December 15, 2014
We have come a long way from the toxic "D" drugs and that pesky zidovudine, yet the current nucleoside/tide antiretroviral options leave much to be desired. Our two reasonable options -- tenofovir (Viread) and abacavir (Ziagen) -- both have well-described tolerability issues that lead to more than just worry. For those on tenofovir, increases in creatinine, regardless of cause, lead to phone calls and return visits for lab tests. When patients with even a whiff of cardiovascular risk are being sized up for abacavir, it's hand wringing galore.
It is no wonder that there remains interest in nuke-free regimens. Until now, however, the challenge has been to cobble together an effective and well-tolerated regimen.
This year we saw results from a couple of studies that help us understand the perils and potential of tenofovir- and abacavir-free combinations. The first was the ARNS NEAT 001 trial. In this study, over 800 treatment-naive patients were randomized to raltegravir + darunavir (Prezista)/ritonavir (Norvir) versus a control of standard tenofovir/emtrictiabine + darunavir/ritonavir. Virologic failure was significantly more common with raltegravir + darunavir/ritonavir, especially when the patient had a high viral load or low CD4+ cell count. No resistance mutations were detected in the standard of care arm, while at least five cases of integrase resistance were detected in the nuke-sparing arm.
The NEAT results echo those from ACTG study A5262, a single-arm study of the same integrase inhibitor and protease inhibitor combination. (However, the PROGRESS study of raltegravir (Isentress) + lopinavir/ritonavir (Kaletra) versus tenofovir/emtricitabine + lopinavir/ritonavir found no significant differences between these two arms.)
A second study yielded more promising results for the lover of minimalistic antiretroviral therapy. The GARDEL trial examined an interesting regimen of lamivudine (3TC, Epivir) + lopinavir/ritonavir versus tenofovir/emtrictiabine + lopinavir/ritonavir in over 400 treatment-naive patients. Impressively, the dual antiretroviral therapy arm held its own against triple antiretroviral therapy, with similarly low rates of virologic failure. Treatment discontinuations were more common in the triple therapy arm. Two patients in the study had viral drug resistance mutations detected at failure: Both were M184V and in the dual therapy arm.
So, what to make of these trials? Overall, an integrase-protease approach should be undertaken very cautiously in those initiating antiretroviral therapy. Most of those treated with such a regimen do fine, but not as many as those getting the usual treatment with first-line regimens recommended in the U.S. Department of Health and Human Services guidelines.
The difference in results between NEAT, A5262 and PROGRESS does raise questions about whether the choice of protease inhibitor plays a role -- lopinavir/ritonavir seems to consistently do better in such novel combinations. Is this because it is a fixed dose formulation and is thus protected from selective adherence, or is it something else?
(These results in treatment-naive patients should be differentiated from work that has shown that switching well-controlled patients to an integrase-protease regimen -- or even integrase+rilpivirine (Edurant) -- can be expected to maintain suppressed viremia. The bar is lower for those with undetectable HIV RNA levels while on stable antiretroviral therapy.)
The GARDEL study adds another dot on a line pointing to the benefits of maintaining something with activity against reverse transcriptase, even if it is little old lamivudine.
All these trials beg further study of newer nuke-free (or mostly nuke-free) combinations, such as darunavir/ritonavir + lamivudine or emtricitabine + dolutegravir. But, lurking behind the curtain is tenofovir alafenamide fumarate (TAF), which may well be the answer to our prayers for a clean and effective nuke. After TAF is approved, it may be Game Over when it comes to playing with a nuke-sparing approach.
What are some other top clinical developments of 2014? Read more of Dr. Wohl's picks.
David Alain Wohl, M.D., is an associate professor of medicine in the Division of Infectious Diseases at the University of North Carolina and site leader of the University of North Carolina AIDS Clinical Trials Unit at Chapel Hill.
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