluate retention in care. CONCLUSIONS: In this study, the odds of men's linkage to care or prevention increased substantially using conditional fixed financial incentives plus partner-delivered HIVST; combinations were potentially affordable. TRIAL REGISTRATION: ISRCTN 18421340.

Cost-Effectiveness of Community-based Human Immunodeficiency Virus Self-Testing in Blantyre, Malawi.

Background: Human immunodeficiency virus self-testing (HIVST) is effective, with scale-up underway in sub-Saharan Africa. We assessed cost-effectiveness of adding HIVST to existing facility-based HIV testing and counseling (HTC) services. Both 2010 (initiate at CD4 <350 cells/µL) and 2015 (initiate all) World Health Organization (WHO) guidelines for antiretroviral treatment (ART) were considered. Methods: A microsimulation model was developed to evaluate cost-effectiveness, from both health provider and societal perspectives, of an HIVST service implemented in a cluster-randomized trial (CRT; ISRCTN02004005) in Malawi. Costs and health outcomes were evaluated over a 20-year time horizon, using a discount rate of 3%. Probabilistic sensitivity analysis was conducted to account for parameter uncertainty. Results: From the health provider perspective and 20-year time horizon, facility HTC using 2010 WHO ART guidelines was the least costly ($294.71 per person; 95% credible interval [CrI], 270.79-318.45) and least effective (11.64 quality-adjusted life-years [QALYs] per person; 95% CrI, 11.43-11.86) strategy. Compared with this strategy, the incremental cost-effectiveness ratio (ICER) for facility HTC using 2015 WHO ART guidelines was $226.85 (95% CrI, 198.79-284.35) per QALY gained. The strategy of facility HTC plus HIVST, using 2010 WHO ART guidelines, was extendedly dominated. The ICER for facility HTC plus HIVST, using 2015 WHO ART guidelines, was $253.90 (95% CrI, 201.71-342.02) per QALY gained compared with facility HTC and using 2015 WHO ART guidelines. Conclusions: HIVST may be cost-effective in a Malawian population with high HIV prevalence. HIVST is suited to an early HIV diagnosis and treatment strategy. Clinical Trials registration: ISRCTN02004005.

Cost and quality of life analysis of HIV self-testing and facility-based HIV testing and counselling in Blantyre, Malawi.

BACKGROUND: HIV self-testing (HIVST) has been found to be highly effective, but no cost analysis has been undertaken to guide the design of affordable and scalable implementation strategies. METHODS: Consecutive HIV self-testers and facility-based testers were recruited from participants in a community cluster-randomised trial ( ISRCTN02004005 ) investigating the impact of offering HIVST in addition to facility-based HIV testing and counselling (HTC). Primary costing studies were undertaken of the HIVST service and of health facilities providing HTC to the trial population. Costs were adjusted to 2014 US$ and INT$. Recruited participants were asked about direct non-medical and indirect costs associated with accessing either modality of HIV testing, and additionally their health-related quality of life was measured using the EuroQol EQ-5D. RESULTS: A total of 1,241 participants underwent either HIVST (n = 775) or facility-based HTC (n = 446). The mean societal cost per participant tested through HIVST (US$9.23; 95 % CI: US$9.14-US$9.32) was lower than through facility-based HTC (US$11.84; 95 % CI: US$10.81-12.86). Although the mean health provider cost per participant tested through HIVST (US$8.78) was comparable to facility-based HTC (range: US$7.53-US$10.57), the associated mean direct non-medical and indirect cost was lower (US$2.93; 95 % CI: US$1.90-US$3.96). The mean health provider cost per HIV positive participant identified through HIVST was higher (US$97.50) than for health facilities (range: US$25.18-US$76.14), as was the mean cost per HIV positive individual assessed for anti-retroviral treatment (ART) eligibility and the mean cost per HIV positive individual initiated onto ART. In comparison to the facility-testing group, the adjusted mean EQ-5D utility score was 0.046 (95 % CI: 0.022-0.070) higher in the HIVST group. CONCLUSIONS: HIVST reduces the economic burden on clients, but is a costlier strategy for the health provider aiming to identify HIV positive individuals for treatment. The provider cost of HIVST could be substantially lower under less restrictive distribution models, or if costs of oral fluid HIV test kits become comparable to finger-prick kits used in health facilities.

