Disentangling the influence of reservoir abundance and pathogen shedding on zoonotic spillover of the Leptospira agent in urban informal settlements.

Rats are major reservoirs for pathogenic Leptospira, the bacteria causing leptospirosis, particularly in urban informal settlements. However, the impact of variation in rat abundance and pathogen shedding rates on spillover transmission to humans remains unclear. This study aimed to investigate how spatial variation in reservoir abundance and pathogen pressure affect Leptospira spillover transmission to humans in a Brazilian urban informal settlement. A longitudinal eco-epidemiological study was conducted from 2013 to 2014 to characterize the spatial distribution of rat abundance and Leptospira shedding rates in rats and determine the association with human infection risk in a cohort of 2,206 community residents. Tracking plates and live-trapping were used to measure rat abundance and quantify rat shedding status and load. In parallel, four sequential biannual serosurveys were used to identify human Leptospira infections. To evaluate the role of shedding on human risk, we built three statistical models for: (1) the relative abundance of rats, (2) the shedding rate by individual rats, and (3) human Leptospira infection, in which "total shedding", obtained by multiplying the predictions from those two models, was used as a risk factor. We found that Leptospira shedding was associated with older and sexually mature rats and varied spatially and temporally-higher at valley bottoms and with seasonal rainfall (December to March). The point estimate for "total shedding" by rat populations was positive, i.e., Leptospira infection risk increased with total shedding, but the association was not significant [odds ratio (OR) = 1.1; 95% confidence interval (CI): 0.9, 1.4]. This positive trend was mainly driven by rat abundance, rather than individual rat shedding (OR = 1.8; 95% CI: 0.6, 5.4 vs. OR = 1.0; 95% CI: 0.7, 1.4]. Infection risk was higher in areas with more vegetative land cover (OR = 2.4; 95% CI: 1.2, 4.8), and when floodwater entered the house (OR = 2.4; 95% CI: 1.6, 3.4). Our findings indicate that environmental and hydrological factors play a more significant role in Leptospira spillover than rat associated factors. Furthermore, we developed a novel approach combining several models to elucidate complex links between animal reservoir abundance, pathogen shedding and environmental factors on zoonotic spillover in humans that can be extended to other environmentally transmitted diseases.

Potential population-level effects of HIV self-test distribution among key populations in Côte d'Ivoire, Mali, and Senegal: a mathematical modelling analysis.

BACKGROUND: During 2019-21, the AutoTest VIH, Libre d'accéder à la connaissance de son Statut (ATLAS) programme distributed around 380 000 HIV self-testing kits to key populations, including female sex workers, men who have sex with men, and their partners, in Côte d'Ivoire, Mali, and Senegal. We aimed to estimate the effects of the ATLAS programme and national scale-up of HIV self-test distribution on HIV diagnosis, HIV treatment coverage, HIV incidence, and HIV-related mortality. METHODS: We adapted a deterministic compartmental model of HIV transmission in Côte d'Ivoire, parameterised and fitted to country-specific demographic, behavioural, HIV epidemiological, and intervention data in Côte d'Ivoire, Mali, and Senegal separately during 1980-2020. We simulated dynamics of new HIV infections, HIV diagnoses, and HIV-related deaths within scenarios with and without HIV self-test distribution among key populations. Models were separately parameterised and fitted to country-specific sets of epidemiological and intervention outcomes (stratified by sex, risk, age group, and HIV status, if available) over time within a Bayesian framework. We estimated the effects on the absolute increase in the proportion of people with HIV diagnosed at the end of 2021 for the ATLAS-only scenario and at the end of 2028 and 2038 for the HIV self-testing scale-up scenario. We estimated cumulative numbers of additional HIV diagnoses and initiations of antiretroviral therapy and the proportion and absolute numbers of new HIV infections and HIV-related deaths averted during 2019-21 and 2019-28 for the ATLAS-only scenario and during 2019-28 and 2019-38 for the HIV self-testing scale-up scenario. FINDINGS: Our model estimated that ATLAS could have led to 700 (90% uncertainty interval [UI] 500-900) additional HIV diagnoses in Côte d'Ivoire, 500 (300-900) in Mali, and 300 (50-700) in Senegal during 2019-21, a 0·4 percentage point (90% UI 0·3-0·5) increase overall by the end of 2021. During 2019-28, ATLAS was estimated to avert 1900 (90% UI 1300-2700) new HIV infections and 600 (400-800) HIV-related deaths across the three countries, of which 38·6% (90% UI 31·8-48·3) of new infections and 70·1% (60·4-77·3) of HIV-related deaths would be among key populations. ATLAS would avert 1·5% (0·8-3·1) of all HIV-related deaths across the three countries during this period. Scaling up HIV self-testing would avert 16·2% (90% UI 10·0-23·1) of all new HIV infections during 2019-28 in Senegal, 5·3% (3·0-8·9) in Mali, and 1·6% (1·0-2·4) in Côte d'Ivoire. HIV self-testing scale-up among key populations was estimated to increase HIV diagnosis by the end of 2028 to 1·3 percentage points (90% UI 0·8-1·9) in Côte d'Ivoire, 10·6 percentage points (5·3-16·8) in Senegal, and 3·6 percentage points (2·0-6·4) in Mali. INTERPRETATION: Scaling up HIV self-test distribution among key populations in western Africa could attenuate disparities in access to HIV testing and reduce infections and deaths among key populations and their partners. FUNDING: Unitaid, Solthis, the UK Medical Research Council Centre for Global Infectious Disease Analysis, the EU European & Developing Countries Clinical Trials Partnership programme, and the Wellcome Trust. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Cost-effectiveness analysis of community-led HIV self-testing among key populations in Côte d'Ivoire, Mali, and Senegal.

