Increasing voluntary medical male circumcision uptake among adult men in Tanzania.

OBJECTIVE: We evaluated a demand-creation intervention to increase voluntary medical male circumcision (VMMC) uptake among men aged 20-34 years in Tanzania, to maximise short-term impact on HIV incidence. METHODS: A cluster randomized controlled trial stratified by region was conducted in 20 outreach sites in Njombe and Tabora regions. The sites were randomized 1 : 1 to receive either a demand-creation intervention package in addition to standard VMMC outreach, or standard VMMC outreach alone. The intervention package included enhanced public address messages, peer promotion by recently circumcised men, facility setup to increase privacy, and engagement of female partners in demand creation. The primary outcome was the proportion of VMMC clients aged 20-34 years. FINDINGS: Overall, 6251 and 3968 VMMC clients were enrolled in intervention and control clusters, respectively. The proportion of clients aged 20-34 years was slightly greater in the intervention than control arm [17.7 vs. 13.0%; prevalence ratio = 1.36; 95% confidence intervals (CI):0.9-2.0]. In Njombe region, the proportion of clients aged 20-34 years was similar between arms but a significant two-fold difference was seen in Tabora region (P value for effect modification = 0.006). The mean number of men aged 20-34 years (mean difference per cluster = 97; 95% CI:40-154), and of all ages (mean difference per cluster = 227, 95% CI:33-420) were greater in the intervention than control arm. CONCLUSION: The intervention was associated with a significant increase in the proportion of clients aged 20-34 years in Tabora but not in Njombe. The intervention may be sensitive to regional factors in VMMC programme scale-up, including saturation

Cost and Cost-Effectiveness of a Demand Creation Intervention to Increase Uptake of Voluntary Medical Male Circumcision in Tanzania: Spending More to Spend Less.

BACKGROUND: Although voluntary medical male circumcision (VMMC) reduces the risk of HIV acquisition, demand for services is lower among men in most at-risk age groups (ages 20-34 years). A randomized controlled trial was conducted to assess the effectiveness of locally-tailored demand creation activities (including mass media, community mobilization, and targeted service delivery) in increasing uptake of campaign-delivered VMMC among men aged 20-34 years. We conducted an economic evaluation to understand the intervention's cost and cost-effectiveness. SETTING: Tanzania (Njombe and Tabora regions). METHODS: Cost data were collected on surgery, demand creation activities, and monitoring and supervision related to VMMC implementation across clusters in both trial arms, as well as start-up activities for the intervention arms. The Decision Makers' Program Planning Tool was used to estimate the number of HIV infections averted and related cost savings, given the total VMMCs per cluster. Disability-adjusted life years were calculated and used to estimate incremental cost-effectiveness ratios. RESULTS: Client load was higher in the intervention arms than in the control arms: 4394 vs. 2901 in Tabora and 1797 vs. 1025 in Njombe, respectively. Despite additional costs of tailored demand creation, demand increased more than proportionally: mean costs per VMMC in the intervention arms were $62 in Tabora and$130 in Njombe, and in the control arms $70 and$191, respectively. More infections were averted in the intervention arm than in the control arm in Tabora (123 vs. 67, respectively) and in Njombe (164 vs. 102, respectively). The intervention dominated the control because it was both less costly and more effective. Cost savings were observed in both regions stemming from the antiretroviral treatment costs averted as a result of the VMMCs performed. CONCLUSIONS: Spending more to address local preferences as a way to increase uptake of VMMC can be cost-saving

Use of Lotteries for the Promotion of Voluntary Medical Male Circumcision Service: A Discrete-Choice Experiment among Adult Men in Tanzania.

Voluntary medical male circumcision (VMMC) is effective in reducing the risk of human immunodeficiency virus (HIV). However, countries like Tanzania have high HIV prevalence but low uptake of VMMC. We conducted a discrete-choice experiment to evaluate the preferences for VMMC service attributes in a random sample of 325 men aged 18 years or older from the general population in 2 Tanzanian districts, Njombe and Tabora. We examined the preference for financial incentives in the form of a lottery ticket or receiving a guaranteed transport voucher for attendance at a VMMC service. We created a random-parameters logit model to account for individual preference heterogeneity and a latent class analysis model for identifying groups of men with similar preferences to test the hypothesis that men who reported sexually risky behaviors (i.e., multiple partners and any condomless sex in the past 12 months) may have a preference for participation in a lottery-based incentive. Most men preferred a transport voucher (84%) over a lottery ticket. We also found that offering a lottery-based financial incentive may not differentially attract those with greater sexual risk. Our study highlights the importance of gathering local data to understand preference heterogeneity, particularly regarding assumptions around risk behaviors

Using discrete choice experiments to inform the design of complex interventions.