Uptake, Accuracy, Safety, and Linkage into Care over Two Years of Promoting Annual Self-Testing for HIV in Blantyre, Malawi: A Community-Based Prospective Study.

BACKGROUND: Home-based HIV testing and counselling (HTC) achieves high uptake, but is difficult and expensive to implement and sustain. We investigated a novel alternative based on HIV self-testing (HIVST). The aim was to evaluate the uptake of testing, accuracy, linkage into care, and health outcomes when highly convenient and flexible but supported access to HIVST kits was provided to a well-defined and closely monitored population. METHODS AND FINDINGS: Following enumeration of 14 neighbourhoods in urban Blantyre, Malawi, trained resident volunteer-counsellors offered oral HIVST kits (OraQuick ADVANCE Rapid HIV-1/2 Antibody Test) to adult (≥16 y old) residents (n = 16,660) and reported community events, with all deaths investigated by verbal autopsy. Written and demonstrated instructions, pre- and post-test counselling, and facilitated HIV care assessment were provided, with a request to return kits and a self-completed questionnaire. Accuracy, residency, and a study-imposed requirement to limit HIVST to one test per year were monitored by home visits in a systematic quality assurance (QA) sample. Overall, 14,004 (crude uptake 83.8%, revised to 76.5% to account for population turnover) residents self-tested during months 1-12, with adolescents (16-19 y) most likely to test. 10,614/14,004 (75.8%) participants shared results with volunteer-counsellors. Of 1,257 (11.8%) HIV-positive participants, 26.0% were already on antiretroviral therapy, and 524 (linkage 56.3%) newly accessed care with a median CD4 count of 250 cells/µl (interquartile range 159-426). HIVST uptake in months 13-24 was more rapid (70.9% uptake by 6 mo), with fewer (7.3%, 95% CI 6.8%-7.8%) positive participants. Being "forced to test", usually by a main partner, was reported by 2.9% (95% CI 2.6%-3.2%) of 10,017 questionnaire respondents in months 1-12, but satisfaction with HIVST (94.4%) remained high. No HIVST-related partner violence or suicides were reported. HIVST and repeat HTC results agreed in 1,639/1,649 systematically selected (1 in 20) QA participants (99.4%), giving a sensitivity of 93.6% (95% CI 88.2%-97.0%) and a specificity of 99.9% (95% CI 99.6%-100%). Key limitations included use of aggregate data to report uptake of HIVST and being unable to adjust for population turnover. CONCLUSIONS: Community-based HIVST achieved high coverage in two successive years and was safe, accurate, and acceptable. Proactive HIVST strategies, supported and monitored by communities, could substantially complement existing approaches to providing early HIV diagnosis and periodic repeat testing to adolescents and adults in high-HIV settings.

Effect of optional home initiation of HIV care following HIV self-testing on antiretroviral therapy initiation among adults in Malawi: a randomized clinical trial.

IMPORTANCE: Self-testing for HIV infection may contribute to early diagnosis of HIV, but without necessarily increasing antiretroviral therapy (ART) initiation. OBJECTIVE: To investigate whether offering optional home initiation of HIV care after HIV self-testing might increase demand for ART initiation, compared with HIV self-testing accompanied by facility-based services only. DESIGN, SETTING, AND PARTICIPANTS: Cluster randomized trial conducted in Blantyre, Malawi, between January 30 and November 5, 2012, using restricted 1:1 randomization of 14 community health worker catchment areas. Participants were all adult (≥16 years) residents (n = 16,660) who received access to home HIV self-testing through resident volunteers. This was a second-stage randomization of clusters allocated to the HIV self-testing group of a parent trial. INTERVENTIONS: Clusters were randomly allocated to facility-based care or optional home initiation of HIV care (including 2 weeks of ART if eligible) for participants reporting positive HIV self-test results. MAIN OUTCOMES AND MEASURES: The preplanned primary outcome compared between groups the proportion of all adult residents who initiated ART within the first 6 months of HIV self-testing availability. Secondary outcomes were uptake of HIV self-testing, reporting of positive HIV self-test results, and rates of loss from ART at 6 months. RESULTS: A significantly greater proportion of adults in the home group initiated ART (181/8194, 2.2%) compared with the facility group (63/8466, 0.7%; risk ratio [RR], 2.94, 95% CI, 2.10-4.12; P < .001). Uptake of HIV self-testing was high in both the home (5287/8194, 64.9%) and facility groups (4433/8466, 52.7%; RR, 1.23; 95% CI, 0.96-1.58; P = .10). Significantly more adults reported positive HIV self-test results in the home group (490/8194 [6.0%] vs the facility group, 278/8466 [3.3%]; RR, 1.86; 95% CI, 1.16-2.97; P = .006). After 6 months, 52 of 181 ART initiators (28.7%) and 15 of 63 ART initiators (23.8%) in the home and facility groups, respectively, were lost from ART (adjusted incidence rate ratio, 1.18; 95% CI, 0.62-2.25, P = .57). CONCLUSIONS AND RELEVANCE: Among Malawian adults offered HIV self-testing, optional home initiation of care compared with standard HIV care resulted in a significant increase in the proportion of adults initiating ART. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01414413.