INTRODUCTION: HIV self-testing (HIVST) is a promising strategy to improve diagnosis coverage among key populations (KP). The ATLAS (Auto Test VIH, Libre d'Accéder à la connaissance de son Statut) programme implemented HIVST in three West African countries, distributing over 380,000 kits up between 2019 and 2021, focussing on community-led distribution by KP to their peers and subsequent secondary distribution to their partners and clients. We aim to evaluate the cost-effectiveness of community-led HIVST in Côte d'Ivoire, Mali and Senegal. METHODS: An HIV transmission dynamics model was adapted and calibrated to country-specific epidemiological data and used to predict the impact of HIVST. We considered the distribution of HIVST among two KP-female sex workers (FSW), and men who have sex with men (MSM)-and their sexual partners and clients. We compared the cost-effectiveness of two scenarios against a counterfactual without HIVST over a 20-year horizon (2019-2039). The ATLAS-only scenario mimicked the 2-year implemented ATLAS programme, whereas the ATLAS-scale-up scenario achieved 95% coverage of HIVST distribution among FSW and MSM by 2025 onwards. The primary outcome is the number of disability-adjusted life-years (DALY) averted. Scenarios were compared using incremental cost-effectiveness ratios (ICERs). Costing was performed using a healthcare provider's perspective. Costs were discounted at 4%, converted to $USD 2022 and estimated using a cost-function to accommodate economies of scale. RESULTS: The ATLAS-only scenario was highly cost-effective over 20 years, even at low willingness-to-pay thresholds. The median ICERs were $126 ($88-$210) per DALY averted in Côte d'Ivoire, $92 ($88-$210) in Mali and 27$ ($88-$210) in Senegal. Scaling-up the ATLAS programme would also be cost-effective, and substantial epidemiological impacts would be achieved. The ICERs for the scale-up scenario were $199 ($122-$338) per DALY averted in Côte d'Ivoire, $224 ($118-$415) in Mali and $61 ($18-$128) in Senegal. CONCLUSIONS: Both the implemented and the potential scale-up of community-led HIVST programmes in West Africa, where KP are important to overall transmission dynamics, have the potential to be highly cost-effective, as compared to a scenario without HIVST. These findings support the scale-up of community-led HIVST to reach populations that otherwise may not access conventional testing services.

The impact of past HIV interventions and diagnosis gaps on new HIV acquisitions, transmissions, and HIV-related deaths in Côte d'Ivoire, Mali, and Senegal.