BACKGROUND: Complex health interventions must incorporate user preferences to maximize their potential effectiveness. Discrete choice experiments (DCEs) quantify the strength of user preferences and identify preference heterogeneity across users. We present the process of using a DCE to supplement conventional qualitative formative research in the design of a demand creation intervention for voluntary medical male circumcision (VMMC) to prevent HIV in Tanzania. METHODS: The VMMC intervention was designed within a 3-month formative phase. In-depth interviews (n = 30) and participatory group discussions (n = 20) sought to identify broad setting-specific barriers to and facilitators of VMMC among adult men. Qualitative results informed the DCE development, identifying the role of female partners, service providers' attitudes and social stigma. A DCE among 325 men in Njombe and Tabora, Tanzania, subsequently measured preferences for modifiable VMMC service characteristics. The final VMMC demand creation intervention design drew jointly on the qualitative and DCE findings. RESULTS: While the qualitative research informed the community mobilization intervention, the DCE guided the specific VMMC service configuration. The significant positive utilities (u) for availability of partner counselling (u = 0.43, p < 0.01) and age-separated waiting areas (u = 0.21, p < 0.05) led to the provision of community information booths for partners and provision of age-separated waiting areas. The strong disutility of female healthcare providers (u = - 0.24, p < 0.01) led to re-training all providers on client-friendliness. CONCLUSION: This is, to our knowledge, the first study documenting how user preferences from DCEs can directly inform the design of a complex intervention. The use of DCEs as formative research may help increase user uptake and adherence to complex interventions

Efficacy and safety of two neutralising monoclonal antibody therapies, sotrovimab and BRII-196 plus BRII-198, for adults hospitalised with COVID-19 (TICO): a randomised controlled trial

BACKGROUND: We aimed to assess the efficacy and safety of two neutralising monoclonal antibody therapies (sotrovimab [Vir Biotechnology and GlaxoSmithKline] and BRII-196 plus BRII-198 [Brii Biosciences]) for adults admitted to hospital for COVID-19 (hereafter referred to as hospitalised) with COVID-19. METHODS: In this multinational, double-blind, randomised, placebo-controlled, clinical trial (Therapeutics for Inpatients with COVID-19 [TICO]), adults (aged ≥18 years) hospitalised with COVID-19 at 43 hospitals in the USA, Denmark, Switzerland, and Poland were recruited. Patients were eligible if they had laboratory-confirmed SARS-CoV-2 infection and COVID-19 symptoms for up to 12 days. Using a web-based application, participants were randomly assigned (2:1:2:1), stratified by trial site pharmacy, to sotrovimab 500 mg, matching placebo for sotrovimab, BRII-196 1000 mg plus BRII-198 1000 mg, or matching placebo for BRII-196 plus BRII-198, in addition to standard of care. Each study product was administered as a single dose given intravenously over 60 min. The concurrent placebo groups were pooled for analyses. The primary outcome was time to sustained clinical recovery, defined as discharge from the hospital to home and remaining at home for 14 consecutive days, up to day 90 after randomisation. Interim futility analyses were based on two seven-category ordinal outcome scales on day 5 that measured pulmonary status and extrapulmonary complications of COVID-19. The safety outcome was a composite of death, serious adverse events, incident organ failure, and serious coinfection up to day 90 after randomisation. Efficacy and safety outcomes were assessed in the modified intention-to-treat population, defined as all patients randomly assigned to treatment who started the study infusion. This study is registered with ClinicalTrials.gov, NCT04501978. FINDINGS: Between Dec 16, 2020, and March 1, 2021, 546 patients were enrolled and randomly assigned to sotrovimab (n=184), BRII-196 plus BRII-198 (n=183), or placebo (n=179), of whom 536 received part or all of their assigned study drug (sotrovimab n=182, BRII-196 plus BRII-198 n=176, or placebo n=178; median age of 60 years [IQR 50-72], 228 [43%] patients were female and 308 [57%] were male). At this point, enrolment was halted on the basis of the interim futility analysis. At day 5, neither the sotrovimab group nor the BRII-196 plus BRII-198 group had significantly higher odds of more favourable outcomes than the placebo group on either the pulmonary scale (adjusted odds ratio sotrovimab 1·07 [95% CI 0·74-1·56]; BRII-196 plus BRII-198 0·98 [95% CI 0·67-1·43]) or the pulmonary-plus complications scale (sotrovimab 1·08 [0·74-1·58]; BRII-196 plus BRII-198 1·00 [0·68-1·46]). By day 90, sustained clinical recovery was seen in 151 (85%) patients in the placebo group compared with 160 (88%) in the sotrovimab group (adjusted rate ratio 1·12 [95% CI 0·91-1·37]) and 155 (88%) in the BRII-196 plus BRII-198 group (1·08 [0·88-1·32]). The composite safety outcome up to day 90 was met by 48 (27%) patients in the placebo group, 42 (23%) in the sotrovimab group, and 45 (26%) in the BRII-196 plus BRII-198 group. 13 (7%) patients in the placebo group, 14 (8%) in the sotrovimab group, and 15 (9%) in the BRII-196 plus BRII-198 group died up to day 90. INTERPRETATION: Neither sotrovimab nor BRII-196 plus BRII-198 showed efficacy for improving clinical outcomes among adults hospitalised with COVID-19. FUNDING: US National Institutes of Health and Operation Warp Speed

