Longer-term effectiveness of protease-inhibitor-based second line antiretroviral therapy in four large sub-Saharan African clinics

Highlights

• Data on longer-term effectiveness of second line ART in Africa are limited.

• We conducted a retrospective study at 4 HIV treatment centers in Africa to estimate the probability of 2^nd line ART failure.

• Among 2,191 subjects initiating 2^nd line, the 5-year estimated probability of virologic failure was 15%.

• The effectiveness of the current 2^nd line ART regimens in Africa appears to be very good.

Summary

Objectives

Data on the longer-term effectiveness of second line combination antiretroviral therapy (ART) in sub-Saharan Africa (SSA) are lacking. We sought to assess the probability and determinants of 2nd line ART failure in SSA.

Methods

A retrospective, multi-center study of 2nd line ART initiated between 2005 and 2017 at four ART centers in Ethiopia, Ghana and Uganda. Main outcome measure was virologic failure (VF) defined as VL>1000 copies/ml after >6 months on 2nd line therapy. Predictors of VF and virologic re-suppression on 2nd line were evaluated using Cox Proportional Hazards and multivariable logistic regression models, respectively.

Results

2191 subjects started 2nd line therapy, 61.5% females. Switching from 1st line (56.4% NVP-based, 70.3% including thymidine-analogues) to 2nd line therapy occurred after mean of 4.1 years. 98.9% of patients started boosted PI with NRTI backbone (TDF+3TC/FTC 67.3%, AZT+3TC 18.5%, others 14.2%). There were 267 (12.0%) VF with a 5-year estimated probability of 15.0% (95% CI 13.2–16.9). Key determinants of VF were concomitant rifampicin use (aHR 2.50 [95% CI 1.54–4.05]) and clinical/immunological failure versus virologic failure as reason for switching therapy (aHR, 0.53 [0.33–0.86]). 138 of 267 (51.7%) subsequently achieved virologic re-suppression and predictors included HIV RNA levels at 2nd-line failure: +1 log higher aOR 0.59 [0.43–0.80], experiencing change within 2nd line ART before VF: aOR 0.17 [0.05–0.56], and more recent calendar year of 2nd line initiation: aOR 0.85 [0.75–0.94].

Conclusions

The effectiveness of current 2nd line ART regimens in SSA is good but challenged by interactions with TB therapy.

Introduction

Of the 37 million people living with HIV globally by 2016, 70% were resident in sub-Saharan Africa (SSA) where a massive roll-out of anti-retroviral therapy has ensued since 2003.¹ First line therapy comprising of two nucleoside reverse transcriptase inhibitors (NRTIs) and a non-nucleoside reverse transcriptase inhibitor (NNRTI) is delivered using a public health approach recommended by the World Health Organization (WHO) and has been reportedly effective with outcomes comparable to those in high-income country settings.2, 3, 4 However, failure on first line therapy is often detected late due to unavailability of routine viral load monitoring and reliance on less sensitive indicators such as clinical and immunological failure often culminating in prolonged exposure to failing first line regimens.5, 6 As a result, second line therapy which comprises of a dual backbone of NRTIs and a boosted protease inhibitor (PI) is potentially challenged by extensive cross-resistance to the second line NRTIs, lack of resistance testing before switching to an individualized and optimized NRTI backbone, drug interactions between PIs and rifampin used to treat tuberculosis and generally a limited repertoire of potential options for second line therapy.

The landmark EARNEST trial in sub-Saharan Africa reported between 55% and 64% probability of good HIV replication control on the three arms of PI-based second line therapy at 96 weeks⁷ and these favorable outcomes were sustained at 144 weeks.⁸ Systematic reviews and meta-analytic data of clinical trials have confirmed the efficacy of second-line therapy among Africans.9, 10, 11 Outside the pristine settings of clinical trials, short-to-medium term outcomes on second line therapy have been reported to be good.12, 13, 14, 15, 16, 17, 18 There is however very limited data on the longer-term virological effectiveness of second line therapy in resource-limited settings in SSA. As most ART programs in SSA mature into their second and third decades, the longer term effectiveness and durability of second line therapy assumes greater importance due to the predicted increasing numbers of patients failing first line therapy in the coming years and the unavailability of third line therapy for patients who fail second line therapy. In fact, a recent simulation model study has estimated that up to 25.6 million people are expected to receive ART in 2020, of whom 0.5 to 3.0 million will be receiving second-line ART.¹⁹ Furthermore, there is a gap in knowledge on the probability and determinants of virological failure on second line therapy administered under routine treatment settings from a multi-center and multi-national perspective across the African continent. Such information is crucial for strategic planning in developing alternative second line therapies as well as preparations for third line therapies. We sought to narrow the existing gap in knowledge by conducting a retrospective, multi-center study of second line ART initiated between 2005 and 2017 at four ART centers in Ethiopia, Ghana and Uganda. Our objectives were to assess the probability and determinants of second ART failure in SSA over the longer term.