OBJECTIVES: To estimate the epidemiological impact of past HIV interventions and the magnitude and contribution of undiagnosed HIV among different risk groups on new HIV acquisitions in Côte d'Ivoire, Mali and Senegal. DESIGN: HIV transmission dynamic models among the overall population and key populations [female sex workers (FSW), their clients, and MSM]. METHODS: Models were independently parameterized and calibrated for each set of country-specific demographic, behavioural, and epidemiological data. We estimated the fraction of new HIV infections over 2012-2021 averted by condom use and antiretroviral therapy (ART) uptake among key populations and non-key populations, the direct and indirect contribution of specific groups to new infections [transmission population-attributable fraction (tPAF)] over 2012-2021 due to prevention gaps, and the distribution of undiagnosed people with HIV (PWH) by risk group in January 2022 and their tPAF over 2022-2031. RESULTS: Condom use and ART may have averted 81-88% of new HIV infections over 2012-2021 across countries, mostly due to condom use by key population. The tPAF of all key populations combined over 2012-2021 varied between 27% (Côte d'Ivoire) and 79% (Senegal). Male key populations (clients of FSW and MSM) contributed most to new infections (>60% in Mali and Senegal) owing to their higher HIV prevalence and larger prevention gaps. In 2022, men represented 56% of all PWH with an undiagnosed infection in Côte d'Ivoire (male key populations = 15%), 46% in Mali (male key populations = 23%), and 69% in Senegal (male key populations = 55%). If HIV testing and ART initiation rates remain at current levels, 20% of new HIV infections could be due to undiagnosed key populations living with HIV in Côte d'Ivoire over 2022-2031, 53% in Mali, and 65% in Senegal. CONCLUSION: Substantial HIV diagnosis gaps remain in Western Africa, especially among male key populations. Addressing these gaps is key to impacting the HIV epidemics in the region and achieving the goal of ending AIDS by 2030.

Trends in HIV testing, the treatment cascade, and HIV incidence among men who have sex with men in Africa: a systematic review and meta-analysis.

BACKGROUND: Gay, bisexual, and other men who have sex with men (MSM) are disproportionately affected by HIV. In Africa, MSM face structural barriers to HIV prevention and treatment that increase their vulnerability to HIV acquisition and transmission, and undermine the HIV response. In this systematic review, we aimed to explore progress towards increases in HIV testing, improving engagement in the HIV treatment cascade, and HIV incidence reductions among MSM in Africa. METHODS: We searched Embase, MEDLINE, Global Health, Scopus, and Web of Science for cross-sectional and longitudinal studies reporting HIV testing, knowledge of status, care, antiretroviral therapy (ART) use, viral suppression, and HIV incidence among MSM in Africa published between Jan 1, 1980, and March 3, 2023. We pooled surveys using Bayesian generalised linear mixed-effects models, used meta-regression to assess time trends, and compared HIV incidence estimates among MSM with those of all men. FINDINGS: Of 9278 articles identified, we included 152 unique studies published in 2005-23. In 2020, we estimate that 73% (95% credible interval [CrI] 62-87) of MSM had ever tested for HIV. HIV testing in the past 12 months increased over time in central, western, eastern, and southern Africa (odds ratio per year [ORyear] 1·23, 95% CrI 1·01-1·51, n=46) and in 2020 an estimated 82% (70-91) had tested in the past 12 months, but only 51% (30-72) of MSM living with HIV knew their HIV status. Current ART use increased over time in central and western (ORyear 1·41, 1·08-1·93, n=9) and eastern and southern Africa (ORyear 1·37, 1·04-1·84, n=17). We estimated that, in 2020, 73% (47-88) of all MSM living with HIV in Africa were currently on ART. Nevertheless, we did not find strong evidence to suggest that viral suppression increased, with only 69% (38-89) of MSM living with HIV estimated to be virally suppressed in 2020. We found insufficient evidence of a decrease in HIV incidence over time (incidence ratio per year 0·96, 95% CrI 0·63-1·50, n=39), and HIV incidence remained high in 2020 (6·9 per 100 person-years, 95% CrI 3·1-27·6) and substantially higher (27-199 times higher) than among all men. INTERPRETATION: HIV incidence remains high, and might not be decreasing among MSM in Africa over time, despite some increases in HIV testing and ART use. Achieving the UNAIDS 95-95-95 targets for diagnosis, treatment, and viral suppression equitably for all requires renewed focus on this key population. Combination interventions for MSM are urgently required to reduce disparities in HIV incidence and tackle the social, structural, and behavioural factors that make MSM vulnerable to HIV acquisition. FUNDING: US National Institutes of Health, UK Medical Research Council, Canadian Institutes of Health Research, and Fonds de Recherche du Québec-Santé. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Estimating the effect of HIV on cervical cancer elimination in South Africa: Comparative modelling of the impact of vaccination and screening.

