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Initial HIV Treatment With a 2-Drug, Nuke-Sparing Regimen Falls Short

By Josep M. Llibre, M.D., and Benjamin Young, M.D., Ph.D.

March 14, 2014

For many years, we've wondered about the long-term safety of nucleoside/tide reverse transcriptase inhibitors (NRTIs). Our sometimes-lethal experiences with dideoxynucleosides cemented this sentiment, one that lingers today, even with far better nuke family members. Many investigations have looked for proof that a nuke-sparing regimen was as good as our conventional two-nuke-plus-third-drug strategy.

In the open-label European study NEAT 001/ANRS 143, about 800 treatment-naive individuals received first-line antiretroviral therapy (ART) with once-daily boosted darunavir (Prezista) and were randomized to receive either fixed-dose tenofovir/emtricitabine (Truvada) or the twice-daily integrase inhibitor raltegravir (Isentress).

After 96 weeks, similar percentages of individuals across both arms achieved viral loads less than 50 copies/mL (93% vs. 89%) and median CD4 count increases (266 vs. 267). However, among participants with baseline viral loads greater than 100,000 copies/mL (P = .09) or CD4 counts below 200 (P = .02), the differences in responses favored the two-NRTI-plus-boosted-darunavir arm.

Additionally, more treatment-emergent drug resistance was observed in the NRTI-sparing arm, particularly in participants with high baseline viral loads. Bear in mind that only virological failures where viral loads were greater than 500 copies/mL were genotyped, so rates of selected resistance in the raltegravir arm will probably raise when participants with viral loads between 200-500 are genotyped. No benefits in lipid profile were seen when avoiding the two NRTIs, while a significant decrease in the eGFR (estimated glomerular filtration rate -- one method for assessing kidney health) was seen with tenofovir/emtricitabine.

Are these data reassuring enough to make us forget about the early ACTG 5262 data and to signal the beginning of the end of NRTIs for initial therapy? We don't believe so.

Importantly, while impressive in scale, NEAT 001's results need to be confirmed in other studies. Second, the finding of lower efficacy in patients with baseline CD4 counts less than 200 and with high viral loads raises concerns. So, a new NRTI-sparing dual therapy will be rated as alternative and only for selected individuals.

Which other studies presented at CROI 2014 will have lasting impact? Read more of Dr. Llibre and Dr. Young's top picks.


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