Much awaited results from two phase III trials on the new generation HIV drug etravirine (experimental name TMC125) show it is effective at suppressing HIV to undetectable levels in patients who have drug resistant strains of the virus.
The results of the two trials, DUET-1 and DUET-2 are published in this week’s issue of The Lancet.
The two randomized trials showed that treatment with TMC125 (etravirine) led to better suppression of HIV than placebo when given as part of antiretroviral therapy in patients who were resistant to non-nucleoside reverse transcriptase inhibitors (NNRTIs).
NNRTIs are a class of antiretrovirals that target a specific part of HIV DNA and stop it reproducing. Other classes of antiretrovirals, known as nucleoside analog reverse transcriptase inhibitors (NARTIs or NRTIs) and nucleotide analog reverse transcriptase inhibitors (NtARTIs or NtRTIs) work on other parts of HIV DNA.
One of the reasons HIV is so successful is its ability to mutate quite quickly in response to drugs. We respond by mixing drugs together, to target different parts of the HIV DNA in the hope that at least one of them will remain effective as it mutates. But eventually, the mutants win and we run out of of options.
A new generation of antriretrovirals has been long awaited. Etravirine, and a number of others appear to fulfill that need.
Etravirine is made by Tibotec (a division of Janssen-Cilag) and they were involved in the trial.
Etravirine and two other new drugs whose phase III trials concluded earlier this year, maraviroc (Pfizer) and raltegravir (Merck), are likely to be submitted for approval by the US Food and Drug Administration (FDA) later this year.
The two international teams of researchers hope that etravirine will be part of what has been termed the second generation of antiretrovirals with the ability to do two things: fight the highly resistant strains of HIV and also provide a genetic barrier to development of resistance, which is exactly what is needed to treat the growing number of HIV patients who either already have the resistant strains or at at risk of developing them.
Also, by keeping the virus at almost undetectable levels, the chances are that it will take much longer for the drug resistant strains to mutate and spread.
The DUET-1 and DUET-2 phase III trials examined the efficacy, safety and tolerability of etravirine when compared with placebo in patients who had already been treated with HIV drugs and were infected with NNRTI resistant strains. The patients were given etravirine along with another retroviral, or placebo with another antiretroviral.
The trials lasted for 24 weeks. In both cases, at the end of trial, a higher percentage of patients on etravirine and the other antiretroviral had a viral load of less than 50 copies per mL (considered to be the definition of undetectable) than those who were on the placebo plus the other antiretroviral (56 versus 39 per cent in DUET-1 and 62 versus 44 per cent in DUET-2).
Also, the safety and tolerability of etravirine was comparable to that of the placebo.
The research team of DUET-2, which was led by Adriano Lazzarin of Raffaele University, Milan, Italy, said that:
“The magnitude of the results seen with TMC125 … and the similarity of the responses across both trials done in different countries, indicate the higher genetic barrier to resistance of TMC125 compared with currently available NNRTIs and its activity against NNRTI resistant virus are central to the ability of TMC125 … to produce significantly better virological responses than the placebo group in treatment experienced patients.”
“The maintenance of the response to 24 weeks without additionally clinically relevant tolerability concerns further suggests that TMC125 is an encouraging new agent in this antiretroviral class,” they added.
Bernard Hirschel and Thomas Perneger, both from Geneva Hospital in Geneva, Switzerland, commented on the trials in an accompanying article. They said important questions had not been addressed, such as:
“Quality-of-life measurements, and detailed correlations between resistant genotype and treatment success which may help gauge etravirine’s prospects in individual patients.”
They also said that the results of the two studies should have been pooled together and analyzed as a whole to show the overall efficacy of etravirine.
However they were upbeat about the fact that many of the new antiretrovirals coming through phase III trials, including etravirine, appear to be effective and well tolerated, and that it shows there is still plenty of incentive to innovate in the HIV drug sector.
Perhaps it will not be unreasonable one day for every HIV patient to expect to attain undetectable levels of HIV.
“Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-1: 24-week results from a randomised, double- blind, placebo-controlled trial.”
José Valdez Madruga, Pedro Cahn, Beatriz Grinsztejn, Richard Haubrich, Jacob Lalezari, Anthony Mills, Gilles Pialoux, Timothy Wilkin, Monika Peeters, Johan Vingerhoets, Goedele de Smedt, Lorant Leopold, Roberta Trefiglio and Brian Woodfall, on behalf of the DUET-1 study group.
The Lancet 2007; 370:29-38.
DOI:10.1016/S0140-6736(07)61047-2
“Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-2: 24-week results from a randomised, double- blind, placebo-controlled trial.”
Adriano Lazzarin, Thomas Campbell, Bonaventura Clotet, Margaret Johnson, Christine Katlama, Arend Moll, William Towner, Benoit Trottier, Monika Peeters, Johan Vingerhoets, Goedele de Smedt, Benny Baeten, Greet Beets, Rekha Sinha and Brian Woodfall, on behalf of the DUET-2 study group.
The Lancet 2007; 370:39-48.
DOI:10.1016/S0140-6736(07)61048-4
Written by: Catharine Paddock
Writer: Medical News Today