Intravenous Aviptadil and Remdesivir for Treatment of COVID-19-Associated Hypoxaemic Respiratory Failure in the USA (Tesico): A Randomised, Placebo-Controlled Trial

BACKGROUND: There is a clinical need for therapeutics for COVID-19 patients with acute hypoxemic respiratory failure whose 60-day mortality remains at 30-50%. Aviptadil, a lung-protective neuropeptide, and remdesivir, a nucleotide prodrug of an adenosine analog, were compared with placebo among patients with COVID-19 acute hypoxaemic respiratory failure. METHODS: TESICO was a randomised trial of aviptadil and remdesivir versus placebo at 28 sites in the USA. Hospitalised adult patients were eligible for the study if they had acute hypoxaemic respiratory failure due to confirmed SARS-CoV-2 infection and were within 4 days of the onset of respiratory failure. Participants could be randomly assigned to both study treatments in a 2 × 2 factorial design or to just one of the agents. Participants were randomly assigned with a web-based application. For each site, randomisation was stratified by disease severity (high-flow nasal oxygen or non-invasive ventilation vs invasive mechanical ventilation or extracorporeal membrane oxygenation [ECMO]), and four strata were defined by remdesivir and aviptadil eligibility, as follows: (1) eligible for randomisation to aviptadil and remdesivir in the 2 × 2 factorial design; participants were equally randomly assigned (1:1:1:1) to intravenous aviptadil plus remdesivir, aviptadil plus remdesivir matched placebo, aviptadil matched placebo plus remdesvir, or aviptadil placebo plus remdesivir placebo; (2) eligible for randomisation to aviptadil only because remdesivir was started before randomisation; (3) eligible for randomisation to aviptadil only because remdesivir was contraindicated; and (4) eligible for randomisation to remdesivir only because aviptadil was contraindicated. For participants in strata 2-4, randomisation was 1:1 to the active agent or matched placebo. Aviptadil was administered as a daily 12-h infusion for 3 days, targeting 600 pmol/kg on infusion day 1, 1200 pmol/kg on day 2, and 1800 pmol/kg on day 3. Remdesivir was administered as a 200 mg loading dose, followed by 100 mg daily maintenance doses for up to a 10-day total course. For participants assigned to placebo for either agent, matched saline placebo was administered in identical volumes. For both treatment comparisons, the primary outcome, assessed at day 90, was a six-category ordinal outcome: (1) at home (defined as the type of residence before hospitalisation) and off oxygen (recovered) for at least 77 days, (2) at home and off oxygen for 49-76 days, (3) at home and off oxygen for 1-48 days, (4) not hospitalised but either on supplemental oxygen or not at home, (5) hospitalised or in hospice care, or (6) dead. Mortality up to day 90 was a key secondary outcome. The independent data and safety monitoring board recommended stopping the aviptadil trial on May 25, 2022, for futility. On June 9, 2022, the sponsor stopped the trial of remdesivir due to slow enrolment. The trial is registered with ClinicalTrials.gov, NCT04843761. FINDINGS: Between April 21, 2021, and May 24, 2022, we enrolled 473 participants in the study. For the aviptadil comparison, 471 participants were randomly assigned to aviptadil or matched placebo. The modified intention-to-treat population comprised 461 participants who received at least a partial infusion of aviptadil (231 participants) or aviptadil matched placebo (230 participants). For the remdesivir comparison, 87 participants were randomly assigned to remdesivir or matched placebo and all received some infusion of remdesivir (44 participants) or remdesivir matched placebo (43 participants). 85 participants were included in the modified intention-to-treat analyses for both agents (ie, those enrolled in the 2 x 2 factorial). For the aviptadil versus placebo comparison, the median age was 57 years (IQR 46-66), 178 (39%) of 461 participants were female, and 246 (53%) were Black, Hispanic, Asian or other (vs 215 [47%] White participants). 431 (94%) of 461 participants were in an intensive care unit at baseline, with 271 (59%) receiving high-flow nasal oxygen or non-invasive ventiliation, 185 (40%) receiving invasive mechanical ventilation, and five (1%) receiving ECMO. The odds ratio (OR) for being in a better category of the primary efficacy endpoint for aviptadil versus placebo at day 90, from a model stratified by baseline disease severity, was 1·11 (95% CI 0·80-1·55; p=0·54). Up to day 90, 86 participants in the aviptadil group and 83 in the placebo group died. The cumulative percentage who died up to day 90 was 38% in the aviptadil group and 36% in the placebo group (hazard ratio 1·04, 95% CI 0·77-1·41; p=0·78). The primary safety outcome of death, serious adverse events, organ failure, serious infection, or grade 3 or 4 adverse events up to day 5 occurred in 146 (63%) of 231 patients in the aviptadil group compared with 129 (56%) of 230 participants in the placebo group (OR 1·40, 95% CI 0·94-2·08; p=0·10). INTERPRETATION: Among patients with COVID-19-associated acute hypoxaemic respiratory failure, aviptadil did not significantly improve clinical outcomes up to day 90 when compared with placebo. The smaller than planned sample size for the remdesivir trial did not permit definitive conclusions regarding safety or efficacy. FUNDING: National Institutes of Health