Budget Impact Analysis of Minimally Invasive versus Open Transforaminal Lumbar Interbody Fusion for Lumbar Degenerative Disease: A European Hospital Perspective.

Purpose: When traditional therapies fail to provide relief from debilitating lower back pain, surgeries such as transforaminal lumbar interbody fusion (TLIF) may be required. This budget impact analysis (BIA) compared minimally-invasive (MI)-TLIF versus open (O)-TLIF for single-level fusion from an Italian hospital perspective. Methods: The BIA compared costs of 100 MI-TLIF and 100 O-TLIF procedures from an Italian hospital perspective over a one-year time horizon. The base case included costs for length of hospital stay (LOS), blood loss, and sterilizing surgical trays. The scenario analysis also included operating room (OR) time and complication costs. Base case inputs were from the Miller et al meta-analysis; scenario analysis inputs were from the Hammad et al meta-analysis. The device costs for MI-TLIF and O-TLIF procedures were from Italian tender prices for Viper Prime™ System and Expedium™ Spine System, respectively. Results: Base case deterministic analysis results showed cost savings of €207,370 for MI-TLIF compared with O-TLIF. MI-TLIF costs were lower for LOS (€215,277), transfusion for blood loss (€16,881), and surgical tray sterilization (€28,232), whereas device costs were lower for O-TLIF (€53,020). The probabilistic result was similar, with MI-TLIF resulting in savings of €211,026 (95% credible interval [CR]: €208,725 - €213,327). All 1000 base case probabilistic sensitivity analysis runs were cost saving. Deterministic scenario analysis results showed cost savings of €166,719 for MI-TLIF. MI-TLIF costs were lower for LOS (€190,813), transfusion for blood loss (€16,881), surgical tray sterilization (€28,232), and complications (€2076), whereas O-TLIF costs were lower for OR time (€18,263) and devices used (€53,020). Conclusion: Despite the increase incremental cost for medical device innovation and OR time, this study demonstrates the economic savings of MI-TLIF compared to O-TLIF from a European hospital perspective. The findings will be useful to policy and hospital decision makers in assessing purchasing, funding and reimbursement decisions.

Provider and female client economic costs of integrated sexual and reproductive health and HIV services in Zimbabwe.

A retrospective facility-based costing study was undertaken to estimate the comparative cost per visit of five integrated sexual and reproductive health and HIV (human immuno-deficiency virus) services (provider perspective) within five clinic sites. These five clinics were part of four service delivery models: Non-governmental-organisation (NGO) directly managed model (Chitungwiza and New Africa House sites), NGO partner managed site (Mutare site), private-public-partnership (PPP) model (Chitungwiza Profam Clinic), and NGO directly managed outreach (operating from New Africa House site. In addition client cost exit interviews (client perspective) were conducted among 856 female clients exiting integrated services at three of the sites. Our costing approach involved first a facility bottom-up costing exercise (February to April 2015), conducted to quantify and value each resource input required to provide individual SRH and HIV services. Secondly overhead financial expenditures were allocated top-down from central office to sites and then respective integrated service based on pre-defined allocation factors derived from both the site facility observations and programme data for the prior 12 months. Costs were assessed in 2015 United States dollars (USD). Costs were assessed for HIV testing and counselling, screening and treatment of sexually transmitted infections, tuberculosis screening with smear microscopy, family planning, and cervical cancer screening and treatment employing visual inspection with acetic acid and cervicography and cryotherapy. Variability in costs per visit was evident across the models being highest for cervical cancer screening and cryotherapy (range: US$6.98-US$49.66). HIV testing and counselling showed least variability (range; US$10.96-US$16.28). In general the PPP model offered integrated services at the lowest unit costs whereas the partner managed site was highest. Significant client costs remain despite availability of integrated sexual and reproductive health and HIV services free of charge in our Zimbabwe study setting. Situating services closer to communities, incentives, transport reimbursements, reducing waiting times and co-location of sexual and reproductive health and HIV services may help minimise impact of client costs.