Background: In 2020, the World Health Organization (WHO) launched its initiative to eliminate cervical cancer as a public health problem. To inform global efforts for countries with high HIV and cervical cancer burden, we assessed the impact of human papillomavirus (HPV) vaccination and cervical cancer screening and treatment in South Africa, on cervical cancer and the potential for achieving elimination before 2120, considering faster HPV disease progression and higher cervical cancer risk among women living with HIV(WLHIV) and HIV interventions. Methods: Three independent transmission-dynamic models simulating HIV and HPV infections and disease progression were used to predict the impact on cervical cancer incidence of three scenarios for all women: 1) girls' vaccination (9-14 years old), 2) girls' vaccination plus 1 lifetime cervical screen (at 35 years), and 3) girls' vaccination plus 2 lifetime cervical screens (at 35 and 45 years) and three enhanced scenarios for WLHIV: 4) vaccination of young WLHIV aged 15-24 years, 5) three-yearly cervical screening of WLHIV aged 15-49 years, or 6) both. Vaccination assumed 90% coverage and 100% lifetime protection with the nonavalent vaccine (against HPV-16/18/31/33/45/52/58). Cervical cancer screening assumed HPV testing with uptake increasing from 45% (2023), 70% (2030) to 90% (2045+). We also assumed that UNAIDS 90-90-90 HIV treatment and 70% male circumcision targets are reached by 2030. We examined three elimination thresholds: age-standardised cervical cancer incidence rates below 4 or 10 per 100,000 women-years, and >85% reduction in cervical cancer incidence rate. We conducted sensitivity analyses and presented the median age-standardised predictions of outcomes of the three models (minimum-maximum across models). Findings: Girls' vaccination could reduce age-standardised cervical cancer incidence from a median of 47.6 (40.9-79.2) in 2020 to 4.5 (3.2-6.3) per 100,000 women-years by 2120, averting on average ∼4% and ∼46% of age-standardised cumulative cervical cancer cases over 25 and 100 years, respectively, compared to the basecase. Adding 2 lifetime screens helped achieve elimination over the century among all women (2120 cervical cancer incidence: 3.6 (1.9-3.6) per 100,000 women-years), but not among WLHIV (10.8 (5.3-11.6)), and averted more cumulative cancer cases overall (∼45% over 25 years and ∼61% over 100 years compared to basecase) than girls' vaccination alone. Adding three-yearly cervical screening among WLHIV (to girls' vaccination and 2 lifetime cervical screens) further reduced age-standardised cervical cancer incidence to 3.3 (1.8-3.6) per 100,000 women-years overall and to 5.2 (3.9-8.5) among WLHIV by 2120 and averted on average 12-13% additional cumulative cancer cases among all women and 21-24% among WLHIV than girls' vaccination and 2 lifetime cervical screens over 25 years or longer. Long-term vaccine protection and using the nonavalent vaccine was required for elimination. Interpretation: High HPV vaccination coverage of girls and 2 lifetime cervical screens could eliminate cervical cancer among women overall in South Africa by the end of the century and substantially decrease cases among all women and WLHIV over the short and medium term. Cervical cancer elimination in WLHIV would likely require enhanced prevention strategies for WLHIV. Screening of WLHIV remains an important strategy to reduce incidence and alleviate disparities in cervical cancer burden between women with and without HIV, despite HIV interventions scale-up. Funding: World Health Organization. National Cancer Institute, National Institutes of Health. MRC Centre for Global Infectious Disease Analysis, UK Medical Research Council. National Institute of Child Health and Human Development research. Cancer Association of South Africa. Canadian Institutes of Health Research and the Fonds de recherche du Québec - Santé research.

Immunogenicity, safety, and efficacy of the HPV vaccines among people living with HIV: A systematic review and meta-analysis.

