Long-term data do not support raltegravir as second-line therapy

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A second-line HIV regimen containing the integrase inhibitor raltegravir failed to meet its primary endpoint of non-inferiority against standard second-line treatment with nucleoside reverse-transcriptase inhibitors, or NRTIs, according to 144-week data from the EARNEST trial.

Dr James G Hakim, of the University of Zimbabwe Clinical Research Centre, and colleagues said their findings have “important implications for second-line therapy in the public health approach” to HIV.

“The good longer term outcomes with the combination of a protease inhibitor (in this case lopinavir) with two NRTIs provides support for this regimen as the World Health Organisation (WHO)-recommended preferred second-line combination,” they write.

Although WHO recommends NRTIs as part of standard second-line therapy, the world health agency’s 2016 guidelines include raltegravir as an alternative option. To determine whether the drug offered any additional benefit over NRTIs, Hakim and colleagues compared the outcomes of 1,277 patients no longer responding to first-line ART in sub-Saharan Africa who were randomly assigned to a regimen containing: 400 mg of lopinavir plus 100 mg of ritonavir twice daily and two to three clinician-selected NRTIs (n = 426); 400 mg of raltegravir and protease inhibitor twice daily (n = 433); or protease inhibitor monotherapy with an initial 12-week induction of raltegravir and reintroduction of combination ART after 96 weeks (n = 418).

The researchers hypothesised that the protease inhibitor plus raltegravir regimen – two new active drug classes – would be superior to a regimen containing NRTIs. The primary outcome was a viral load less than 400 copies/mL at week 144.

At the end of the study period, the proportion of patients with viral loads less than 400 copies/mL was 86% in the protease inhibitor plus NRTI group vs. 81% in the protease inhibitor plus raltegravir group. Although the raltegravir-containing regimen did not meet the 10% non-inferiority margin, it was not significantly inferior to the NRTI-containing regimen. In the protease inhibitor monotherapy group, 78% of patients had less than 400 copies/mL.

There were no significant differences in the incidence of serious adverse events, grade 3 or 4 adverse events or events that led to treatment modifications, according to the researchers. In the protease inhibitor plus raltegravir group, 7% of patients had resistance to raltegravir and 3% had resistance to lopinavir. In the control group, 3% of patients had resistance to one or more NRTIs and 2% had resistance to lopinavir. Among those who received protease inhibitor monotherapy, 11% had resistance to lopinavir.

“Taking into account the higher cost of raltegravir, the absence of clear advantages of protease inhibitor plus raltegravir seen in any trial and the failure to show non-inferiority consistently across all analyses after 144 weeks of treatment in this trial suggest that there is no compelling reason for national programs to adopt this combination as the standardized second-line therapy in the public health approach to (ART),” Hakim and colleagues wrote.

The researchers suggested that dolutegravir – an integrase strand transfer inhibitor with a high genetic barrier to resistance and longer half-life than settings.

In a related editorial, Dr Andrew M Hill, senior visiting research fellow in the department of translational medicine at the University of Liverpool, and Dr Francois Venter, deputy executive director of the Wits Reproductive Health and HIV Institute, University of the Witwatersrand, noted that several countries are beginning to transition both first- and second-line treatment regimens to include dolutegravir. This could be an “important step” toward simplifying treatment and lowering costs, according to the authors. They estimated that fixed-dose combinations of tenofovir/lamivudine/dolutegravir average $75 per person-year in low-income countries, which is much less than the price of current first-line therapy.

“The results from EARNEST and other similar clinical trials suggest that NRTIs will retain efficacy in second-line treatment when used with protease inhibitors,” they wrote. “We now need to ensure that this protective effect also allows newer drugs such as dolutegravir to be used with recycled NRTIs in second-line treatment.”

Raltegravir is sold under the brand name Isentress (Merck). Lopinavir/ritonavir is sold under the brand name Kaletra (AbbVie).

Background: Millions of HIV-infected people worldwide receive antiretroviral therapy (ART) in programmes using WHO-recommended standardised regimens. Recent WHO guidelines recommend a boosted protease inhibitor plus raltegravir as an alternative second-line combination. We assessed whether this treatment option offers any advantage over the standard protease inhibitor plus two nucleoside reverse-transcriptase inhibitors (NRTIs) second-line combination after 144 weeks of follow-up in typical programme settings.
Methods: We analysed the 144-week outcomes at the completion of the EARNEST trial, a randomised controlled trial done in HIV-infected adults or adolescents in 14 sites in five sub-Saharan African countries (Uganda, Zimbabwe, Malawi, Kenya, Zambia). Participants were those who were no longer responding to non-NRTI-based first-line ART, as assessed with WHO criteria, confirmed by viral-load testing. Participants were randomly assigned to receive a ritonavir-boosted protease inhibitor (lopinavir 400 mg with ritonavir 100 mg, twice per day) plus two or three clinician-selected NRTIs (protease inhibitor plus NRTI group), protease inhibitor plus raltegravir (400 mg twice per day; protease inhibitor plus raltegravir group), or protease inhibitor monotherapy (plus raltegravir induction for first 12 weeks, re-intensified to combination therapy after week 96; protease inhibitor monotherapy group). Randomisation was by computer-generated randomisation sequence, with variable block size. The primary outcome was viral load of less than 400 copies per mL at week 144, for which we assessed non-inferiority with a one-sided α of 0·025, and superiority with a two-sided α of 0·025. The EARNEST trial is registered with ISRCTN, number 37737787.
Findings: Between April 12, 2010, and April 29, 2011, 1837 patients were screened for eligibility, of whom 1277 patients were randomly assigned to an intervention group. In the primary (complete-case) analysis at 144 weeks, 317 (86%) of 367 in the protease inhibitor plus NRTI group had viral loads of less than 400 copies per mL compared with 312 (81%) of 383 in the protease inhibitor plus raltegravir group (p=0·07; lower 95% confidence limit for difference 10·2% vs specified non-inferiority margin 10%). In the protease inhibitor monotherapy group, 292 (78%) of 375 had viral loads of less than 400 copies per mL; p=0·003 versus the protease inhibitor plus NRTI group at 144 weeks. There was no difference between groups in serious adverse events, grade 3 or 4 adverse events (total or ART-related), or events that resulted in treatment modification.
Interpretation: Protease inhibitor plus raltegravir offered no advantage over protease inhibitor plus NRTI in virological efficacy or safety. In the primary analysis, protease inhibitor plus raltegravir did not meet non-inferiority criteria. A regimen of protease inhibitor with NRTIs remains the best standardised second-line regimen for use in programmes in resource-limited settings.

James G Hakim, Jennifer Thompson, Cissy Kityo, Anne Hoppe, Andrew Kambugu, Joep J van Oosterhout, Abbas Lugemwa, Abraham Siika, Raymond Mwebaze, Aggrey Mweemba, George Abongomera, Margaret J Thomason, Philippa Easterbrook, Peter Mugyenyi, A Sarah Walker, Nicholas I Paton

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