Old World cutaneous leishmaniasis (OWCL) is a sand fly-transmitted skin infection caused by Leishmania species that extends from West Africa to China. Afghanistan probably has the highest burden of OWCL and is home chiefly to Leishmania tropica and Leishmania major, which cause anthroponotic and zoonotic CL, respectively. Although data on the species distribution in Afghanistan are patchy, L. tropica predominates over L. major, reflecting its concentration in large cities. CL prevalence in Afghanistan increases with increasing age to peak at 5–10 y, depending on the local epidemiology. Clinically, there is a spectrum of lesions common to both main species with nodules, ulcerated nodules and papules accounting for the majority (50–80%) of lesions at presentation. When healed, CL lesions leave pale scars that often have deleterious psychosocial effects. Leishmania control involves vector control and treating patients, but these are severely challenged by decades of war and disruption to the health system. In the public sector, only injectable antimonials, sodium stibogluconate or meglumine antimoniate, are available and, anecdotally, efficacy remains high. Few clinical trials have been conducted in Afghanistan and data support antimonial efficacy; small clinical series suggest good efficacy of oral miltefosine against the two main species. Herein, we focus our review on the epidemiological and clinical aspects of CL in Afghanistan and suggest avenues of future research.

Clinical trials in settings with intermittent or non-existent internet and power connectivity, for example during humanitarian emergencies, present challenges in the synchronisation of data across different sites, in addition to accessing a centralised database in real-time. To overcome these, we designed a novel hybrid analogue/digital data management system which was deployed during the rapid implementation of a Phase III evaluation of a two-dose preventative vaccine for Ebola virus disease in Goma, Democratic Republic of the Congo, from 2019 to 2022. We provided study participants with an Enhanced Participant Record Card (EPRC) that served as eligibility for, and confirmation of, vaccination and was used in combination with Open Data Kit (ODK) electronic case report forms to create an off-grid study participant management system. To understand the utility of the EPRC, we analysed data from 15,327 study participants who received both vaccines and various types of prompts or reminders to return for dose 2, including home visits, telephone calls, or short messaging service (SMS). A total of 53% participants referred to the date on the EPRC as a prompt to return for dose 2 and 36.1% mentioned this as the only prompt. A multivariable generalised linear mixed-effects model showed that those who were not working, those aged 45–64 years or who had a chronic medical condition identified prior to receiving dose 2 were more likely to use the date on the EPRC as a prompt. Our findings demonstrate the utility of this system in the facilitation of decentralised data collection in off-grid locations that may be useful for future trials in complex humanitarian settings.

BACKGROUND

Dolutegravir in second-line antiretroviral therapy (ART) is more effective with recycled tenofovir than switching to zidovudine. However, dolutegravir resistance is more frequent in second-line compared to first-line ART.

OBJECTIVES

We report long-term virologic outcomes from a clinical trial.

METHOD

AntiRetroviral Therapy In Second-line: investigating Tenofovir-lamivudine-dolutegravir (ARTIST) was a randomised, double-blind, phase II clinical trial. Eligible participants had two consecutive HIV-1 RNA ≥ 1000 copies/mL on first-line ART, mostly tenofovir-emtricitabine-efavirenz. Participants were switched to tenofovir-lamivudine-dolutegravir (TLD) with lead-in 50 mg dolutegravir twice daily in stage one (n = 62), and randomised to TLD with additional lead-in 50 mg dolutegravir or placebo for the first 14 days in stage two (n = 130). We present results up to 158 weeks, combining stages one and two.

RESULTS

We enrolled 192 participants: 127/176 (72%) had resistance (Stanford score ≥ 15) to both tenofovir and lamivudine. At week 48, 151/186 (81%; 95% confidence interval [CI] 75%, 87%) had HIV-1 RNA < 50 copies/mL. Of 127 participants with follow-up through week 158, 78% (95% CI 70%, 85%) maintained HIV-1 RNA < 50 copies/mL, 11% had HIV-1 RNA 50–999 copies/mL, and 11% had HIV-1 RNA ≥ 1000 copies/mL. Twenty-nine participants met criteria for resistance testing: one developed intermediate-level dolutegravir resistance (G118R mutation) at week 96, and one had high-level dolutegravir resistance (E138K, G118R, G163R, T66A mutations) detected at week 146.

CONCLUSION

Among adults switching to TLD with detectable HIV-1 RNA and substantial tenofovir and lamivudine resistance, a high proportion maintained virologic suppression up to 158 weeks. Emergent dolutegravir resistance occurred in ~1% of participants after 2–3 years on second-line TLD.

BACKGROUND

Studies have demonstrated an inverse log-linear relationship between body mass index (BMI) and tuberculosis incidence. However, a person’s BMI is dynamic and longitudinal changes may be more informative than cross-sectional assessments. We evaluate the association between cross-sectional and changing BMI and risk of tuberculosis and describe longitudinal trajectories in a high-risk cohort.

