Challenging the dogma of genotype-defined resistance to ARVs

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HIVMedGenotype-defined resistance to antiretrovirals supposedly predicts future virological failure. Findings from clinical studies, including the 144-week results from the EARNEST trial, challenge this decades-long dogma, certainly when it comes to nucleoside analogues.

The World Health Organisation (WHO) currently recommends second-line treatment with two nucleoside reverse-transcriptase inhibitors (NRTIs) and a boosted protease inhibitor. However, there is evidence for widespread resistance to NRTIs after virological failure of first-line treatment in low-income countries, which might limit future treatment options.

The EARNEST trial was set up to evaluate alternatives for second-line treatment, including the current WHO recommendation, which involves sequencing without genotype guidance using virological, immunological, and clinical failure. The novel combination of two drug classes, the integrase inhibitor raltegravir with the boosted protease inhibitor ritonavir-boosted lopinavir (LPV/r), was predicted to outperform the control of two NRTIs plus LPV/r.

Patients in the EARNEST trial, identified through the WHO definitions of failure retrospectively, had extensive resistance at randomisation, 95% of patients had at least one NRTI mutation, and 59% of patients had no active NRTIs. Despite extensive NRTI resistance, the control of NRTIs plus LPV/r outperformed the other non-NRTI groups, with 317 (86%) of 426 patients having HIV RNA suppression below 400 copies per mL by week 144, compared with 312 (81%) of 433 patients in the LPV/r plus raltegravir group and 292 (78%) of 418 patients in the LPV/r monotherapy group. Findings from two other randomised trials, SELECT and SECOND-LINE, have also shown no benefits for protease inhibitor plus integrase inhibitor second-line combinations.

These results suggest that NRTIs are retaining high levels of efficacy despite the predictions of failure from genotypic resistance. In a subgroup analysis of the NRTI plus LPV/r group of EARNEST, patients who were taking NRTIs with no predicted activity had the highest levels of viral suppression. This effect was also seen in two other randomised trials of NRTI plus protease inhibitor (with ritonavir) combinations as second-line treatment (table). In the SELECT trial, which also evaluated NRTI plus LPV/r as second-line treatment, there was no benefit from resistance testing before starting second-line treatment. These negative correlations between viral suppression and number of active NRTIs were independent of potential confounding effects of adherence levels or baseline viral load in multivariate analysis of SELECT, EARNEST, and SECOND-LINE.

Investigators of the DAWNING study compared the standard second-line combination of two NRTIs plus LPV/r with two NRTIs (at least one of which had efficacy, according to genotyping) plus the integrase inhibitor dolutegravir. DAWNING was stopped early after the NRTI plus dolutegravir group showed viral suppression rates higher than the control group (82% vs 69% at week 24, p<0·001). Patients in the DAWNING study taking fewer than two active NRTIs had higher rates of suppression compared with those taking two fully active NRTIs, consistent again with studies of treatment based on protease inhibitor (with ritonavir; table).

Fixed-dose combinations of tenofovir, lamivudine, and dolutegravir are now available for US$75 per person-year in low-income countries, a price far below the standard price of protease inhibitors, or current first-line therapy. Dolutegravir was safer and more effective than LPV/r in DAWNING. So, should the single-dose combination of tenofovir–lamivudine–dolutegravir become the new WHO-recommended second-line treatment, over two NRTIs plus protease inhibitor? There are two key unanswered questions. First, the DAWNING study excluded patients with no active NRTIs at baseline. Can we be sure that the high retained efficacy of NRTIs combined with protease inhibitors will also be seen when NRTIs are combined with dolutegravir? Secondly, a high percentage of patients in low-income countries will be taking first-line tenofovir plus lamivudine and efavirenz, so a switch to second-line tenofovir–lamivudine–dolutegravir will involve changing only one antiretroviral. Will the benefits of recycled NRTIs be retained in this situation – will dolutegravir behave like a protease inhibitor?

The transition to tenofovir–lamivudine–dolutegravir for both first-line and second-line treatment, which has started in countries like Botswana (for first-line) and likely to expand across the region in 2018, has the potential to be an important step forward in simplifying HIV treatment with improved tolerability and adherence at a cheaper cost. Real-time resistance surveillance systems will be essential to ensure that this transition is a success. The results from EARNEST and other similar clinical trials suggest that NRTIs will retain efficacy in second-line treatment when used with protease inhibitors. 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. Finally, the interpretation and use of routine genotype resistance testing, an expensive and complex test to interpret, requires reappraisal in the context of modern antiretroviral combinations.

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

The Lancet material
The Lancet Infectious Diseases abstract
WHO Guidelines

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