The transition to dolutegravir and other new antiretrovirals in low-income and middle-income countries

Abstract

: There are currently approximately 16 million people taking NNRTI-based first-line treatment in low-income and middle-income countries. Most of these patients are using the combination of tenofovir (TDF), lamivudine (3TC) and efavirenz (EFV). The integrase inhibitor dolutegravir (DTG) has shown an improved safety profile compared with EFV in randomized studies. DTG also has a high barrier to development of drug resistance. New co-formulated tablets with TDF/3TC/DTG are being introduced into LMICs, for a median price of $75 per person-year. The prodrug of TDF, tenofovir alafenamide (TAF) is cheaper to manufacture than TDF. A combined pill with TAF/3TC/DTG is also being launched in LMICs, at a similar low price. However, the clinical development programmes for DTG and TAF did not include extensive analysis of several key populations: pregnant women, people with HIV-tuberculosis (TB) coinfection taking rifampicin-based treatment, and treatment-naive or pretreated patients with NRTI drug resistance. An observational study in Botswana has shown an increased risk of neural tube defects when dolutegravir is used in early pregnancy. In LMICs, only 50% of patients have access to regular viral load testing, and genotypic resistance testing is rarely performed. There is currently no clinical data to support switching patients from TDF/3TC/EFV directly to TDF/3TC/DTG if their viral load is either detectable or unknown. New clinical trials and observational studies will be needed to better understand the consequences of this switch of treatment in LMICs. Clinical trials of new antiretrovirals in key populations should be conducted earlier in their development. This will ensure that new treatments can be introduced into LMICs soon after their launch in high-income countries.

Modern Human Immunodeficiency Virus Therapy: Progress and Prospects

“…Because the mass dose of dolutegravir is so much lower than that of efavirenz (50 mg/day vs. 600 mg/day), the drug can be produced and distributed generically for a fraction of the cost of current efavirenz‐based regimens. The estimated cost of a three‐drug generic STR of dolutegravir plus lamivudine plus tenofovir disoproxil fumarate is about US $75 per‐person‐per‐year, less than half that of any currently available three‐drug regimen . Dolutegravir's cost, combined with its excellent efficacy and safety profile, has prompted the WHO to recommend transitioning to dolutegravir‐based regimens as the preferred global first‐line standard…”

“…Dolutegravir does not cause birth defects in pregnant rats or rabbits, and similar findings have not been seen in other countries where dolutegravir is used or in pregnant women taking other integrase inhibitors. This observation complicates the planned global rollout of dolutegravir as a first‐line drug for all, given that ~50% of patients infected with HIV in many parts of the world are women, and most are of child‐bearing age . It is important to note that postmarketing surveillance for pregnancy outcomes is an integral component of global HIV treatment programs.…”

“…In parts of the world with a high prevalence of HBV, a tenofovir‐containing ART regimen is, therefore, preferred. Switching from an ARV regimen that contains anti‐HBV agents to one without would require screening patients for HBV, because the discontinuation of anti‐HBV antivirals can result in rebound HBV viremia and the risk of acute liver disease …”

“…The estimated cost of a threedrug generic STR of dolutegravir plus lamivudine plus tenofovir disoproxil fumarate is about US $75 per-person-per-year, less than half that of any currently available three-drug regimen. 27 Dolutegravir's cost, combined with its excellent efficacy and STATE of the ART safety profile, has prompted the WHO to recommend transitioning to dolutegravir-based regimens as the preferred global firstline standard. 19 A recent preliminary report from a passive surveillance study of birth outcomes in Botswana found a fourfold increase in neural tube defects in a small number of infants born to women taking dolutegravir at the time of conception, as compared to the expected neural tube defect rate in that country.…”

“…This observation complicates the planned global rollout of dolutegravir as a first-line drug for all, given that ~50% of patients infected with HIV in many parts of the world are women, and most are of child-bearing age. 27 It is important to note that postmarketing surveillance for pregnancy outcomes is an integral component of global HIV treatment programs. Sometimes this surveillance has yielded surprising results; for example, although initial reports suggested possible teratogenicity of efavirenz in primates, this drug was later shown to be safe and nonteratogenic in pregnant women.…”