Understanding adverse drug reactions to dolutegravir and isoniazid in HIV-positive Ugandans: incidence, risk factors, management and patient-reporting

Thanks to medical advances, people living with HIV (PLHIV) can now live long, healthy lives. To remain healthy, PLHIV will need to take drugs against the virus (called antiretrovirals) for the rest of their lives. Antiretrovirals are generally safe but cause serious side effects in some people, particularly with long-term use. Common side effects are discovered in clinical trials; if they are too severe or too common, the drug will fail the trial. It isn't possible to test enough people in a clinical trial to discover less common side effects. These can only be found by monitoring people taking the drug in the real world. Recording which people have side effects and understanding why they happen is essential for making drugs safer.

We work in Uganda where 1.5 million people (3.5%) live with HIV. Uganda recently began a programme to rapidly roll-out antiretroviral combinations including dolutegravir (DTG), the new drug recommended by the World Health Organisation (WHO), to PLHIV. Uganda is also rolling-out Isoniazid Preventive Therapy (IPT) to prevent active tuberculosis - the main cause of death in PLHIV. Systems for monitoring drug-related side effects have only recently been developed in Uganda, so we do not understand the risk factors for side effects of the new HIV drugs in Ugandan PLHIV. These include 'clinical' risk factors, such as having other medical conditions, or 'genetic' risk factors, natural variations in a person's DNA that increase the risk of a side effect. Some DNA variations are more common in people of particular ethnicity, so it is essential that we record side effects across all ethnic groups.

We aim to: 1) understand which PLHIV are at risk of a side effect to DTG or DTG with IPT and why; and 2) strengthen the systems for reporting drug-related side effects by empowering PLHIV to make their own reports. These are essential steps to enable us to treat each PLHIV with the right antiretrovirals at the right dose in the future.

We will recruit 10000 people receiving DTG or DTG plus IPT from eight clinics across Uganda to investigate: 1) how the clinics currently aim to prevent, monitor and treat side effects in these people; 2) which side effects occur and how common they are; 3) whether there are common clinical risk factors across people with side effects; 4) whether there are genetic risk factors for the most concerning of these side effects, high blood sugar.

We will also recruit 15,000 people receiving DTG or DTG and IPT to investigate whether mobile applications, 'apps', can improve monitoring of drug-related side effects in Ugandan PLHIV. We will test the Med Safety(R) mobile phone-based app, developed by a European drug safety project. The app has been adapted for Uganda's National Drug Authority (NDA) by the UK's Medicines and Healthcare products Regulatory Agency (MHRA) but isn't yet widely used. The app will enable PLHIV to report side effects directly to NDA. In return, NDA will provide PLHIV with updates on drug safety and take actions to safeguard their health.

By the end of the project we will know the main clinical risk factors for side effects in people treated with DTG or DTG with IPT in Uganda and the genetic risk factors for developing high blood sugar. This will form the basis for personalised treatment in the future. In the longer term, our work has the potential to benefit those living throughout sub-Saharan Africa and beyond. The risk factors for drug-related side effects seen in Uganda could give insight into the complex interplay between clinical, genetic and environmental factors in other population groups. Our learning from deploying the Med Safety(R) app across a population that encompasses large, developed cities and isolated rural areas will be invaluable for wider global efforts in drug safety monitoring. Our strong links with National and International agencies including the NDA, MHRA and WHO will help to ensure that our work improves the safety of PLHIV.

Uganda recently rolled-out dolutegravir (DTG)-containing antiretroviral therapy (ART) alongside Isoniazid Preventive Therapy (IPT) to prevent active tuberculosis in people living with HIV (PLHIV). The safety of DTG and concomitant DTG and IPT (DTG+IPT) has been studied in some populations, however, the lack of a strong pharmacovigilance (PV) system in Uganda means that we do not know the incidence of or risk factors for adverse drug reactions (ADRs) to these drugs in Ugandan PLHIV.

We shall recruit a clinical cohort of ART-naïve and ART-experienced Ugandan PLHIV to i) determine the incidence, characteristics and risk factors for ADRs linked to DTG- or DTG+IPT; and; ii) investigate the prevention, monitoring and management of DTG- and DTG+IPT-linked ADRs. This cohort will comprise 10,000 PLHIV recruited from eight ART-sites from across Uganda, with all PLHIV receiving DTG or DTG+IPT from these sites eligible for inclusion. Within this cohort, we will recruit participants for a nested case-control genome-wide association study to identify genetic polymorphisms associated with DTG-associated hyperglycaemia, the ADR of most pressing concern in this population.

We shall also recruit a 15,000-strong 'mobile app cohort' to investigate whether the Med Safety(R) mobile application, developed by the European Union WEB-RADR programme, can improve PV through self-reporting of ADRs by PLHIV to the National Dug Authority (NDA); embedding the practice of digital PV among PLHIV. We will evaluate whether interventions involving the app are effective at increasing ADR reporting by PLHIV and whether those suffering from ADRs receive attention from clinicians, NDA and Ministry of Health. This work underpins potential national roll-out of Med Safety(R) among PLHIV in collaboration with Uganda's National Pharmacovigilance Centre at NDA.