Tenofovir recommended as second-line treatment.

In HIV-1-infected patients, the addition of dolutegravir—an integrase strand-transfer inhibitor—to nucleoside reverse-transcriptase inhibitor (NRTI) treatment is effective, even in those with extensive resistance to NRTIs, according to a recent noninferiority study published in The New England Journal of Medicine.

Researchers also found that tenofovir was as effective as zidovudine as second-line treatment in these patients.

“The World Health Organization recommends dolutegravir with two nucleoside reverse-transcriptase inhibitors (NRTIs) for second-line treatment of human immunodeficiency virus type 1 (HIV-1) infection. Evidence is limited for the efficacy of this regimen when NRTIs are predicted to lack activity because of drug resistance, as well as for the recommended switch of an NRTI from tenofovir to zidovudine,” according to Nicholas I. Paton, MD, of the National University of Singapore, and fellow researchers.

For this two-by-two factorial, open-label, noninferiority trial, Paton et al randomized 464 patients at seven sub-Saharan African sites in Uganda, Kenya, and Zimbabwe who were failing first-line HIV treatment (viral load ≥1,000 copies/ml) to treatment with either dolutegravir (50 mg once daily) or ritonavir-boosted darunavir (100 mg/800 mg) in combination with tenofovir (300 mg) or zidovudine (300 mg). All patients also received lamivudine (150 mg twice daily).

The primary efficacy outcome measure was a viral load of <400 copies/ml at week 48, as assessed with the FDA snapshot algorithm. In the intention-to-treat population, this was achieved by 90.2% of patients treated with dolutegravir, and 91.7% of those treated with darunavir (difference: −1.5 percentage points; 95% CI: −6.7 to 3.7; P=0.58), showing noninferiority but not superiority of dolutegravir. The primary outcome was also achieved by 92.3% of patients treated with tenofovir and 89.6% of those treated with zidovudine (difference: 2.7 percentage points; 95% CI: −2.6 to 7.9; P=0.32), showing noninferiority of tenofovir, but not superiority.

“We did not find evidence of the superiority of dolutegravir that was seen in three previous trials in which dolutegravir was compared with a protease inhibitor, each given with NRTIs, in first-line or second-line therapy. The absence of superiority may reflect a better side-effect profile or a greater potency of darunavir as compared with those of the alternative protease inhibitors that were used in some earlier trials, the effect of the NRTI resistance milieu… or differences among trials in their approach to the detection and management of nonsuppressed viral load,” specified Paton and colleagues.

Even in patients in whom NRTIs were predicted to have no activity, researchers found that 90% of those treated with dolutegravir had a viral load of less than 400 copies/ml. Virologic rebound was confirmed in 6.0% of patients treated with dolutegravir vs 5.7% in the darunavir group. Increases in CD4+ cell counts were also similar between the two groups.

“Responses were good in subgroups of patients with a high viral load, those with a low CD4+ cell count, and, crucially, those for whom NRTIs that had no predicted activity had been prescribed,” noted researchers.

There were no between-group differences in the rate of adverse events, and overall, 30 Grade 3/4 adverse events occurred, two of which led to discontinuation of zidovudine.

Paton and colleagues noted that throughout the world, first-line therapy is tenofovir-based in most patients, who then switch to zidovudine as second-line therapy. But their finding that tenofovir is noninferior to zidovudine “indicates that the WHO guidelines could be simplified to recommend maintaining tenofovir and lamivudine at the time of a switch to second-line treatment.” This would be beneficial not only for patients due to zidovudine’s recommended twice-daily dosing and worse side effect profile compared with tenofovir, but for programs as well as the maintenance of treatment with tenofovir would allow for better drug standardization, they added.

“Our trial provides evidence to support broad use of dolutegravir in the public health approach and provides confidence that the use of this drug leads to high levels of virologic suppression even when used with NRTIs that are predicted to have no activity. Our results also support maintaining tenofovir in second-line therapy rather than switching to zidovudine,” concluded Paton and colleagues.

Study limitations include its open-label treatment protocol.

  1. In HIV-infected patients, dolutegravir added to treatment with nucleoside reverse-transcriptase inhibitors (NRTIs) is effective, even in those with extensive resistance to NRTIs.

  2. Results support broad use of dolutegravir as first-line treatment for HIV, and maintenance with tenofovir as second-line treatment.

Liz Meszaros, Deputy Managing Editor, BreakingMED™

This study was supported by Janssen.

Paton reports grants and non-financial support from Janssen during the conduct of the study; grants from Janssen, personal fees from AbbVie, and personal fees, non-financial support, and other from Sanofi outside the submitted work.

Cat ID: 339

Topic ID: 338,339,284,339,730,125,190,27,192,151,925