The uncertain role of substandard and falsified medicines in the emergence and spread of antimicrobial resistance.

Approximately 10% of antimicrobials used by humans in low- and middle-income countries are estimated to be substandard or falsified. In addition to their negative impact on morbidity and mortality, they may also be important drivers of antimicrobial resistance. Despite such concerns, our understanding of this relationship remains rudimentary. Substandard and falsified medicines have the potential to either increase or decrease levels of resistance, and here we discuss a range of mechanisms that could drive these changes. Understanding these effects and their relative importance will require an improved understanding of how different drug exposures affect the emergence and spread of resistance and of how the percentage of active pharmaceutical ingredients in substandard and falsified medicines is temporally and spatially distributed.

Mortality rate and associated factors among patients co-infected with drug resistant tuberculosis/HIV at Mulago National Referral Hospital, Uganda, a retrospective cohort study.

Drug resistant tuberculosis (DR-TB)/HIV co-infection remains a growing threat to public health and threatens global TB and HIV prevention and care programs. HIV is likely to worsen the outcomes of DR-TB and DR-TB is likely to worsen the outcomes of HIV despite the scale up of TB and HIV services and advances in treatment and diagnosis. This study determined the mortality rate and factors associated with mortality among persons on treatment co-infected with drug resistant TB and HIV at Mulago National Referral Hospital. We retrospectively reviewed data of 390 persons on treatment that had a DR-TB/HIV co-infection in Mulago National Referral Hospital from January 2014 to December 2019.Modified poisson regression with robust standard errors was used to determine relationships between the independent variables and the dependent variable (mortality) at bivariate and multivariate analysis. Of the 390 participants enrolled, 201(53.9%) were males with a mean age of 34.6 (±10.6) and 129 (33.2%,95% CI = 28.7-38.1%) died. Antiretroviral therapy(ART) initiation (aIRR 0.74, 95% CI = 0.69-0.79), having a body mass index (BMI)≥18.5Kg/m2 (aIRR 1.01, 95% CI = 1.03-1.17), having a documented client phone contact (aIRR 0.85, 95% CI = 0.76-0.97), having a mid-upper arm circumference,(MUAC) ≥18.5cm (aIRR 0.90, 95% CI = 0.82-0.99), being on first and second line ART regimen (aIRR 0.83, 95% CI = 0.77-0.89),having a known viral load (aIRR 1.09, 95% CI = 1.00-1.21) and having an adverse event during the course of treatment (aIRR 0.88, 95% CI = 0.83-0.93) were protective against mortality. There was a significantly high mortality rate due to DR-TB/HIV co-infection. These results suggest that initiation of all persons living with HIV/AIDS (PLWHA) with DR-TB on ART and frequent monitoring of adverse drug events highly reduces mortality.

Implementation of a peer support intervention to promote the detection, reporting and management of adverse drug reactions in people living with HIV in Uganda: a protocol for a quasi-experimental study.

INTRODUCTION: Patients have contributed <1% of spontaneous adverse drug reaction (ADR) reports in Uganda's pharmacovigilance database. Peer support combined with mobile technologies could empower people living with HIV (PLHIV) to report ADRs and improve ADR management through linkage to care. We seek to test the feasibility and effect of a peer support intervention on ADR reporting by PLHIV receiving combination antiretroviral therapy (cART) in Uganda; identify barriers and facilitators to the intervention; and characterise ADR reporting and management. METHODS AND ANALYSIS: This is a quasi-experimental study to be implemented over 4 months at 12 intervention and 12 comparison cART sites from four geographical regions of Uganda. Per region, two blocks each with a tertiary, secondary and primary care cART site will be selected by simple random sampling. Blocks per region will be randomly assigned to intervention and comparison arms.Study units will include cART sites and PLHIV receiving cART. PLHIV at intervention sites will be assigned to peer supporters to empower them to report ADRs directly to the National Pharmacovigilance Centre (NPC). Peer supporters will be expert clients from among PLHIV and/or recognised community health workers.Direct patient reporting of ADRs to NPC will leverage the Med Safety App and toll-free unstructured supplementary service data interface to augment traditional pharmacovigilance methods.The primary outcomes are attrition rate measured by number of study participants who remain in the study until the end of follow-up at 4 months; and number of ADR reports submitted to NPC by PLHIV as measured by questionnaire and data abstraction from the national pharmacovigilance database at baseline and 4 months. ETHICS AND DISSEMINATION: The study received ethical approval from: School of Health Sciences Research and Ethics Committee at Makerere University (MAKSHSREC-2020-64) and Uganda National Council for Science and Technology (HS1206ES). Results will be shared with PLHIV, policy-makers, the public and academia. TRIAL REGISTRATION NUMBER: ISRCTN75989485.

High Burden of Adverse Drug Reactions to Isoniazid Preventive Therapy in People Living With HIV at 3 Tertiary Hospitals in Uganda: Associated Factors.