Social Relations and Relational Incentives

This paper studies how social relationships between managers and employees affect relational incentive contracts. To this end we develop a simple dynamic principal-agent model where both players may have feelings of altruism or spite toward each other. The contract may contain two types of incentives for the agent to work hard: a bonus and a threat of dismissal. We find that good social relationships undermine the credibility of a threat of dismissal but strengthen the credibility of a bonus. Among others, these two mechanisms imply that better social relationships sometimes lead to higher bonuses, while worse social relationships may increase productivity and players' utility in equilibrium

"To speak or not to speak": A qualitative analysis on the attitude and willingness of women to start conversations about voluntary medical male circumcision with their partners in a peri-urban area, South Africa.

INTRODUCTION:Voluntary medical male circumcision (VMMC) reduces the risk of HIV infection in heterosexual men and has long-term indirect protection for women, yet VMMC uptake in South Africa remains low (49.8%) in men (25-49 years). We explored the attitude and willingness of women to start conversations on VMMC with their sexual partners in a South African peri-urban setting to increase VMMC uptake. METHODS:Thirty women with median age of 30 years (inter-quartile range 26-33 years) were interviewed in a language of their choice. Key questions included: types of approach to use, gender roles, benefits and barriers to introducing the topic of VMMC, and perceptions of VMMC. Interviews were digitally-recorded, transcribed, and translated. Through a standard iterative process, a codebook was developed (QSR NVIVO 10 software) and inductive thematic analysis applied. RESULTS:Most women were willing talk to their sexual partners about circumcision, but indicated that the decision to circumcise remained that of their sexual partner. Women felt that they should encourage their partners, show more interest in circumcision, be patient, speak in a caring and respectful tone, choose a correct time when their partner was relaxed and talk in a private space about VMMC. Using magazine/newspaper articles, pamphlets or advertisements were identified as tools that could aid their discussion. Substantial barriers to initiating conversations on VMMC included accusations by partner on infidelity, fear of gender-based violence, cultural restrictions and hesitation to speak to a mature partner about circumcision. CONCLUSIONS:Women need to ensure that before talking to their partner about circumcision, the environment and approach that they use are conducive. Female social network forums could be used to educate women on conversation techniques, skills to use when talking to their partners and how to address communication challenges about circumcision. Involvement of women in VMMC awareness campaigns could encourage circumcision uptake among men

