HIV-1 drug resistance testing is essential for heavily-treated patients switching from first- to second-line regimens in resource-limited settings: Evidence from routine clinical practice in Cameroon

BackgroundWith the phase-out of stavudine (d4T), change to first-line regimens with zidovudine (AZT) or tenofovir (TDF) in resource-limited settings (RLS) might increase risks of cross-resistance to nucleos(t) ide reverse transcriptase inhibitors (NRTI). This would restrict the scope of switching to the World Health Organisation (WHO)-recommended standard second-line combinations (SLC) without HIV drug resistance (HIVDR)-testing in routine clinical practice.MethodsAn observational study was conducted among 101 Cameroonian patients (55.4% male, median [IQR] age 34 [10-41] years) failing first-line antiretroviral therapy (ART) in 2016, and stratified into three groups according to NRTIs exposure: exposure to both thymidine analogues AZT and D4T (group-A, n=55); exposure to both TDF and AZT or D4T (group-B, n=22); exposure solely to D4T (group-C, n=24). Protease-reverse transcriptase HIVDR was interpreted using the HIVdb penalty scores (60: high-resistance; 20-59: intermediate-resistance; <20: susceptible). The acceptable threshold for potential-efficacy was set at 80%.ResultsThe median [IQR] CD4, viral RNA, and time on ART, were respectively 129 [29-466] cells/l, 71,630 [19,041-368,000] copies/ml, and 4 [2-5] years. Overall HIVDR-level was 89.11% (90/101), with 83.2% harbouring M184V (high-level 3TC/FTC-resistance) and only 1.98% (2/101) major HIVDR-mutations to ritonavir-boosted protease-inhibitors (PI/r). Thymidine-analogue mutations (TAMs)-1 [T215FY (46.53%), M41L (22.77%), L210W (8.91%)], with cross-resistance to AZT and TDF, were higher compared to TAMs-2 [D67N (21.78%), K70R (19.80%), K219QE (18.81%)]. As expected, K65R was related with TDF-exposure: 0% (0/55) in group-A, 22.72% (5/22) group-B, 4.17% (1/24) group-C (p=0.0013). The potential-efficacy of AZT vs. TDF was respectively 43.64% (24/55) vs. 70.91% (39/55) in group-A (p=0.0038); 63.64% (14/22) vs. 68.28% (15/22) in group-B (p=1.0000); and 37.50% (9/24) vs. 83.33% (20/24) in group-C (p=0.0032). CRF02_AG was the prevailing subtype (63.40%), followed by CRF11.cpx (8.91%), A(1) (7.92%), G (5.94%); without any significant effect of the subtype-distribution on HIVDR (92.2% in CRF02_AG vs. 83.8% in non-AG; p=0.204).ConclusionFirst-line ART-failure exhibits high-level NRTI-resistance, with potential lower-efficacy of AZT compared to TDF. Significantly, using our 80% efficacy-threshold, only patients without NRTI-substitution on first-line could effectively switch to SLC following the WHO-approach. Patients with multiple NRTI-substitutions (exposed to both thymidine-analogues and TDF) on first-line ART would require HIVDR-testing to select active NRTIs for SLC