METHODS

ERASE-TB was a prospective longitudinal cohort study of household contacts ≥10 years in Southern Africa (Zimbabwe, Tanzania, and Mozambique), with 6-monthly follow-up up to 24 months. Associations between BMI and tuberculosis were investigated based on baseline (including haemoglobin) and changing BMI, using logistic, Poisson, and Cox models. Prevalent tuberculosis was defined as diagnosis during &lt;30 days after recruitment. Growth mixture modelling (GMM) was used to model longitudinal latent trajectories.

RESULTS

Of 2,107 recruited household contacts (621 [29.5%] adolescents and 1,310 [62.2%] female), 520 (24.7%) were underweight. There were 21 and 41 people diagnosed with prevalent and incident tuberculosis, of whom 5/21 (23.8%) and 12/41 (29.3%) were underweight. Being underweight and anaemic (aHR: 3.77, 95% CI: 1.50-9.51) and &gt;10% negative change in BMI during follow-up (aIRR: 2.27 (95% CI: 0.22-22.9) were associated with increased risk of incident tuberculosis. The association between continuous BMI-for-age Z-scores were non-linear, with increased risk of tuberculosis with lower BMI. Four latent groups were defined in the GMM: increasing, decreasing, and low/high stable BMI.

CONCLUSIONS

Declining BMI, regardless of absolute value, is a strong predictor of tuberculosis among household contacts. Longitudinal measurements should be considered in active case finding among tuberculosis-affected households.

People living with HIV (PLHIV) have an increased risk of tuberculosis (TB) and severe COVID-19. TB and COVID-19 present with overlapping symptoms and co-infection can lead to poor outcomes. We assessed the frequency of SARS-CoV-2 positive serology and SARS-CoV-2 infection and the risk of mortality at 6 months in PLHIV with TB disease and SARS-CoV-2 infection. This multi-country, prospective, observational study, conducted between 7^th September 2020 and 7^th April 2022, included ambulatory adult PLHIV investigated for TB (with symptoms of TB or advanced HIV disease) in Kenya, Uganda, and South Africa. Testing included CD4 cell count, Xpert MTB/RIF Ultra assay (sputum), Determine TB LAM Ag assay (urine), chest X-ray, blood SARS-CoV-2 serology test and SARS-CoV-2 PCR (only if TB or COVID-19 symptoms). Individuals were followed for 6 months. Among 1254 participants, 1204 participants had SARS-CoV-2 serology (54% women, median CD4 344 cells/µL [IQR 132–673]), and 487 had SARS-CoV-2 PCR. SARS-CoV-2 serology positivity was 27.0% (325/1204), lower in PLHIV with CD4 counts <200 cells/µL (19.9%, 99/497) than in those with CD4 counts ≥200 cells/µL (31.6%, 222/703), p<0.001. SARS-CoV-2 PCR positivity was 8.6% (42/487) and 27.7% (135/487) had probable or confirmed SARS-CoV-2 infection. Among PLHIV with symptoms of TB or of COVID-19, 6.6% (32/487) had SARS-CoV-2 infection and TB disease. In multivariable analyses, the risk of death was higher in PLHIV with both SARS-CoV-2 infection and TB compared to those with only SARS-CoV-2 infection (adjusted hazard ratio [aHR] 8.90, 95%CI 1.47-53.96, p=0.017), with only TB (aHR 3.70, 95%CI 1.00-13.72, p=0.050) or with none of them (aHR 6.83, 95%CI 1.75-26.72, p=0.006). These findings support SARS-CoV-2 testing in PLHIV with symptoms of TB, and SARS-CoV-2 vaccination, especially for those with severe immunosuppression. PLHIV with COVID-19 and TB have an increased risk of mortality and would benefit from comprehensive management and close monitoring.

Tuberculosis (TB) among hospitalized patients is underdiagnosed. This study assessed systematic TB-screening, followed by an enhanced TB-diagnostic package for hospitalized patients implemented by trained lay health workers in KwaZulu-Natal, South Africa. In this before-and-after study we included patients ≥ 18 years. The intervention consisted of systematic clinical screening for TB, HIV and diabetes mellitus by lay health workers and provision of an enhanced TB-diagnostic package including sputum Xpert MTB/Rif Ultra, urine lateral-flow lipoarabinomannan assay (LF-LAM), chest x-ray, and sputum culture. We compared TB case findings with people hospitalized one year preceding the intervention. In the pre-intervention phase, 5217 people were hospitalized. Among 4913 (94.2%) people not on TB treatment, 367 (7.5%) were diagnosed with TB. In the intervention phase, 4015 eligible people were hospitalized. Among 3734 (93.0%) people not on TB treatment, 560 (15.0%) were diagnosed with TB. The proportion of patients diagnosed with TB was higher in the intervention phase (15.0% vs. 7.5%, p < 0.001). Overall in-hospital mortality was lower in the intervention phase [166/3734(4.5%) vs. 336/4913(6.8%), p < 0.001]. Lay health worker-led implementation of systematic TB-screening, coupled with provision of an enhanced TB-diagnostic package significantly improved TB case detection and mortality among hospitalized adults.