Background: Vaccines have been demonstrated to protect against high-risk human papillomavirus infection (HPV), including HPV-16/18, and cervical lesions among HIV negative women. However, their efficacy remains uncertain for people living with HIV (PLHIV).We systematically reviewed available evidence on HPV vaccine on immunological, virological, or other biological outcomes in PLHIV. Methods: We searched five electronic databases (PubMed, Medline and Embase, clinicaltrials.gov and the WHO clinical trial database) for longitudinal prospective studies reporting immunogenicity, virological, cytological, histological, clinical or safety endpoints following prophylactic HPV vaccination among PLHIV. We included studies published by February 11th, 2021. We summarized results, assessed study quality, and conducted meta-analysis and subgroup analyses, where possible. Findings: We identified 43 publications stemming from 18 independent studies (Ns =18), evaluating the quadrivalent (Ns =15), bivalent (Ns =4) and nonavalent (Ns =1) vaccines. A high proportion seroconverted for the HPV vaccine types. Pooled proportion seropositive by 28 weeks following 3 doses with the bivalent, quadrivalent, and nonavalent vaccines were 0.99 (95% confidence interval: 0.95-1.00, Ns =1), 0.99 (0.98-1.00, Ns =9), and 1.00 (0.99-1.00, Ns =1) for HPV-16 and 0.99 (0.96-1.00, Ns =1), 0.94 (0.91-0.96, Ns =9), and 1.00 (0.99-1.00, Ns =1) for HPV-18, respectively. Seropositivity remained high among people who received 3 doses despite some declines in antibody titers and lower seropositivity over time, especially for HPV-18, for the quadrivalent than the bivalent vaccine, and for HIV positive than negative individuals. Seropositivity for HPV-18 at 29-99 weeks among PLHIV was 0.72 (0.66-0.79, Ns =8) and 0.96 (0.92-0.99, Ns =2) after 3 doses of the quadrivalent and bivalent vaccine, respectively and 0.94 (0.90-0.98, Ns =3) among HIV-negative historical controls. Evidence suggests that the seropositivity after vaccination declines over time but it can lasts at least 2-4 years. The vaccines were deemed safe among PLHIV with few serious adverse events. Evidence of HPV vaccine efficacy against acquisition of HPV infection and/or associated disease from the eight trials available was inconclusive due to the low quality. Interpretation: PLHIV have a robust and safe immune response to HPV vaccination. Antibody titers and seropositivity rates decline over time but remain high. The lack of a formal correlate of protection and efficacy results preclude definitive conclusions on the clinical benefits. Nevertheless, given the burden of HPV disease in PLHIV, although the protection may be shorter or less robust against HPV-18, the robust immune response suggests that PLHIV may benefit from receiving HPV vaccination after acquiring HIV. Better quality studies are needed to demonstrate the clinical efficacy among PLHIV. Funding: World Health Organization. MRC Centre for Global Infectious Disease Analysis, Canadian Institutes of Health Research, UK Medical Research Council (MRC).

Under-Reporting of Known HIV-Positive Status Among People Living with HIV: A Systematic Review and Meta-analysis.

Monitoring progress towards the UNAIDS 'first 90' target requires accurate estimates of levels of diagnosis among people living with HIV (PLHIV), which is often estimated using self-report. We conducted a systematic review and meta-analysis quantifying under-reporting of known HIV-positive status using objective knowledge proxies. Databases were searched for studies providing self-reported and biological/clinical markers of prior knowledge of HIV-positive status among PLHIV. Random-effects models were used to derive pooled estimates of levels of under-reporting. Thirty-two estimates from 26 studies were included (41,465 PLHIV). The pooled proportion under-reporting known HIV-positive status was 20% (95% confidence interval 13-26%, I2 = 99%). In sub-group analysis, under-reporting was higher among men who have sex with men (32%, number of estimates [Ne] = 10) compared to the general population (9%, Ne = 10) and among Black (18%, Ne = 5) than non-Black (3%, Ne = 3) individuals. Supplementing self-reported data with biological/clinical proxies may improve the validity of the 'first 90' estimates.

Effects of adjunctive lacosamide on mood and quality of life in patients with epilepsy.

We examined the effects of adjunctive lacosamide (LCM) on mood and quality of life (QOL) in adult patients with partial-onset seizures in a prospective, controlled, single-blind study. Patients in whom LCM was added to their AED regimen for clinical indications comprised the LCM group (n=18), while the control group (n=32) comprised patients on ≥2 AEDs with anticipated stable dosing for the duration of the study. Profile of Mood States (POMS) and QOLIE-89 were used to assess mood and QOL at enrollment and 12-16weeks later. Adherence to LCM was measured electronically with the Medication Event Monitoring System (MEMS) and using a self-report measure. There were no significant between-group differences in age, AED load, side-effects (A-B Neurotoxicity Scale), MoCA mental status, or seizure-related factors. LCM adherence (measured by MEMS) was 70.7%. There was a significant decrease in negative mood states in the LCM group (estimated marginal mean at baseline=49.4, at follow-up=29.7; p=0.02), after controlling for seizure freedom. Based on previously reported benchmarks, clinically significant change on the POMS occurred in 7 (38%) LCM patients. The effect of LCM on the overall QOL was not significant (p=0.078). Correlation between POMS Total Mood Distress and Emotional-Wellbeing on the QOLIE-89 was significant (r=-0.783; p=0.01). These results suggest that LCM may have a favorable impact on mood.