Effectiveness of an “Exclusive Intervention Strategy” to increase medical male circumcision uptake among men aged 25–49 years in South Africa

Abstract Background South Africa introduced medical male circumcision (MMC) to reduce HIV incidence. Mathematical modeling suggested that targeting MMC services to men aged 20–34 years could provide the most immediate impact on HIV incidence. However the majority of MMCs performed have been among males aged ≤25 years. We evaluated an intervention package to increase MMC uptake among men aged 25–49 years. Methods We conducted a pre-post study to compare the proportion of men (aged 25–49 years) presenting for MMC during the formative (Phase 1) and intervention (Phase 2) phases in Ekurhuleni, Johannesburg, South Africa. The intervention included infrastructure changes that separated adults from adolescents at the MMC site, an exclusive men’s health club, adult-specific demand generation materials, and discussions with community members. Results Overall 2817 enrolled in the study with 1601 from Phase 1 and 1216 in Phase 2. A higher proportion of participants aged 25–49 years accessed MMC in Phase 2 compared to Phase 1 (59.4% vs. 54.9%; Prevalence Ratio = 1.08; 95% Confidence Interval: 1.01–1.15; p = 0.019). Participants with multiple partners in the past 12 months in Phase 2 were more likely to access MMC services compared to participants in Phase 1 (unadjusted Odds Ratio, 1.37; 95% CI:1.17–1.61; p < 0.001). After adjusting for age, multiple partners remained a risk factor in Phase 2 (adjusted OR, 1.39; 95% CI: 1.18–1.63; p < 0.001). Conclusions The “Exclusive Intervention Strategy” was associated with a slight increase in the proportion of participants aged 25–49 years accessing MMC services, and an increase in those with HIV risk behaviors, during the intervention phase. These findings may provide important insights to overcoming barriers for accessing MMC services among men aged 25–49 years. Trial registration The study is registered at ClinicalTrials.gov, number NCT02352961

Predictors of voluntary medical male circumcision prevalence among men aged 25-39 years in Nyanza region, Kenya: Results from the baseline survey of the TASCO study

<div><p>Introduction</p><p>Uptake of voluntary medical male circumcision (VMMC) as an intervention for prevention of HIV acquisition has been low among men aged ≥25 years in Nyanza region, western Kenya. We conducted a baseline survey of the prevalence and predictors of VMMC among men ages 25–39 years as part of the preparations for a cluster randomized controlled trial (cRCT) called the <u><b>Ta</b></u>rget, <u><b>S</b></u>peed and <u><b>Co</b></u>verage (TASCO) Study. The TASCO Study aimed to assess the impact of two demand creation interventions—interpersonal communication (IPC) and dedicated service outlets (DSO), delivered separately and together (IPC + DSO)—on VMMC uptake.</p><p>Methods</p><p>As part of the preparatory work for implementation of the cRCT to evaluate tailored interventions to improve uptake of VMMC, we conducted a survey of men aged 25–39 years from a traditionally non-circumcising Kenyan ethnic community within non-contiguous locations selected as study sites. We determined their circumcision status, estimated the baseline circumcision prevalence and assessed predictors of being circumcised using univariate and multivariate logistic regression.</p><p>Results</p><p>A total of 5,639 men were enrolled of which 2,851 (50.6%) reported being circumcised. The odds of being circumcised were greater for men with secondary education (adjusted Odds Ratio (aOR) = 1.65; 95% CI: 1.45–1.86, p<0.001), post-secondary education (aOR = 1.72; 95% CI: 1.44–2.06, p <0.001), and those employed (aOR = 1.32; 95% CI: 1.18–1.47, p <0.001). However, the odds were lower for men with a history of being married (currently married, divorced, separated, or widowed).</p><p>Conclusion</p><p>Among adult men in the rural Nyanza region of Kenya, men with post-primary education and employed were more likely to be circumcised. VMMC programs should focus on specific sub-groups of men, including those aged 25–39 years who are married, divorced/separated/ widowed, and of low socio-economic status (low education and unemployed).</p></div