Clinical trials are considered to be the largest contributor to pharmaceutical development costs. However, public disclosure of the costs of individual clinical trials is rare. Médecins Sans Frontières (MSF) sponsored a phase 2b-3 randomised controlled trial (TB-PRACTECAL), which identified a new treatment regimen for drug-resistant TB. We aimed to analyse the costs of undertaking a pivotal clinical trial conducted in relatively low-resource health settings and to demonstrate the feasibility of reporting clinical trial costs. TB-PRACTECAL trial costs were analysed using MSF accounting documents. Costs were broken down by cost category, year, and trial site. Total costs for TB-PRACTECAL were €33.9 million and the average cost per patient was €61,460. Twenty-six percent of total costs represented central activities (e.g. trial planning, trial management) and 72% represented trial site activities, with 2% uncategorizable. Within trial site costs, personnel costs were the largest cost (43%) followed by external diagnostic services (11%), medicines (9%), and other medical consumables (7%). Cost variation across trial sites was driven by different varying levels of pre-existing trial infrastructure. A review of previous studies yielded a wide range of cost estimates for clinical trials (ranging US$7–221 million/trial for pharmaceutical phase 2 and 3 trials). Nearly all previous estimates derive from industry reporting that is neither standardized nor auditable; to our knowledge, this is the first published comprehensive analysis of direct expenditures of a specific clinical trial including detailed cost breakdowns. The €34 million cost of TB-PRACTECAL included investments in developing clinical trial infrastructure, the complexity of managing six sites across three health systems, and medical expenditures that are not typical of standard clinical trials. Greater transparency in drug development costs can inform medicine pricing negotiations and is a key element in the design and implementation of more equitable systems of biomedical research and development.

• A 1-day symposium brought together over 100 individuals with lived experience of noma, expertise in neglected tropical diseases, and public health, including researchers, health advocates, and clinicians. The involvement of noma survivors was invaluable and added an important perspective in defining the research agenda.
• The most pressing research needs identified were:
  • Clear case definition of noma
  • Early case detection and robust surveillance
  • Psychosocial and economic impact of noma
  • Decision support for diagnosing acute necrotizing gingivitis and associated antibiotic regimen(s) with treatment duration
  • Deeper understanding of risk factors and social determinants
  • Identification of effective information, education, and communication strategies
  • Effectiveness of surgical services
  • Testing decentralized follow-up for patients
  • An important conclusion was that noma research and control activities must be integrated across sectors and disciplines, such as neglected tropical diseases, oral health, nutrition, and child health programs including immunization.

BACKGROUND

The global epidemic of Mycoplasma genitalium (MG) is marked by its widespread prevalence, varied resistance patterns, and significant impact on sexual health. This study aimed to understand the prevalence and interaction of MG infections with other sexually transmitted infections (STIs) in a low-resource setting, as well as the implications for routine STIs care.

METHODS

This nested cross-sectional study was conducted from July 2022 to April 2023 across six outpatient care sites in Shiselweni, Eswatini. Participants completed a self-questionnaire, underwent syndromic case management, and provided urine samples for parallel molecular-based testing using the Cepheid GeneXpert® platform for MG, Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG), and Trichomonas vaginalis (TV). The proportion of MG mono-infection and coinfections were calculated. Multivariable logistic regression models identified predictors of symptomatic MG mono-infections, which could be used to streamline at-risk patients for MG testing.

RESULTS

Among 735 participants, the median age was 27 (interquartile range 23—34) years, 65.9% were women, and 9.5% were HIV-positive. MG infection was detected in 10.5% (n = 77) of clients, with 45.5% (n = 35) coinfected with any of CT/NG/TV, and one case (0.1%) showing macrolide resistance. Among women with vaginal discharge syndrome (28.1%, n = 136), 0.7% (n = 1) had MG mono-infection, and 10.3% (n = 14) had MG and CT/NG/TV coinfections. Among men with male urethral syndrome (31.9%, n = 80), 3.8% (n = 3) had MG mono-infection, and 2.5% (n = 2) had MG and CT/NG/TV coinfections. Most MG-positive cases (66.2%, n = 51) did not receive antibiotic therapy, despite 68.6% (n = 35) reporting symptoms of STIs. Of treated cases, 26.0% (n = 20) received azithromycin monotherapy, 6.5% (n = 5) doxycycline monotherapy, and 1.3% (n = 1) both drugs. Of 305 individuals reporting STIs symptoms but tested negative for CT/NG/TV, 23 (7.5%) had symptomatic MG mono-infections. Unemployment and never having been tested for HIV were identified as risk factors. Streamlining 108/305 (35.4%) at-risk individuals for molecular-based MG testing would identify 14.8% (16/108) as positive, capturing 69.6% (16/23) of all symptomatic MG mono-infections.

CONCLUSIONS

MG was common among outpatients and frequently co-occurred with CT, NG, and TV infections. Syndromic case management often misclassified MG infections, leading to ineffective treatment. Expanding molecular-based MG testing could enhance antibiotic stewardship, crucial for preventing the spread of drug-resistant strains.