ATLANTA – Nucleoside reverse transcriptase inhibitors can be safely omitted when switching patients from a failing HIV regimen to an optimized regimen with more than two active agents, according to data from the OPTIONS trial.

"We don’t need to hang on to this older class of medications that we’ve grown to be very comfortable with, but [that] add pill burden, add toxicity, add costs," Dr. Karen Tashima said during a press briefing at the Conference on Retroviruses and Opportunistic Infections.

Nucleoside reverse transcriptase inhibitors (NRTIs) have been used to boost antiviral efficacy when constructing antiretroviral (ARV) regimens for patients with virologic failure. But questions have arisen about their role as newer, more potent agents have become available and long-term NRTI toxicities and resistance have become more apparent.

To explore this issue, the AIDS Clinical Trials Group (ACTG) OPTIONS (Optimized Treatment that Includes or Omits NRTIs) study enrolled 360 patients who had an HIV viral load of at least 1,000 copies/mL, were on a protease inhibitor–containing regimen, and had exposure or resistance to NRTIs and nonnucleoside reverse transcriptase inhibitors (NNRTIs).

Guided by resistance and tropism testing, the investigators created individualized regimens from among 20 potential three- and four-drug combinations containing more than two active drugs, defined by a continuous phenotypic susceptibility score (cPSS) of more than 2. Patients were then randomized to open-label treatment with or without an NRTI.

At baseline, patients had an average CD4 count of 200 cells/mm³ and a mean HIV viral load of 4.2 log₁₀ copies/mL, and had been on antiretrovirals for an average of 11 years.

The most common regimen (56%) was raltegravir (Isentress), darunavir/ritonavir (Prezista), and the NNRTI etravirine (Intelence), said Dr. Tashima, associate director of the Brown University AIDS program in Providence, R.I.

After randomization, the most commonly selected NRTIs were tenofovir disoproxil fumarate/emtricitabine (Truvada) (82%) and tenofovir/emtricitabine/zidovudine (Retrovir) (12%), according to the late-breaking abstract.

At 1 year, regimen failure was not more likely among those omitting NRTIs versus adding NRTIs to an optimized new regimen (30% vs. 26%), Dr. Tashima reported. Virologic failure occurred in 25% of patients in both groups.

The primary safety end point – time to initial episode of severe signs/symptoms or laboratory abnormality prior to discontinuation of NRTI assignment – was also similar between arms (P = .93).

However, there were six deaths during follow-up among patients randomized to receive NRTIs, compared with none among the omit-NRTI patients. The causes of death were heart failure, Listeria meningitis, renal failure, sepsis, progressive multifocal leukoencephalopathy, and intra-abdominal bleeding. In two cases, the investigators could not rule out a relationship to the study treatment, she said.

Treatment-experienced patients can develop resistance to therapy due to poor adherence, said Dr. Richard Haubrich, study cochair and professor of medicine at the University of California, San Diego. Designing an antiretroviral regimen using new drugs from new classes and omitting NRTIs would lead to fewer pills and, hopefully, better adherence, he said.

"Until now, most clinicians accepted that nucleosides would be an important component for multiple-class–experienced patients," Dr. Haubrich noted. "However, our results are very clear: We can safely exclude NRTIs, giving physicians a new paradigm for ART prescription in clinic and potentially changing treatment guidelines."

That potential impact on practice was apparent among some meeting attendees.

"The term ‘game-changer’ has been thrown around a lot at this conference; this is a game-changer," noted Dr. Andrew Zolopa, infectious disease professor at Stanford (Calif.) University, during the discussion period. "For many of our patients in our practices, we’ve been recycling nukes. It looks quite convincing that we don’t have to do that, at least for patients like the ones in this study with a PSS [genotypic susceptibility score]" greater than 2.

For patients with a PSS less than 2, Dr. Tashima noted, NRTIs were added to their regimen, and that follow-up is continuing.

The results are interesting, but they may be applicable only in rich countries, cautioned Dr. Jintanat Ananworanich, who comoderated the session and is deputy director of the HIV Netherlands Australia Thailand Research Collaboration (HIV-NAT) in Bangkok.

"The drugs used in this study are not available in any resource-limited setting," she said in an interview. "So, we would not be able to do this, and we would continue to use NRTIs.

"In terms of reduced cost, an NRTI costs much, much less than any of the drugs used in the OPTIONS study," she added, "and we have shown in Thailand that recycling NRTI with one or two active drugs works very well."

The National Institute of Allergy and Infectious Diseases funded the study. The study drugs were supplied by Merck, Janssen, Pfizer, Hoffmann-La Roche, and Boehringer Ingelheim. Monogram Biosciences provided resistance and tropism testing. Dr. Tashima reported honoraria from Gilead Sciences.

Omitting NRTIs safe with optimized HIV regimen