Switching to second-line ART – we need to do better

Monitoring and switching of first-line antiretroviral therapy in sub-Saharan Africa: collaborative analysis of adult treatment cohorts.

Haas AD, Keiser O, Balestre E, Brown S, Bissagnene E, Chimbetete C, Dabis F, Davies MA, Hoffmann CJ, Oyaro P, Parkes-Ratanshi R, Reynolds SJ, Sikazwe I, Wools-Kaloustian K, Zannou DM, Wandeler G, Egger M, for IeDea Southern Africa EA, West A. Lancet HIV. 2015 Jul 1;2(7):e271-e278.

Background: HIV-1 viral load testing is recommended to monitor antiretroviral therapy (ART) but is not universally available. The aim of our study was to assess monitoring of first-line ART and switching to second-line ART in sub-Saharan Africa.

Methods: We did a collaborative analysis of cohort studies from 16 countries in east Africa, southern Africa, and west Africa that participate in the international epidemiological database to evaluate AIDS (IeDEA). We included adults infected with HIV-1 who started combination ART between January, 2004, and January, 2013. We defined switching of ART as a change from a non-nucleoside reverse-transcriptase inhibitor (NNRTI)-based regimen to one including a protease inhibitor, with adjustment of one or more nucleoside reverse-transcriptase inhibitors (NRTIs). Virological and immunological failures were defined according to WHO criteria. We calculated cumulative probabilities of switching and hazard ratios with 95% CIs comparing routine viral load monitoring, targeted viral load monitoring, CD4 monitoring, and clinical monitoring, adjusting for programme and individual characteristics.

Findings: Of 297 825 eligible patients, 10 352 (3%) switched to second-line ART during 782 412 person-years of follow-up. Compared with CD4 monitoring, hazard ratios for switching were 3·15 (95% CI 2·92–3·40) for routine viral load monitoring, 1·21 (1·13–1·30) for targeted viral load monitoring, and 0·49 (0·43–0·56) for clinical monitoring. Of 6450 patients with confirmed virological failure, 58·0% (95% CI 56·5–59·6) switched by 2 years, and of 15 892 patients with confirmed immunological failure, 19·3% (18·5–20·0) switched by 2 years. Of 10 352 patients who switched, evidence of treatment failure based on one CD4 count or viral load measurement ranged from 86 (32%) of 268 patients with clinical monitoring to 3754 (84%) of 4452 with targeted viral load monitoring. Median CD4 counts at switching were 215 cells per μL (IQR 117–335) with routine viral load monitoring, but were lower with other types of monitoring (range 114–133 cells per μL).

Interpretation: Overall, few patients switched to second-line ART and switching happened late in the absence of routine viral load monitoring. Switching was more common and happened earlier after initiation of ART with targeted or routine viral load testing.

Abstract access  [1]

Editor’s notes: Routine viral load monitoring should allow the early identification of first-line antiretroviral therapy (ART) failure, allowing prompt switch to second-line ART. Prolongation of treatment with a failing regimen compromises future therapeutic options (through the accumulation of drug resistance mutations) and potentially leads to increased morbidity and mortality. Previous reports from Africa have suggested that surprisingly few people switch to second-line therapy, even in programmes with routine viral load monitoring. This raises concerns that there are challenges on the ground with identification and management of ART failure.

This is a comprehensive analysis bringing together data from a number of well-characterised cohorts in Africa. In this analysis, switching to second-line ART was rare (3% over an average of almost three years follow-up). In programmes with routine viral load monitoring, only half of the people with confirmed virologic failure on first-line ART (two viral loads >1000 copies/ml) were recorded as having been switched to second-line ART. Furthermore, half of the people that were switched to a second-line regimen did not have evidence of confirmed virologic failure, suggesting that some may have been switched too early without first attempting adherence programmes which may achieve re-suppression on first-line ART. Unsurprisingly, rates of switching were lower in programmes with CD4+ monitoring (with or without targeted viral load testing) or clinical monitoring alone. 

While guidelines and algorithms around identification and management of first-line ART failure are relatively clear and straightforward, translating this into action on the ground seems to be difficult. At least part of this is likely to be due to the lack of tools to reliably measure adherence and the consequent difficulty that frontline health care workers have in identifying people that truly require a switch to second-line ART. Moreover, most programmes still do not routinely monitor indicators relating to virologic suppression or treatment failure and so this might not be seen as a priority by health care workers and programme managers. There is a need for research to explore how best to maximise virologic suppression in resource-constrained settings, as well as studies to evaluate the impact of programmes such as point-of-care viral load testing.

Epidemiology [4], Health care delivery [5], HIV Treatment [6]
Africa [7]
Burkina Faso [8], Côte d'Ivoire [9], Guinea-Bissau [10], Kenya [11], Lesotho [12], Malawi [13], Mali [14], Mozambique [15], Nigeria [16], South Africa [17], Togo [18], Uganda [19], United Republic of Tanzania [20], Zambia [21], Zimbabwe [22]
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