Modelling Methods of Economic Evaluations of HIV Testing Strategies in Sub-Saharan Africa: A Systematic Review.

BACKGROUND AND OBJECTIVE: Economic evaluations, a decision-support tool for policy makers, will be crucial in planning and tailoring HIV prevention and treatment strategies especially in the wake of stalled and decreasing funding for the global HIV response. As HIV testing and treatment coverage increase, case identification becomes increasingly difficult and costly. Determining which subset of the population these strategies should be targeted to becomes of vital importance as well. Generating quality economic evidence begins with the validity of the modelling approach and the model structure employed. This study synthesises and critiques the reporting around modelling methodology of economic models in the evaluation of HIV testing strategies in sub-Saharan Africa. METHODS: The following databases were searched from January 2000 to September 2020: MEDLINE, Embase, Scopus, EconLit and Global Health. Any model-based economic evaluation of a unique HIV testing strategy conducted in sub-Saharan Africa presenting a cost-effectiveness measure published from 2013 onwards was eligible. Data were extracted around three components: general study characteristics; economic evaluation design; and quality of model reporting using a novel tool developed for the purposes of this study. RESULTS: A total of 21 studies were included; 10 cost-effectiveness analyses, 11 cost-utility analyses. All but one study was conducted in Eastern and Southern Africa. Modelling approaches for HIV testing strategies can be broadly characterised as static aggregate models (3/21), static individual models (6/21), dynamic aggregate models (5/21) and dynamic individual models (7/21). Adequate reporting around data handling was the highest of the three categories assessed (74%), and model validation, the lowest (45%). Limitations to model structure, justification of chosen time horizon and cycle length, and description of external model validation process were all adequately reported in less than 40% of studies. The predominant limitation of this review relates to the potential implications of the narrow inclusion criteria. CONCLUSIONS: This review is the first to synthesise economic evaluations of HIV testing strategies in sub-Saharan Africa. The majority of models exhibited dynamic, stochastic and individual properties. Model reporting against the 13 criteria in our novel tool was mixed. Future model-based economic evaluations of HIV testing strategies would benefit from transparency around the choice of modelling approach, model structure, data handling procedures and model validation techniques.

Psychometric performance of the Chichewa versions of the EQ-5D-Y-3L and EQ-5D-Y-5L among healthy and sick children and adolescents in Malawi.

OBJECTIVES: The EuroQol Group has developed an extended version of the EQ-5D-Y-3L with five response levels for each of its five dimensions (EQ-5D-Y-5L). The psychometric performance has been reported in several studies for the EQ-5D-Y-3L but not for the EQ-5D-Y-5L. This study aimed to psychometrically evaluate the EQ-5D-Y-3L and EQ-5D-Y-5L Chichewa (Malawi) versions. METHODS: The EQ-5D-Y-3L, EQ-5D-Y-5L and PedsQL™ 4.0 Chichewa versions were administered to children and adolescents aged 8-17 years in Blantyre, Malawi. Both of the EQ-5D-Y versions were evaluated for missing data, floor/ceiling effects, and validity (convergent, discriminant, known-group and empirical). RESULTS: A total of 289 participants (95 healthy, and 194 chronic and acute) self-completed the questionnaires. There was little problem with missing data (< 5%) except in children aged 8-12 years particularly for the EQ-5D-Y-5L. Ceiling effects was generally reduced in moving from the EQ-5D-Y-3L to the EQ-5D-Y-5L. For both EQ-5D-Y-3L and EQ-5D-Y-5L, convergent validity tested with PedsQL™ 4.0 was found to be satisfactory (correlation ≥ 0.4) at scale level but mixed at dimension /sub-scale level. There was evidence of discriminant validity (p > 0.05) with respect to gender and age, but not for school grade (p < 0.05). For empirical validity, the EQ-5D-Y-5L was 31-91% less efficient than the EQ-5D-Y-3L at detecting differences in health status using external measures. CONCLUSIONS: Both versions of the EQ-5D-Y-3L and EQ-5D-Y-5L had issues with missing data in younger children. Convergent validity, discriminant validity with respect to gender and age, and known-group validity of either measures were also met for use among children and adolescents in this population, although with some limitations (discriminant validity by grade and empirical validity). The EQ-5D-Y-3L seems particularly suited for use in younger children (8-12 years) and the EQ-5D-Y-5L in adolescents (13-17 years). However, further psychometric testing is required for test re-test reliability and responsiveness that could not be carried out in this study due to COVID-19 restrictions.

