POSITIVELY AWARE NOVEMBER/DECEMBER 2010
Rilpivirine causes a stir
Anticipation surrounds a new single-tablet regimen
There has been much interest and anticipation around rilpivirine (TMC278) and an upcoming second, single-tablet regimen that will contain it. The surrounding buzz at the last two AIDS conferences was about the latest research findings on rilpivirine Phase 3 studies and the development of a single-pill combination of Truvada (Viread + Emtriva) and rilpivirine which we shall call “NewTripla” in this article. The big question is will “NewTripla” become the preferred treatment over the current first-line Atripla?
Atripla, composed of Sustiva (efavirenz) and Truvada (tenofovir/emtricitabine), has had a monopoly on the single-pill regimen. To meet this gold standard in treatment, newer therapies needed to match Atripla’s efficacy (show non-inferiority) in clinical studies. Other excellent first-line choices all require several pills, some using twice-daily dosing. Based on U.S. guidelines, the currently preferred nucleoside backbone is Truvada, a duo of nucleoside reverse transcriptase inhibitors, combined with several possible agents including Isentress, boosted Prezista, or boosted Reyataz.
By early June of 2011, if FDA approved, “NewTripla,” the new single-tablet treatment, will become available. Perhaps more than one year following, we will have a third single-tablet regimen called the Quad, containing the cobicistat-boosted integrase inhibitor elvitegravir combined with Truvada. Prepare for the seismic shake-up in physicians’ choices for first-line treatment of HIV disease that is imminent.
In the U.S., 5-7% of HIV patients harbor the K103N viral mutation or baseline drug resistance to non-nukes (due to transmission of resistant virus), making the administering of Atripla contraindicated. This number reaches above 20% in various geographic areas, including Northstar’s Chicago neighborhood of Lakeview, parts of southern California, and southern Florida. As with any treatment, Atripla has side effects which may become more carefully weighed as therapeutic alternatives become available. The side effects of the keystone component of Atripla—Sustiva—include CNS (central nervous system) effects. These are marked by various sleep disorders and nightmares, increased anxiety, morning grogginess, and difficulties in concentration. Also, note that Sustiva is associated with elevated cholesterol levels and lipodystrophy, or body habitus changes, including atrophy and visceral adiposity (belly fat) previously described in the sub-analysis of study ACTG 5142. These drawbacks were less discussed in the past, but, as “NewTripla” becomes available, I believe these will surface in discussions.
The components of this new single-tablet formulation, Truvada and rilpivirine, both have long serum (blood) and intracellular half-lives (time that half the drug gets metabolized); rilpivirine’s half life is about 45 hours, making a combination with Truvada a nice pairing and easy to administer once daily.
Two antiretroviral naïve studies, ECHO and THRIVE, randomized the study participants 1:1 to receive either rilpivirine or Sustiva. In ECHO, all study subjects (690) were additionally administered Truvada as the nucleoside backbone. In THRIVE, (678 patients) the investigator chose the backbone treatment; thus, 60% of patients were administered Truvada, 10% were given Epzicom, and 30% received Combivir. As principle investigator at Northstar Healthcare in Chicago, I’ve been involved with the ECHO trial since April of 2008.
The patients were demographically diverse: 25% female, 23-24% of African descent, 11-14% Asian and 7-9% co-infected with hepatitis B or C. At baseline, of the patients on rilpivirine versus Sustiva, 52% and 46% had viral loads above 100,000 copies/mL, median CD4 counts were at 249 and 260 cells/mm3 respectively.
At 48 weeks, both in the pooled analysis (both studies analyzed together) and in each study individually, rilpivirine was shown to be non-inferior to Sustiva. Overall, 84% versus 82% achieved undetectable levels (less than 50 copies/ml) and CD4 count gains were 190 and 172 cells, in the rilpivirine versus Sustiva arms, respectively. Patients responding to rilpivirine and Sustiva were also not statistically different among participants starting treatment with more than 100,000 copies at baseline—76% vs. 82% in ECHO and 79% vs. 80% in THRIVE. In pooled analysis, of the patients with less than 100,000 copies at baseline, treated with rilpivirine vs. Sustiva, 90% vs. 84% achieved undetectability out to 48 weeks (ECHO, 90% vs. 83%; THRIVE 91% vs. 84%).
We can expect that if rilpivirine gains FDA approval,
this new single-tablet regimen will make its appearance
on pharmacy shelves in May or June of 2011.
