Laboratory Based Surveillance of HIV-1 Acquired Drug Resistance in Cameroon: Implications for Use of Tenofovir-Lamivudine-Dolutegravir (TLD) as Second- or Third-Line Regimens

Abstract

Increased HIV drug resistance (HIVDR) with antiretroviral therapy (ART) rollout may jeopardize therapeutic options, especially in this era of transition to fixed-dose tenofovir-lamivudine-dolutegravir (TLD). We studied acquired HIVDR (ADR) patterns and describe potentially active drugs after first- and second-line failure in resource-limited settings (RLS) like Cameroon. A laboratory-based study with 759 patients (≥15 years) experiencing virological failure was carried out at the Chantal Biya International Reference Centre (CIRCB), Yaoundé, Cameroon. Socio-demographic, therapeutic and immunovirological data from patient records were analysed according to HIV-1 genotypic profiles. Median (IQR) ART-duration was 63 (50-308) months. Median CD4 and viremia were 153 (IQR:50-308) cells/mm³ and 138,666 (IQR:28,979-533,066) copies/mL, respectively. Overall ADR was high (93.4% first-line; 92.9%-second-line). TDF, potentially active in 35.7% of participants after first-line and 45.1% after second-line, suggested sub-optimal TLD-efficacy in second-line (64.3%) and third-line (54.9%). All PI/r preserved high efficacy after first-line failure while only DRV/r preserved high-level efficacy (87.9%) after second-line failure. In this resource-limited setting (RLS), ADR is high in ART-failing patients. PI/r strategies remain potent backbones for second-line ART, while only DRV/r remains very potent despite second-line failure. Though TLD use would be preferable, blind use for second- and third-line regimens may be sub-optimal (functional monotherapy with dolutegravir) with high risk of further failure, thus suggesting strategies for selective ART switch to TLD in failing patients in RLS.

Keywords: TLD; acquired drug resistance; first-line failure; laboratory-based surveillance; second-line failure; tenofovir-lamivudine-dolutegravir.

Figure 1

Mutational profiles for (a) NRTI, (b) NNRTI and (c) PI/r resistance.

Figure 1

Mutational profiles for (a) NRTI, (b) NNRTI and (c) PI/r resistance.

Figure 2

Potential efficacy of commonly used antiretroviral drugs with respect to therapeutic lines. The figure shows the percentage of participants (y axis) in whom the listed antiretroviral drugs (x axis) appeared effective after first-line (left) and second-line (right) failure. Note the high levels of effective DRV/r even after second-line failure. AZT: zidovudine; TDF: tenofovir; 3TC: lamivudine; ABC: abacavir; EFV: efavirenz; NVP: nevirapine; ATV/r: atazanavir; LPV/r: lopinavir; DRV/r: darunavir.

Figure 3

Efficacy of nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) after (a) first- and (b) second-line failures. This figure shows the percentage of participants with preserved efficacy (y axis) of locally available NRTIs (zidovudine (AZT), abacavir (ABC) and tenofovir (TDF); x axis), with respect to NRTI exposure in both first- and second-line failing patients. Note the poor levels of efficacy of ABC and TDF after sole exposure to AZT in both first- and second-line regimens are explained by cross-resistance due to thymidine analogue mutations.

Figure 4

Efficacy of protease inhibitors (PI/r) with respect to PI/r exposure. The figure demonstrates the percentage of participants with preserved efficacy (y axis) of PI/r (x axis) after PI/r exposure. ‘Others’ refers to older protease inhibitors such as nelfinavir and indinavir. We note that irrespective of the initial PI/r used, viral susceptibility to DRV/r was observed in a good number of second-line failing participants. ATV/r: atazanavir; LPV/r: lopinavir; DRV/r: darunavir.