Health misinformation and freedom of expression: considerations for policymakers.

Health misinformation, most visibly following the COVID-19 infodemic, is an urgent threat that hinders the success of public health policies. It likely contributed, and will continue to contribute, to avoidable deaths. Policymakers around the world are being pushed to tackle this problem. Legislative acts have been rolled out or announced in many countries and at the European Union level. The goal of this paper is not to review particular legislative initiatives, or to assess the impact and efficacy of measures implemented by digital intermediaries, but to reflect on the high constitutional and ethical stakes involved in tackling health misinformation through speech regulation. Our findings suggest that solutions focused on regulating speech are likely to encounter significant constraints, as policymakers grasp with the limitations imposed by freedom of expression and ethical considerations. Solutions focused on empowering individuals - such as media literacy initiatives, fact-checking or credibility labels - are one way to avoid such hurdles.

Ambient temperature and mental health: a systematic review and meta-analysis.

BACKGROUND: Increasing evidence indicates that ambient outdoor temperature could affect mental health, which is especially concerning in the context of climate change. We aimed to comprehensively analyse the current evidence regarding the associations between ambient temperature and mental health outcomes. METHODS: We did a systematic review and meta-analysis of the evidence regarding associations between ambient outdoor temperature and changes in mental health outcomes. We searched WebOfScience, Embase, PsychINFO, and PubMed for articles published from database origin up to April 7, 2022. Eligible articles were epidemiological, observational studies in humans of all ages, which evaluated real-world responses to ambient outdoor temperature, and had mental health as a documented outcome; studies of manipulated or controlled temperature or those with only physical health outcomes were excluded. All eligible studies were synthesised qualitatively. If three or more studies reported the same or equivalent effect statistics and if they had equivalent exposure, outcome, and metrics, the studies were pooled in a random-effects meta-analysis. The risk of bias for individual studies was assessed using the Newcastle-Ottawa Scale. The quality of evidence across studies was assessed using the Office of Health Assessment and Translation (OHAT) approach. FINDINGS: 114 studies were included in the systematic review, of which 19 were suitable for meta-analysis. Three meta-analyses were conducted for suicide outcomes: a 1°C increase in mean monthly temperature was associated with an increase in incidence of 1·5% (95% CI 0·8-2·2, p<0·001; n=1 563 109, seven effects pooled from three studies); a 1°C increase in mean daily temperature was associated with an increase in incidence of 1·7% (0·3-3·0, p=0·014; n=113 523, five effects pooled from five studies); and a 1°C increase in mean monthly temperature was associated with a risk ratio of 1·01 (95% CI 1·00-1·01, p<0·001; n=111 794, six effects pooled from three studies). Three meta-analyses were conducted for hospital attendance or admission for mental illness: heatwaves versus non-heatwave periods were associated with an increase in incidence of 9·7% (95% CI 7·6-11·9, p<0·001; n=362 086, three studies); the risk ratio at the 99th percentile of daily mean temperature compared with the 50th percentile was 1·02 (95% CI 1·01-1·03, p=0·006; n=532 296, three studies); and no significant association was found between a 10°C increase in daily mean temperature and hospital attendance. In a qualitative narrative synthesis, we found that ambient outdoor temperature (including absolute temperatures, temperature variability, and heatwaves) was positively associated with attempted and completed suicides (86 studies), hospital attendance or admission for mental illness (43 studies), and worse outcomes for community mental health and wellbeing (19 studies), but much of the evidence was of low certainty with high heterogeneity. INTERPRETATION: Increased temperature and temperature variability could be associated with increased cases of suicide and suicidal behaviour, hospital attendance or admission for mental illness, and poor community health and wellbeing. Climate change is likely to increase temperature anomalies, variability, and heatwaves as well as average temperatures; as such, health system leaders and policy makers must be adequately prepared and should develop adaptation strategies. More high-quality, standardised research is required to improve our understanding of these effects. FUNDING: None.