However, 10% in the rilpivirine versus 6% in the Sustiva arms developed virologic failure. Virologic failure was defined as never achieving two consecutive viral loads below 50 copies and having at least a 0.5-log rise from the lowest viral load; reaching consecutive viral loads below 50 copies followed by two consecutive viral loads above 50 copies; or one above 50 copies if it was the last viral load measured. However, suboptimal adherence was associated with virologic failures. In the group with higher baseline viral load, the effect of suboptimal adherence on virologic failure was more apparent with the rilpivirine-treated patients than with the Sustiva-treated. Presenting the resistance data at the Boston ICAAC meeting in September, Dr. Joseph Eron commented that these observations may help explain why virologic failure rates were higher with rilpivirine. Interestingly, patients participating in ECHO, who were all administered Truvada—the stronger nuke backbone—did not show any lower failure rates.
Of the failures, 86% in whom rilpivirine failed and 72% in whom Sustiva failed had genotype testing (resistance mutations testing) completed. Among these, 68% taking rilpivirine and 32% taking Sustiva had (IAS-USA-defined) nucleoside-associated mutations emerging during treatment, which was a statistically significant difference. The most frequent NRTI mutation with rilpivirine was M184I, an unusual mutation, and we’re uncertain as to why this is occurring here. Dr. Michael Miller of Gilead Sciences commented to me that “the mutation appears to be more stable among rilpivirine/Truvada failures and we’re investigating why.” As of now, we’ve understood that the M184I appears to be another FTC (Emtriva) resistance pattern, but appears to be also seen with rilpivirine treatment.
It appears that the most commonly observed non-nucleoside mutation associated with failure of rilpivirine is the E138K. 50% of patients who develop the E138K are expected to have cross resistance to Sustiva and more than 90% to Intelence (etravirine). Intelence is a non-nuke used for treatment of patients with non-nucleoside resistant virus. Patients who fail rilpivirine during first line therapy will have many other options but will not have the ability to be sequenced to Intelence. I believe that because of the widespread use of more patient-friendly medications, patients tend not to fail treatment at the rates observed years ago, however.
Overall, 6.7% discontinued due to adverse events in the Sustiva-treated patients versus 2.2% in the rilpivirine patients, demonstrating better tolerability in patients being treated with rilpivirine. Moreover, neurologic-related adverse events were fewer in the rilpivirine-treated patients than Sustiva (17 versus 38%) and psychiatric associated events were also fewer with rilpivirine (15 vs. 23%). Skin rash was also more common in Sustiva, 3% in rilpivirine-treated patients versus 14% observed in the Sustiva-treated subjects.
Lipids (blood fats) data were also reported. For the rilpivirine-treated patients, the mean changes from baseline in total cholesterol, LDL-cholesterol, and triglycerides were statistically significantly lower than for Sustiva-treated patients.
Four years ago, Atripla became the first single-tablet, once-daily regimen in HIV disease treatment. Historically, with continued progress and medical advances, newer, more convenient, more patient- friendly medications have replaced older HIV treatments. Visionary pharmaceutical companies set their bar higher to develop competitive treatments that demonstrate an evolution in therapy. There is hardly a simpler therapy than a complete cocktail formulated in a single tablet taken once daily. However, recent news showed that another single-tablet combination in development is better tolerated and may be considered a step towards further innovation in HIV therapy.
Rilpivirine combined with Truvada has been shown to be non-inferior virologically to the gold standard, Atripla. There is pause to consider the particulars of virologic failures in ECHO and THRIVE and the resistance pattern associated with the rilpivirine arm in these studies. In contrast, people taking rilpivirine discontinued treatment less often for adverse events and other reasons than people taking Sustiva. There were significantly fewer side effects related to central nervous system and sleep disorders and significantly less elevation in cholesterol and triglycerides.
Available medications, however, are only effective when people do indeed take them as prescribed. In my mind, there is little doubt that an easily administered single-tablet regimen with fewer side effects will help contribute to better adherence.
We can expect that if rilpivirine gains FDA approval, this new single-tablet regimen will make its appearance on pharmacy shelves in May or June of 2011. 48-week data from a third single-tablet regimen, referred to as the Quad, which in contrast contains the boosted integrase inhibitor elvitegravir, was just presented in Boston at the 50th ICAAC (see page 38) and has good probability of making it to market in the not too distant future. (See The Buzz, May/June 2010, “Something to CROI About”.) As in the tradition of changing treatments, newer improved options continue to alter the landscape of HIV therapeutics.
Dr. Daniel S. Berger is a leading HIV physician in the U.S. and is Clinical Associate Professor of Medicine at the University of Illinois at Chicago and founder and medical director of Northstar Healthcare in Chicago. Dr. Berger has published extensively in, among others, The Lancet and The New England Journal of Medicine and serves on the Medical Issues Committee for the Illinois AIDS Drug Assistance Program and is a member of the board of directors of the AIDS Foundation of Chicago. He can be reached at DSBergerMD@aol.com and www.Nstarmedical.com.