Pharmacovigilance in low‐ and middle‐income countries: A review with particular focus on Africa

Dolutegravir (S/GSK1349572), a once-daily, unboosted integrase inhibitor, was recently approved in the United States for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in combination with other antiretroviral agents. Dolutegravir, in combination with abacavir-lamivudine, may provide a simplified regimen. We conducted a randomized, double-blind, phase 3 study involving adult participants who had not received previous therapy for HIV-1 infection and who had an HIV-1 RNA level of 1000 copies per milliliter or more. Participants were randomly assigned to dolutegravir at a dose of 50 mg plus abacavir-lamivudine once daily (DTG-ABC-3TC group) or combination therapy with efavirenz-tenofovir disoproxil fumarate (DF)-emtricitabine once daily (EFV-TDF-FTC group). The primary end point was the proportion of participants with an HIV-1 RNA level of less than 50 copies per milliliter at week 48. Secondary end points included the time to viral suppression, the change from baseline in CD4+ T-cell count, safety, and viral resistance. A total of 833 participants received at least one dose of study drug. At week 48, the proportion of participants with an HIV-1 RNA level of less than 50 copies per milliliter was significantly higher in the DTG-ABC-3TC group than in the EFV-TDF-FTC group (88% vs. 81%, P=0.003), thus meeting the criterion for superiority. The DTG-ABC-3TC group had a shorter median time to viral suppression than did the EFV-TDF-FTC group (28 vs. 84 days, P<0.001), as well as greater increases in CD4+ T-cell count (267 vs. 208 per cubic millimeter, P<0.001). The proportion of participants who discontinued therapy owing to adverse events was lower in the DTG-ABC-3TC group than in the EFV-TDF-FTC group (2% vs. 10%); rash and neuropsychiatric events (including abnormal dreams, anxiety, dizziness, and somnolence) were significantly more common in the EFV-TDF-FTC group, whereas insomnia was reported more frequently in the DTG-ABC-3TC group. No participants in the DTG-ABC-3TC group had detectable antiviral resistance; one tenofovir DF-associated mutation and four efavirenz-associated mutations were detected in participants with virologic failure in the EFV-TDF-FTC group. Dolutegravir plus abacavir-lamivudine had a better safety profile and was more effective through 48 weeks than the regimen with efavirenz-tenofovir DF-emtricitabine. (Funded by ViiV Healthcare; SINGLE ClinicalTrials.gov number, NCT01263015 .).

Background Patients with extensively drug resistant tuberculosis (TB) have limited treatment options with historically poor outcomes. We investigated treatment with 3 oral drugs, bedaquiline (B), pretomanid (Pa) and linezolid (L), (B-Pa-L), with TB bactericidal activity and little pre-existing resistance. Methods Nix-TB is an open label single arm study ongoing at three South African sites evaluating the safety and efficacy of B-Pa-L for 26 weeks for extensively drug-resistant TB or treatment intolerant /non-responsive multidrug-resistant TB. We present the efficacy and safety outcomes for all 109 patients enrolled in the trial followed to the predefined primary endpoint, six months after the end of treatment. Results In the intent to treat analysis, 98 patients (90%), (95% CI 82.7-94.9%) had a favourable outcome at 6 months after the end of treatment. Six patients died during the early stages of treatment, one withdrew during treatment, one died during follow-up without evidence of relapse, one relapsed, one relapsed and subsequently died during follow up and one was lost to follow-up. The expected linezolid toxicities of peripheral neuropathy (experienced by 81% of patients) and myelosuppression (48%), while common, were manageable, often requiring reductions of dose and/or interruptions in linezolid. Conclusions These results suggest that B-Pa-L is a viable option for tuberculosis patients with highly resistant forms of TB, provided adequate safety management is available. Trial registration: ClinicalTrials.gov Identifier: NCT02333799 Sponsor: Global Alliance for TB Drug Development (TB Alliance)

Two drugs under consideration for inclusion in antiretroviral therapy (ART) regimens for human immunodeficiency virus (HIV) infection are dolutegravir (DTG) and tenofovir alafenamide fumarate (TAF). There are limited data on their use in low- and middle-income countries.