Individual and population level costs and health-related quality of life outcomes of third-generation cephalosporin resistant bloodstream infection in Blantyre, Malawi.

Data which accurately enumerate the economic costs of antimicrobial resistance (AMR) in low- and middle- income countries are essential. This study aimed to quantify the impact of third-generation cephalosporin resistant (3GC-R) bloodstream infection (BSI) on economic and health related quality of life outcomes for adult patients in Blantyre, Malawi. Participants were recruited from a prospective, longitudinal cohort study of hospitalised patients with bloodstream infection caused by Enterobacterales at Queen Elizabeth Central Hospital (QECH). Primary costing studies were used to estimate the direct medical costs associated with the inpatient stay. Recruited participants were asked about direct non-medical and indirect costs associated with their admission and their health-related quality of life was measured using the EuroQol EQ-5D questionnaire. Multiple imputation was undertaken to account for missing data. Costs were adjusted to 2019 US Dollars. Cost and microbiology surveillance data from QECH, Blantyre was used to model the annual cost of, and quality-adjusted life years lost to, 3GC-R and 3GC-Susceptible BSI from 1998 to 2030 in Malawi. The mean health provider cost per participant with 3GC-R BSI was US$110.27 (95%CR; 22.60-197.95), higher than for those with 3GC-S infection. Patients with resistant BSI incurred an additional indirect cost of US$155.48 (95%CR; -67.80, 378.78) and an additional direct non-medical cost of US$20.98 (95%CR; -36.47, 78.42). Health related quality of life outcomes were poor for all participants, but participants with resistant infections had an EQ-5D utility score that was 0.167 (95% CR: -0.035, 0.300) lower than those with sensitive infections. Population level burden estimates suggest that in 2016, 3GC-R accounted for 84% of annual societal costs from admission with bloodstream infection and 82% of QALYs lost. 3GC-R bloodstream infection was associated with higher health provider and patient level costs than 3GC-S infection, as well as poorer HRQoL outcomes. We demonstrate a substantial current and future economic burden to society as a result of 3GC-R E. coli and Klebsiella spp. BSI, data urgently needed by policy makers to provide impetus for implementing strategies to reduce AMR.

Evaluating the responsiveness of the Warwick Edinburgh Mental Well-Being Scale (WEMWBS): group and individual level analysis.

BACKGROUND: Mental well-being now features prominently in UK and international health policy. However, progress has been hampered by lack of valid measures that are responsive to change. The objective of this study was to evaluate the responsiveness of the Warwick Edinburgh Mental Well-being Scale (WEMWBS) at both the individual and group level. METHODS: Secondary analysis of twelve different interventional studies undertaken in different populations using WEMWBS as an outcome measure. Standardised response mean (SRM), probability of change statistic (P(^)) and standard error of measurement (SEM) were used to evaluate whether WEMWBS detected statistically important changes at the group and individual level, respectively. RESULTS: Mean change in WEMWBS score ranged from -0.6 to 10.6. SRM ranged from -0.10 (95% CI: -0.35, 0.15) to 1.35 (95% CI: 1.06, 1.64). In 9/12 studies the lower limit of the 95% CI for P(^) was greater than 0.5, denoting responsiveness. SEM ranged from 2.4 to 3.1 units, and at the threshold 2.77 SEM, WEMWBS detected important improvement in at least 12.8% to 45.7% of participants (lower limit of 95% CI>5.0%). CONCLUSIONS: WEMWBS is responsive to changes occurring in a wide range of mental health interventions undertaken in different populations. It offers a secure base for research and development in this rapidly evolving field. Further research using external criteria of change is warranted.

Cross-Cultural Adaptation of the Beta EQ-5D-Y-5L Into Chichewa (Malawi).