BACKGROUND: HIV is one of the most important risk factors of tuberculosis (TB)-related morbidity and mortality. Isoniazid preventive therapy (IPT) is recommended to prevent latent TB reactivation in patients with HIV. However, due to multiple therapies and comorbidities, these patients are predisposed to adverse drug reactions (ADRs) that lead to increased morbidity and mortality. The aim of this study was to determine the prevalence and associated factors of suspected IPT-linked ADRs in HIV-positive patients using IPT. METHODS: A cross-sectional study was conducted between February and March 2020 at 3 regional referral hospitals (RRHs) in central Uganda. We sampled 660 HIV-positive patients aged 10 years or older who received IPT between July and December 2019 inclusive. Patients were interviewed using a pretested structured questionnaire, and their treatment records were reviewed. A modified Poisson regression model with clustered robust standard errors was used to identify factors associated with suspected IPT-linked ADRs. RESULTS: The prevalence of the suspected ADRs was 51% (334 of the 660; 95% confidence interval [CI]: 18% to 83%). Patients self-reported 7-fold the number of suspected ADRs documented in the clinical files by the health care workers. Musculoskeletal symptoms were the most frequently experienced reaction (14%), followed by dizziness (13%) and peripheral neuropathy (11%). Serious suspected ADRs were experienced by 12% of the study participants; the most common were hepatotoxicity (26%), dizziness (23%), and neuropathy (17%). Female sex (aPR [adjusted prevalence ratio]: 0.92, 95% CI: = 0.88 to 0.95), study site (aPR: 1.09, 95% CI: = 1.09 to 1.18), level of education (aPR: 0.94, 95% CI: = 0.94 to 0.99), history of TB (aPR: 0.93, 95% CI: = 0.87 to 0.99), good IPT adherence (aPR: 1.16, 95% CI: = 1.05 to 1.29), and use of protease inhibitor (PI)-based antiretroviral therapy (aPR: 1.01, 95% CI: = 1.00 to 1.02) were significantly associated with suspected IPT-linked ADRs. CONCLUSION: The prevalence of suspected IPT-linked ADRs is high, and hepatotoxicity is the most commonly reported serious suspected ADR. Patients self-reported more suspected ADRs than those documented in clinical files by health care workers. Patient engagement could improve ADR detection and potentially strengthen the pharmacovigilance system. Patients with a high risk of ADR ought to be monitored regularly to enable early detection and management.

Ethical considerations for involving adolescents in biomedical HIV prevention research.

BACKGROUND: Involvement of adolescent girls in biomedical HIV research is essential to better understand efficacy and safety of new prevention interventions in this key population at high risk of HIV infection. However, there are many ethical issues to consider prior to engaging them in pivotal biomedical research. In Uganda, 16-17-year-old adolescents can access sexual and reproductive health services including for HIV or other sexually transmitted infections, contraception, and antenatal care without parental consent. In contrast, participation in HIV prevention research involving investigational new drugs requires adolescents to have parental or guardian consent. Thus, privacy and confidentiality concerns may deter adolescent participation. We describe community perspectives on ethical considerations for involving adolescent girls in the MTN 034 study in Uganda. METHODS: From August 2017 to March 2018, we held five stakeholder engagement meetings in preparation for the MTN 034 study in Kampala, Uganda (NCT03593655): two with 140 community representatives, two with 125 adolescents, and one with 50 adolescents and parents. Discussions were moderated by the study team. Proceedings were documented by notetakers. Summary notes described community perspectives of adolescent participation in HIV research including convergent, divergent or minority views, challenges, and proposed solutions. RESULTS: Most community members perceived parental or guardian consent as a principal barrier to study participation due to concerns about adolescent disclosure of pre-marital sex, which is a cultural taboo. Of 125 adolescent participants, 119 (95%) feared inadvertent disclosure of sexual activity to their parents. Community stakeholders identified the following critical considerations for ethical involvement of adolescents in HIV biomedical research: (1) involving key stakeholders in recruitment, (2) ensuring confidentiality of sensitive information about adolescent sexual activity, (3) informing adolescents about information to be disclosed to parents or guardians, (4) offering youth friendly services by appropriately trained staff, and (5) partnering with community youth organizations to maximize recruitment and retention. CONCLUSIONS: Stakeholder engagement with diverse community representatives prior to conducting adolescent HIV prevention research is critical to collectively shaping the research agenda, successfully recruiting and retaining adolescents in HIV clinical trials and identifying practical strategies to ensure high ethical standards during trial implementation.

National Antimicrobial Consumption: Analysis of Central Warehouses Supplies to In-Patient Care Health Facilities from 2017 to 2019 in Uganda.

Antimicrobial consumption (AMC) surveillance at global and national levels is necessary to inform relevant interventions and policies. This study analyzed central warehouse antimicrobial supplies to health facilities providing inpatient care in Uganda. We collected data on antimicrobials supplied by National Medical Stores (NMS) and Joint Medical Stores (JMS) to 442 health facilities from 2017 to 2019. Data were analyzed using the World Health Organization methodology for AMC surveillance. Total quantity of antimicrobials in defined daily dose (DDD) were determined, classified into Access, Watch, Reserve (AWaRe) and AMC density was calculated. There was an increase in total DDDs distributed by NMS in 2019 by 4,166,572 DDD. In 2019, Amoxicillin (27%), Cotrimoxazole (20%), and Metronidazole (12%) were the most supplied antimicrobials by NMS while Doxycycline (10%), Amoxicillin (19%), and Metronidazole (10%) were the most supplied by JMS. The majority of antimicrobials supplied by NMS (81%) and JMS (66%) were from the Access category. Increasing antimicrobial consumption density (DDD per 100 patient days) was observed from national referral to lower-level health facilities. Except for NMS in 2019, total antimicrobials supplied by NMS and JMS remained the same from 2017 to 2019. This serves as a baseline for future assessments and monitoring of stewardship interventions.