7.5.1 Second-line ART for adults and adolescents

Consolidated ARV guidelines, June 2013

Rationale and supporting evidence

PI options for second-line ART

Since first-line ART should preferably be based on an NNRTI, PI-based regimens are recommended for second-line therapy. Of the PI options, ATV/r and LPV/r are preferred. DRV/r is an alternative but is currently not available as a fixed-dose combination, although one is in development. The other PIs (FPV/r, IDV/r and SQV/r) are not available as heat-stable fixed-dose combinations and/or are associated with high pill burden and higher frequency of side effects.

The Guidelines Development Group emphasized the importance of simplifying second-line ART by reducing the pill burden and limiting the number of preferred second-line regimens that could be used across populations (adults, adolescents, children, pregnant women and people coinfected with TB, HBV and HCV). The use of less toxic, more convenient and more efficacious heat-stable fixed-dose combinations was also considered critical.

A systematic review (Web Annex of data from six clinical trials comparing drugs used for second-line ART (ATV/r, LPV/r and DRV/r) concluded that there was no evidence to support changing the recommendation in the 2010 guidelines (221–226). These studies showed low- to very-low-quality evidence (downgraded in the GRADE evaluation primarily for indirectness and imprecision) for using ATV/r or DRV/r (once-daily) over LPV/r (twice-daily) or vice versa as preferred boosted PI options. ATV/r was considered to be comparable to LPV/r in one trial among ART-experienced individuals (221).

In a trial among ART-naive individuals, ATV/r showed a better virological response and better retention in care when compared with LPV/r (224). In two studies, people receiving DRV/rcontaining regimens also showed better virological response and retention in care than people receiving LPV/r, both in treatment-naive and experienced people (222,226). DRV/r has been used for second-line therapy in high-income settings. However, two key factors currently preclude DRV/r as a preferred option in these guidelines. These include the high cost and it not being available as a heat-stable fixed-dose combination. Additional research is required to better understand sequencing strategies for PIs in second- and third-line therapy.

The different drug toxicity profiles of ATV/r and LPV/r, the contraindication of ATV/r and rifampicin and the lack of WHO approval for its use in children younger than six years provide additional grounds for maintaining both PIs as equal options (Table 7.19). The Guidelines Development Group recommended that DRV/r should be maintained as a preferred third-line drug. However, using it as an alternative option to LPV/r or ATV/r for second-line therapy can be considered, especially when competitively priced fixed-dose combinations are available.