OBJECTIVES: The EuroQol Group is developing a new EQ-5D-Y-5L version with 5 severity levels for each of the 5 dimensions. The 5 severity levels describe different health severities and there is a potential for severity level inversion. This article aims to report the process of cross-cultural adaptation of the beta EQ-5D-Y-5L into Chichewa (Malawi) using the card ranking exercise, which has been added to the EQ-5D-Y-5L translation protocol. METHODS: To assess the correct hierarchical ordering of severity levels, the adaptation followed the EQ-5D-Y-5L translation protocol. Cognitive interviews were undertaken to establish conceptual equivalence. Thereafter, 4 iterations of ranking exercises were conducted, leading to amendments of the translated Chichewa version to arrive at a final version. RESULTS: The iterations were assessed by 18 participants aged 8 to 14 years. Health proved to be a difficult concept to translate as was "discomfort." Cognitive interviews identified further conceptual issues, particularly with the "looking after myself" dimension. Considerations about lack of soap or water indicated that some children did not fully comprehend this dimension as being about the ability to wash and dress themselves. The iterative card ranking exercise detected severity level inversion between "a little bit" and "some," and between "a lot" and "extreme" and alternative Chichewa words/phrases were then tested. Ultimately, the intended hierarchical severity ranking was achieved and an acceptable Chichewa version was produced. CONCLUSIONS: Conceptual and linguistic equivalence to the English EQ-5D-Y-5L was established for the Chichewa EQ-5D-Y-5L version. The card ranking exercise was instrumental in correcting severity level inversion and supporting the comprehensible translation.

Cost-effectiveness of single, high-dose, liposomal amphotericin regimen for HIV-associated cryptococcal meningitis in five countries in sub-Saharan Africa: an economic analysis of the AMBITION-cm trial.

BACKGROUND: HIV-associated cryptococcal meningitis is a leading cause of AIDS-related mortality. The AMBITION-cm trial showed that a regimen based on a single high dose of liposomal amphotericin B deoxycholate (AmBisome group) was non-inferior to the WHO-recommended treatment of seven daily doses of amphotericin B deoxycholate (control group) and was associated with fewer adverse events. We present a five-country cost-effectiveness analysis. METHODS: The AMBITION-cm trial enrolled patients with HIV-associated cryptococcal meningitis from eight hospitals in Botswana, Malawi, South Africa, Uganda, and Zimbabwe. Taking a health service perspective, we collected country-specific unit costs and individual resource-use data per participant over the 10-week trial period, calculating mean cost per participant by group, mean cost-difference between groups, and incremental cost-effectiveness ratio per life-year saved. Non-parametric bootstrapping and scenarios analyses were performed including hypothetical real-world resource use. The trial registration number is ISRCTN72509687, and the trial has been completed. FINDINGS: The AMBITION-cm trial enrolled 844 participants, and 814 were included in the intention-to-treat analysis (327 from Uganda, 225 from Malawi, 107 from South Africa, 84 from Botswana, and 71 from Zimbabwe) with 407 in each group, between Jan 31, 2018, and Feb 17, 2021. Using Malawi as a representative example, mean total costs per participant were US$1369 (95% CI 1314-1424) in the AmBisome group and $1237 (1181-1293) in the control group. The incremental cost-effectiveness ratio was $128 (59-257) per life-year saved. Excluding study protocol-driven cost, using a real-world toxicity monitoring schedule, the cost per life-year saved reduced to $80 (15-275). Changes in the duration of the hospital stay and antifungal medication cost showed the greatest effect in sensitivity analyses. Results were similar across countries, with the cost per life-year saved in the real-world scenario ranging from $71 in Botswana to $121 in Uganda. INTERPRETATION: The AmBisome regimen was cost-effective at a low incremental cost-effectiveness ratio. The regimen might be even less costly and potentially cost-saving in real-world implementation given the lower drug-related toxicity and the potential for shorter hospital stays. FUNDING: European Developing Countries Clinical Trials Partnership, Swedish International Development Cooperation Agency, Wellcome Trust and Medical Research Council, UKAID Joint Global Health Trials, and the National Institute for Health Research. TRANSLATIONS: For the Chichewa, Isixhosa, Luganda, Setswana and Shona translations of the abstract see Supplementary Materials section.