Resistance in Patients Failing Integrase Strand Transfer Inhibitors: A Call to Replace Raltegravir With Dolutegravir in Third-Line Treatment in South Africa

Abstract

Data on integrase resistance patterns in low- and middle-income countries (LMICs) is scarce. We assessed genotypic drug resistance in 43 patients with virological failure on integrase strand transfer inhibitors (INSTIs) containing regimens as part of the third-line treatment program in South Africa. Of the raltegravir (RAL)-exposed patients 20 of 34 (59%) had ≥1 major INSTI mutation, including 2 (6%) with dolutegravir (DTG) cross-resistance. Dolutegravir resistance was detected in 1 of 4 DTG-exposed patients. Replacing RAL with DTG may reduce the risk of INSTI mutations. We recommend DTG drug resistance monitoring when DTG is introduced at a larger scale in LMICs.

HIV-1 Subtype C Drug Resistance Mutations in Heavily Treated Patients Failing Integrase Strand Transfer Inhibitor-Based Regimens in Botswana

“…In our study, E138K (n = 5), S147G (n = 4), Q148R (n = 4) and N155H (n = 4) where the most frequent INSTI DRMs identified. This is in contrast to Y143C/R/H (n = 12), N155H (n = 9) and T97A(n = 13) from a similar study in the region where HIV-1C also predominates [ 29 ]. The longer duration of cART treatment of our participants with subsequent accumulation of mutations could explain these differences.…”

HIV-1 integrase resistance associated mutations and the use of dolutegravir in Sub-Saharan Africa: A systematic review and meta-analysis

“…Ten studies reported data concerning HIV genetic diversity within their settings [25,28,29,33,[40][41][42][43][44]46]; we thus confirmed the circulation of HIV-2 in West Africa (Senegal), HV-1 group O, HIV-1 CRF02_AG and CRF18_cpx in Central Africa (Cameroon), mostly HIV-1 subtype C and few HIV-1 subtype G in Southern Africa (South Africa and Botswana), HIV-1 subtype A, subtype C and subtype D in East Africa (Uganda and Kenya).…”

Pan-resistant HIV-1: what's next?

“…8 In addition, a number of cases with resistance to all four classes of antiretrovirals available in LMICs have already been reported in sub-Saraharan Africa, meaning that these cases are essentially untreatable in this context. [9][10][11][12] These cases include one individual in Zimbabwe 11 and one individual in Botswana, 10 both of whom had virological failure to a salvage regimen containing ritonavir-boosted…”

“…12 A 2019 study done in South Africa reported three patients with intermediate-to-high level dolutegravir resistance, two of whom had been exposed to raltegravir, and the remaining patient had been exposed to a salvage regimen containing dolutegravir. 9 The magnitude of the impact that emerging multidrug-resistant HIV could have on public health is a function of the number of available therapeutic options, with the important caveat that HIV treatment is a lifelong intervention. There is thus a strong imperative for LMICs to safeguard the limited number of available drug options, especially among groups that are most at risk of multidrug resistance.…”