Top HIV/AIDS-Related Clinical Developments of 2010
December 8, 2010
A review of:
If coating an orifice with tenofovir can help prevent the transmission of HIV, how about tackling the problem from the other side -- that is, take the medication orally and let it concentrate in the linings of the surfaces exposed to HIV during sex? That was the premise of the important and exciting iPrEx trial. In this study, 2,499 HIV-uninfected men and transgender women (born male) who have sex with men living in one of six countries (Peru, Ecuador, Brazil, South Africa, Thailand and the U.S.) were randomized to receive either tenofovir/emtricitabine (Truvada) once daily or a placebo. The participants were at very high risk for HIV: The median number of sex partners in the past 12 weeks prior to entry was 18 and 60% had unprotected anal sex during that time period. Tellingly, 13% had a reactive test for syphilis at baseline.
During the course of the trial (median follow-up 1.2 years), 100 participants became HIV infected: 64 in the placebo arm and 36 of those receiving the active drug. That's a 44% reduction in the incidence of HIV (95% CI, 15 to 63; P = .005) among those receiving tenofovir/emtricitabine. Importantly, in the tenofovir/emtricitabine group, the study drug was detected in the blood of 51% of those who remained HIV uninfected, but in only 9% of those who became infected. For those in the active treatment arm who had detectable levels of tenofovir/emtricitabine, the protective effect of tenofovir/emtricitabine exceeded a 90% reduction in risk.
There were no differences between the two study arms in reported sexual practices during the study. Use of the active drug (compared to placebo) was associated with greater risk of nausea and weight loss. Further, some mild changes in renal function were seen in the tenofovir/emtricitabine arm, although this was reversible with cessation of the drug.
Among those who acquired HIV while on the active study drug, none had resistance detected to either tenofovir or emtricitabine. Ten cases of acute HIV infection at study entry were detected, and three of these had emtricitabine-resistant virus detected subsequently (2 of 2 in the active arm and 1 of 8 in the placebo arm). There was no tenofovir resistance detected among the acute infection cases.
The Bottom Line
This is a big deal. The iPrEx trial has made clear that pre-exposure prophylaxis (PrEP) is not just plausible, it actually works. The impressive reduction in new infections demonstrates that humans, like other primates, have a harder time getting infected with HIV when they have tenofovir on board.
However, the study also showcases the limitations of PrEP. Despite self-reported levels of adherence to the study medication of about 90%, it was clear from drug levels that this was an exaggeration bordering on the delusional. Those who apparently took the active therapy had a much greater benefit, but in real life many will not be adherent.
Further, tenofovir/emtricitabine did produce some side effects, which is not too surprising. It's likely that this will become an issue as use of the drug broadens. However, many women take oral contraceptives to prevent pregnancy despite the risk of potentially serious adverse events. Fortunately, the effects described in this trial were easily reversed upon stopping the drug. Therefore, many may opt to use PrEP even if there is a chance for a side effect. The potential for problems with longer-term administration, such as decreased bone mineralization, is a concern and will require dedicated study.
Other logistical issues will need to be sorted out, including who should receive the medication, who will prescribe it and who will pay for it. The population studied in iPrEx was quite high risk. Is PrEP worthwhile for those with fewer risky behaviors? What about the risk of drug resistance that may come with wider use of tenofovir/emtricitabine? Can PrEP be given intermittently, such as before an anticipated exposure to HIV, rather than daily?
As the dust settles, these are important questions that the HIV prevention and treatment communities will have to tackle. For now, as with CAPRISA, we can look to iPrEx as a major step forward and beyond the condom.
A review of:
Rimsky L, Eron J, Clotet B, et al. Characterization of the resistance profile of TMC278: 48-week analysis of the phase 3 studies ECHO and THRIVE. In: Program and abstracts of the 50th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 12-15, 2010; Boston, Mass. Abstract H-1810. Available at: www.abstractsonline.com.
New and improved! It's the exclamatory catchphrase used by the makers of everything from cereal to colas. For HIV medications, "even better" can come from playing with the chemical structure of a drug (e.g., fosamprenavir [Lexiva, Telzir]) or through new formulations that reduce pill count, size or palatability (e.g., nelfinavir [Viracept], zidovudine [AZT, Retrovir] and lopinavir/ritonavir [Kaletra]). Many of our most popular drugs have changed little other than to be included in fixed-dose combinations. Efavirenz (Sustiva, Stocrin), a flagship NNRTI (non-nucleoside reverse transcriptase inhibitor), received a great boost by being incorporated with tenofovir and emtricitabine in a formulation known as Atripla. However, it has well-understood limitations, including central nervous system (CNS) effects, the risk of serious rash and worrisome teratogenicity (risk of birth defects). More recently, efavirenz has been associated with dyslipidemia, peripheral fat loss and reduced vitamin D levels. It is a testimony to its attributes that despite these annoying problems the drug is so commonly prescribed. But there is room for improvement.
