Clinicians Find Advances ‘Mind-Boggling’
By Annette M. Boyle
ATLANTA – Therapeutic options for patients with human immunodeficiency virus (HIV) continue to expand, enabling more veterans to begin treatment with fewer adverse side effects and far less complicated regimens than even a few years ago.
“Now that we have multiple documented treatments that work and are well tolerated, we have better options for patients with underlying problems such as heart or kidney disease and those who have developed resistance to the drugs they are on,” said David Rimland, chief of infectious diseases at the Atlanta VAMC.
With HIV, unlike many other conditions, dissemination of information on new treatments is extremely rapid. “One of the interesting things about working with HIV compared to a lot of other diseases is that, as soon as significant results are presented, clinicians latch on to them very quickly, often even before official recommendations or guidelines come out,” Rimland noted.
That’s good news for the more than 24,000 HIV-infected veterans who receive healthcare through the VA. Recent studies may bring even better tidings to veterans who have been unable to take or tolerate the most common combinations of HIV medications.
In October, researchers led by Jeffrey Lennox, MD, professor of medicine at Emory University and Grady Memorial Hospital, both in Atlanta, published results of the first head-to-head study of three non-efavirenz therapies in the Annals of Internal Medicine. That study showed that all three achieved equivalent and high rates of virologic suppression, though there were some differences in their tolerability levels. 1
“We are very pleased that our study showed the drug combinations tested, without efavirenz, are good options for initial HIV antiretroviral therapy. This is critical information for patients who cannot tolerate efavirenz, and we believe this head-to-head comparison will provide useful information to guide clinicians about choosing among them,” Lennox said.
The researchers conducted a Phase 3, open-label study at 57 sites in the U.S. and Puerto Rico. The 1,809 participants were equally divided among the study’s three arms and followed for at least 96 weeks. The combinations included: atazanazir with ritonavir; raltegravir; and darunavir, each administered with embricitabine and tenofovir disoproxil fumarate.
The researchers found that raltegravir or ritonavir-boosted darunavir were better tolerated than ritonavir-boosted atazanavir. Looking at both virological efficacy and tolerability, the researchers concluded that raltegravir outperformed the other two therapies, particularly in women. Ritonavir-boosted darunavir was superior to ritonavir-boosted atazanavir, largely because of jaundice and other gastrointestinal toxicity associated with atazanavir.
The study authors noted, however, that “patients randomly assigned to raltegravir frequently developed integrase mutations and nucleoside backbone resistance when virologic failure occurred.” Virologic failure with resistance occurred in 3% of raltegravir-arm participants compared with 15% of those on either of the ritonavir-boosted protease inhibitors.
Efavirenz-based combinations have been the mainstay of HIV treatment for more than 15 years, but they have some undesirable side effects and are contraindicated in certain patient subgroups. The most common problem is the development of rashes. “In some people, it is also associated with central nervous system toxicity that may cause nightmares, anxiety or nervousness when they first start taking efavirenz. While that usually goes away in a few weeks, some patients have to choose a different drug,” Rimland said.
“It’s not clear how important the third problem is, but trials indicate that patients on efavirenz may be more likely to have suicidal ideation, so there is some reluctance to use it in cases of underlying severe depression and other mental health disorders,” Rimland told U.S. Medicine. A meta-analysis of four large randomized clinical trials with more than 5,000 combined treatment-naïve patients followed for an average of three years found that efavirenz was associated with a doubling or tripling of the risk of suicide.2
Efavirenz is also not recommended by the U.S. Department of Health and Human Services (DHHS) for use in the first two trimesters of pregnancy based on data showing teratogenicity in animal studies. Other studies indicate a two-to-three times increase in risk of neural tube birth defects following first trimester exposure to efavirenz. As a result, combinations with the drug are not preferred for women of child-bearing age.3
Increasing evidence of non-nucleoside reverse transcriptase inhibitor resistance also is an emerging issue with the efavirenz combinations. Resistance rates have reached 5% to 8% in parts of the world, posing some questions about the long-term efficacy of efavirenz-based therapies.
With the three combinations evaluated in the Annals of Internal Medicine study, “we now have four non-efavirenz combinations available that are applicable to a large group of HIV patients. DHHS recommendations include three regimens in single-pill form and a fourth that is taken more than once a day,” Rimland said.
For patients who are on efavirenz combinations and tolerate them, there’s no reason to switch, as the medications work quite well, he noted.
Rimland said he is astonished that so many single-pill options exist today. “The progress we’ve made in treating this disease is mind-boggling in terms of how well people are doing and how much we’ve reduced mortality. It’s now a very manageable chronic disease with simple regimens. When I first started, we had very complex regimens that required taking multiple pills every three or four hours and the drugs were much more problematic.”
1Lennox JL, Landovitz RJ, Ribaudo HJ, Ofotokun I, Na LH, et al. Efficacyy and tolerability of 3 nonnucleoside reverse transciptase inhibitor-sparing antiretroviral regimes for treatment-naïve volunteers infected with HIV-1. Ann Intern Med. 2014;161:461-471.
2 Mollan K et al. Hazard of suicidality in patients randomly assigned to efavirenz for initial treatment of HIV-1: a cross-study analysis conducted by the AIDS Clinical Trials Group (ACTG). Abstracts of IDWeek 2013. 2-6 October 2013, San Francisco. Abstract 670.
3 Raffi F, Pozniak AL, Wainberg MA. Has the time come to abandon efavirenz for first-line antiretroviral therapy? J Antimicrob Chemother 2014; 69: 1742–1747