High level of HIV drug resistance informs dolutegravir roll-out and optimized NRTI backbone strategy in Mozambique

Abstract

Background HIV drug resistance (HIV-DR) is rising in sub-Saharan Africa in both ART-naive and ART-experienced patients. Objectives To estimate the level of acquired DR (ADR) and pre-treatment DR (PDR) across selected urban and rural sites in Southern Africa, in Mozambique. Methods We conducted two cross-sectional surveys among adult HIV patients (October 2017–18) assessing ADR and PDR. In the (ADR) survey, those on NNRTI-based first-line ART for ≥6 months were recruited (three sites). In the PDR survey, those ART-naive or experienced with ≥3 months of treatment interruption prior were enrolled (eight sites). Results Among 1113 ADR survey participants 83% were receiving tenofovir (TDF)/lamivudine (3TC)/efavirenz (EFV). The median time on ART was 4.5 years (Maputo) and 3.2 years (Tete), 8.3% (95% CI 6.2%-10.6%, Maputo) and 15.5% (Tete) had a VL ≥ 1000 copies/mL, among whom 66% and 76.4% had NNRTI+NRTI resistance, and 52.8% and 66.7% had 3TC+TDF-DR. Among those on TDF regimens, 31.1% (Maputo) and 42.2% (Tete) were still TDF susceptible, whereas 24.4% and 11.5% had TDF+zidovudine (ZDV)-DR. Among those on ZDV regimens, 25% and 54.5% had TDF+ZDV-DR. The PDR survey included 735 participants: NNRTI-PDR was 16.8% (12.0–22.6) (Maputo) and 31.2% (26.2–36.6) (Tete), with a higher proportion (≥50%) among those previously on ART affected by PDR. Conclusions In Mozambique, viral failure was driven by NNRTI and NRTI resistance, with NRTI DR affecting backbone options. NNRTI-PDR levels surpassed the WHO 10% ‘alert’ threshold. Replacing NNRTI first-line drugs is urgent, as is frequent viral load monitoring and resistance surveillance. Changing NRTI backbones when switching to second-line regimens may need reconsideration.

Nevirapine hair and plasma concentrations and HIV-1 viral suppression among HIV infected ante-partum and post-partum women attended in a mother and child prevention program in Maputo city, Mozambique

“…Recent surveys among pregnant women in south rural Mozambique HIV-1 drug resistant mutation (DRM) was around 10% mainly due to NNNRTI and NRTI including NVP, EFV, 3TC, ABC, TDF [ 48 ]. In a survey of general population that included childbearing women as participants in south urban and central rural Mozambique [ 48 ] 83% were on tenofovir (TDF)/ lamivudine (3TC)/efavirenzes (EFV) and the pre-treatment drug resistance PDR (NNRTI) varied from 16.8% to 31.2% in south urban and central rural setting, respectively and mainly due to EFV/NVP drug resistance, mostly among pre-exposed. Acquired drug resistance (ADR) varied from 8.3% to 15.5% and the majority had NNRTI-NRTI dual resistance.…”

“…Acquired drug resistance (ADR) varied from 8.3% to 15.5% and the majority had NNRTI-NRTI dual resistance. The most common NRTI (ADR) was to 3TC/Emtricitabine and Abacavir [ 48 ]. These results support the probability of existence of drug resistance for the most first line drugs currently used for PMTCT reinforcing the need for individual HIV1-RNA and drugs resistance status assessment.…”

“…Similarly, it is well documented NVP/EFV pharmacokinetics is influenced by CYP2B6 single nucleotide polymorphisms (SNPs) [43,44] Populations of African origins have the highest genetic diversity of CYP2B6 mostly causing NVP/EFV low clearance and high plasmatic and hair exposure [44]. A Mozambican study found the frequency of CYP2B6 SNPs (516T/785G of (34.7% and 42.6%) and 516T associated to high NVP toxicity among HIV/AIDS patients [48,49]. Likewise, carriers of CYP2B6 516G>T SNPs under NVP based ART had significantly higher NVP plasma concentration particularly the homozygotes CYP2B6 c.516T/T [41][42][43][44]50] Additionally, over threefold increase on EFV exposure in hair (long) and plasma (short) was reported among African American women [27,51] Nigerian patients [52] carrier of CYP2B6 516TT genotype.…”

HIV-1 Pretreatment and Acquired Antiretroviral Drug Resistance before tenofovir/ /lamivudine /dolutegravir (TLD) roll-out in Mozambique Running title: Pretreatment and Acquired HIV Drug Resistance in Mozambique

“…Documented levels of pre-treatment (transmitted) drug resistance (PDR) for non-nucleoside reverse transcriptase inhibitors (NNRTI) for Low and Middle-Income Countries (LMICs) and across the world in 2015 showed increased rates over the 10% WHO threshold [11][12][13]. For Mozambique, a study in Maputo and Tete provinces also showed levels of NNRTI-PDR above the 10% threshold, and ADR for NNRTI and NRTI in 66% and 76% of the participants, respectively [14]. Altogether such studies were crucial when the country decided to transition to tenofovir/lamivudine/dolutegravir (TLD), and such results helped identify issues with emerging drug resistance [15].…”

Affordable drug resistance genotyping of HIV-1 reverse transcriptase, protease and integrase genes, for resource limited settings

“…Following ART scale-up, there have been global concerns over increasing levels of transmitted HIVDR [3]. Most studies have shown increasing levels of pretreatment HIV-1 drug resistance (PDR) mainly driven by non-nucleoside reverse transcriptase inhibitor (NNRTI) mutations [4,5], with a modelling study by Phillips et al, showing a benefit of changing first-line ART regimens in a setting of high NNRTI resistance [6]. This resulted in the World Health Organization (WHO) recommendation for use of dolutegravir (DTG) in all ART regimens [7], given DTG's better tolerability, less adverse effects, higher genetic barrier to resistance, and availability in a fixed dose combination with tenofovir (TDF) and lamivudine (3TC), i.e.…”