Rilpivirine (formerly TMC278) is a single-pill NNRTI with a long half life permitting once-daily dosing and which causes no apparent CNS side effects. Therefore, at face value this drug looked like a good candidate to ascend the NNRTI throne. All that remained was a couple of head-to-head trials against efavirenz: the ECHO and THRIVE studies. In the former, the NNRTIs were paired with tenofovir/emtricitabine; in the latter, clinicians were able to select from the three marketed dual-NRTI (nucleoside/nucleotide reverse transcriptase inhibitor) fixed-dose combinations. Almost 700 treatment-naive patients were enrolled in each trial.
It is notable that the dose of rilpivirine used in these studies was 25 mg daily -- the lowest among three doses that included 75 mg and 150 mg in early studies of the drug. While 75 mg was the originally selected dose for development, prolongation of the QT interval (a measurement of the pacing of the electrical activity of the heart seen on an electrocardiogram [ECG] tracing) at that dose required proceeding with the next-lowest dose studied, 25 mg.
The 48-week results of the trials were generally similar. In pooled analyses, the proportion of participants with a confirmed viral load less than 50 copies/mL (using time to loss of virologic response, which is an intent-to-treat analysis method) was 84.3% for rilpivirine and 82.3% for efavirenz. When looking at those with a baseline viral load below 100,000 copies/mL, rilpivirine tended to have a better response rate compared to efavirenz (90% vs. 84%; difference = 6.6 [95% CI: 1.6, 11.5]). However, at the higher viral load stratum (above 100,000 copies/mL), efavirenz tended to do better (81% vs. 77%; difference = -3.6 [95% CI: -9.8, 2.5]).
Importantly, the TLOVR analysis favored by the U.S. Food and Drug Administration (FDA) includes loss of viral response for reasons of virologic failure as well as drug intolerance. When comparing just the virologic failure rate between the two NNRTIs, 9.0% of those assigned to rilpivirine failed versus 4.8% of those randomized to efavirenz. Conversely, the rate of treatment failure due to adverse events was higher with efavirenz compared to rilpivirine (6.7 vs. 2.0). As expected, CNS toxicity was more common with efavirenz than with rilpivirine, as was rash (14% vs. 3%).
Among those with failure, many had no resistance mutations detected. For those with resistance, the K103N mutation emerged in those treated with efavirenz, whereas the E138K mutation was observed in the rilpivirine failures.
The Bottom Line
The findings from these two trials serve as a coming-out party for this newest member of the NNRTI family. There have been high hopes for rilpivirine to be a kinder-and-gentler efavirenz -- one that can actually be taken during daylight hours. However, this debut has come with mixed reviews. On the one hand, the results show what the studies set out to show: that rilpivirine is not worse than efavirenz. On the other hand, rilpivirine appeared to be less potent, albeit better tolerated. One cannot help but wonder whether this less-than-optimal performance is a consequence of the need to study rilpivirine at a lower dose than originally intended.
What we have with rilpivirine in the ECHO and THRIVE trials is a tradeoff between efficacy and tolerability, particularly among those with higher plasma HIV RNA levels. If and when the drug comes to market, it will be important to see whether clinicians will feel comfortable prescribing rilpivirine to those with higher HIV RNA levels (a viral load greater than 100,000 copies/mL or so). The convenience and tolerability advantages of this NNRTI, especially if it is coformulated with tenofovir and emtricitabine as planned, may trump potency concerns for some.
There are some other warts. Rilpivirine cannot be taken with proton-pump inhibitors and needs to be taken with food. Additionally, there is the sequencing issue: Failure of efavirenz can be expected to be salvaged with etravirine (TMC125, Intelence), while some patients failing rilpivirine were found to be resistant to this second-generation NNRTI.
These trials will yield additional data as the study volunteers are followed to 96 weeks. Such results may further help us understand where this new NNRTI will fit in the ever-growing list of treatment options for those initiating HIV therapy.
This article was provided by TheBody.
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