Virologic efficacy of tenofovir, lamivudine and dolutegravir as second-line antiretroviral therapy in adults failing a tenofovir-based first-line regimen

Abstract

Objective: Recycling tenofovir and lamivudine/emtricitabine (XTC) with dolutegravir would provide a more tolerable, affordable, and scalable second-line regimen than dolutegravir with an optimized nucleoside reverse transcriptase inhibitor (NRTI) backbone. We evaluated efficacy of tenofovir/lamivudine/dolutegravir (TLD) in patients failing first-line tenofovir/XTC/efavirenz or nevirapine.

Design: Single arm, prospective, interventional study.

Setting: Two primary care clinics in Khayelitsha, South Africa.

Participants: Sixty adult patients with two viral loads greater than 1000 copies/ml.

Intervention: Participants were switched to TLD with additional dolutegravir (50 mg) for 2 weeks to overcome efavirenz induction.

Primary outcome: Proportion achieving viral load less than 50 copies/ml at week 24 using the FDA snapshot algorithm.

Results: Baseline median CD4+ cell count was 248 cells/μl, viral load 10 580 copies/ml and 48 of 54 (89%) had resistance (Stanford score ≥15) to one or both of tenofovir and XTC. No participants were lost to follow-up. At week 24, 51 of 60 [85%, 95% confidence interval (CI) 73-93%] were virologically suppressed, six had viral load 50-100 copies/ml, one had viral load 100-1000 copies/ml, one no viral load in window, and one switched because of tenofovir-related adverse event. No integrase mutations were detected in the one participant meeting criteria for resistance testing. Virological suppression was achieved by 29 of 35 (83%, 95% CI 66-93%) with resistance to tenofovir and XTC, 11 of 13 (85%, 95% CI 55-98%) with resistance to XTC, and six of six (100%, 95% CI 54-100%) with resistance to neither.

Conclusion: A high proportion of adults switching to second-line TLD achieved virologic suppression despite substantial baseline NRTI resistance and most not suppressed had low-level viraemia (≤100 copies/ml). This suggests recycling tenofovir and XTC with dolutegravir could provide an effective second-line option.

Figure 1. Study recruitment and enrolment

Figure 2. Proportion suppressed at each study visit in the modified intention-to-treat (mITT)

NRTI (nucleoside reverse transcriptase inhibitor), VL (viral load), XTC (lamivudine or emtricitabine) * Genotypic resistance was classified using the Stanford algorithm (version 8.9-1), with a score ≥15 indicating at least low-level resistance. Results were categorised as 6/54 having 2 fully active NRTIs (both with a Stanford score <15), 13/54 with resistance to lamivudine (3TC) only (tenofovir with a Stanford score <15 and XTC with a Stanford score ≥15), 0/54 with resistance to tenofovir only and 35/54 with resistance to both NRTIs (both with a Stanford score ≥15)⁷

Figure 3. Tenofovir diphosphate (TFV-DP) dried blood spot concentrations at baseline, week 12 and week 24

TFV-DP concentration, used as a marker of adherence, was categorised using the thresholds defined by Anderson et al²³ as:

1. <350 fmol/punch (equivalent of men: <1.2 doses per week and women: <0.6 doses per week)

2. 350-700 fmol/punch (men: 1.2 -3.2 doses per week and women: 0.6 -2.0 doses per week)

3. 700-1250 fmol/punch (men: 3.2-6 doses per week and women: 2.0-5.3 doses per week)

4. 1250 fmol/punch (men: >6 doses per week and women: >5.3 doses per week)