"The virological responses noted in the TMC125 group were better than those of the placebo group, despite all patients having at least one documented NNRTI resistance-associated mutation and an extensive treatment history," a research team led by Jose Valdez Madruga, of the Centro de Referencia e Treinamento DST/AIDS in Sao Paulo, Brazil, noted in one of the studies published in the Jul 07 issue of The Lancet.

"Other currently available NNRTIs would not generally be expected to provide a virological response in such patients, since the presence of a single NNRTI resistance-associated mutation has been shown to cause cross-resistance," Madruga's team added. "TMC125 therefore offers a new treatment option within the NNRTI class."

A team led by Adriano Lazzarin, of San Raffaele University in Milan, Italy, offered a similar endorsement of the drug.

"The magnitude of the results seen with TMC125 in DUET-1 and DUET-2 ... and the similarity of the responses across both trials done in different countries, indicate that 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," Lazzarin's group stated in The Lancet.

"The maintenance of the response to 24 weeks without additional clinically relevant tolerability concerns further suggests that TMC125 is an encouraging new agent in this antiretroviral class," Lazzarin and colleagues added.

TMC125 has not yet received regulatory approval and Tibotec has not indicated when it plans to file for marketing authorization of the drug. The company's protease inhibitor, Prezista, was approved by the U.S. Food and Drug Administration last year.

Bernard Hirschel and Thomas Perneger, both of Geneva Hospital in Switzerland, think a pooled analysis of both studies would have lent increased support for the efficacy of TMC125 as well as answered additional questions about the compound.

"A combined analysis of the DUET studies would have allowed the investigators to claim as of today a clinically important benefit for etravirine (TMC125)," Hirschel and Perneger stated. "It is a shame to see this opportunity delayed."

As for the additional questions a pooled analysis could have answered, the commentators pointed out that combining the data reveals that TMC125 reduced the incidence of clinical events and lowers by half the risk of clinical progression compared to patients in the control group.

"People care whether they get sick and die, and rather less whether their laboratory results are normal," Hirschel and Perneger noted. "Therefore it matters whether a new drug improves outcomes of clinical importance, in addition to surrogate measures, such as viral HIV RNA concentrations and CD4 counts."

The commentators said the DUET studies show that there is still both the scientific and economic incentive for innovation in the anti-HIV sector. In addition to TMC125, innovative therapies in development include Pfizer's CCR5 entry inhibitor, maraviroc, Tibotec's NNRTI, TMC278 and Merck's integrase inhibitor Isentress.

All these drugs are both effective and well tolerated, which raises hopes that "the day will come when suppression of viral load to undetectable levels can be attained by all," Hirschel and Perneger stated.

related report
Tibotec Drugs Zap Resistant HIV
by Ed Susman
West Palm Beach Fla., (UPI) Jul 05 - Researchers said Thursday that new anti-AIDS drug can suppress virus to undetectable levels even for patients with highly resistant strains of HIV. "We were able to take the sickest patients -- people with no options and desperately short life expectancy -- and drive their virus levels to undetectable," Tony Mills, assistant professor of clinical medicine at the University of California, Los Angeles, told United Press International.

In studies that will be published in Saturday's editions of the London-based medical journal Lancet, doctors said that both the experimental non-nucleoside reserve transcriptase etravirine -- TMC125 being developed by Tibotec of Belgium -- and the newly-approved protease inhibitor darunavir -- Prezista, also made by Tibotec -- were efficient in suppressing the virus.

"Some of the patients that were treated in this trial had never been able to suppress their viral loads to undetectable," Mills said. "Yet with these drugs we were able to get half of them to the point where virus was not seen using the very stringent 50-copy/milliter assay."

In the so-called DUET-1 and DUET-2 studies, patients were recruited if they had virus that was resistant to current treatments, including patients who were resistant to other non-nucleoside reverse transcriptase drugs such as efavirenz -- Bristol-Myers Squibb's Sustiva. Mills noted that previously patients who were resistant to any non-nucleoside analogue were resistant to all drugs in that class.

Doctors were told to optimize the regimens of the patients -- including what each clinician thought was the best drug available -- and then were told to add Prezista to all the patients' therapies. Half the 612 patients received that regimen and the rest received those drugs plus etravirine.

In DUET-1, the group that received Prezista, 39 percent were able to achieve undetectable viral loads, Mills said, while 56 percent of those who received etravirine were able to achieve undetectable viral loads. The researchers reported on the first 24 weeks of the ongoing study. The DUET-1 patients were from North and South America; Duet II patients were from the rest of the world. The results of both trials were similar.

"Many of these patients were concerned about adding these new drugs because of side effects suffered with other anti-HIV treatments," Mills said. "However, we found that both etravirine and Prezista, alone or together, resulted in very few side effects. Some patients on etravirine developed a rash that was fairly well tolerated."

In the issue of Lancet, devoted virtually entirely to HIV issues in anticipation of the International AIDS Society conference on treatment and prevention of HIV in Sydney, Australia, later this month, researchers also reported on a head-to-head trial comparing Prezista to the gold standard of protease inhibitor-based treatment, Kaletra (Abbott), the combination of lopinavir and ritonaivr.

Ritonavir is often used in small doses to help boost concentrations of other protease inhibitors. It is used with both Kaletra and Prezista.

"We believe that this trial shows we have paradigm in treatment," said Daniel Berger, clinical assistant professor of medicine at the University of Illinois-Chicago, and medical director and founder of Northstar Medical Center, Chicago, one of the largest AIDS-treatment facilities in the United States.

In the TITAN trial, 600 patients whose medication no longer was able to keep HIV replication in check were assigned to receive either Kaletra or Prezista as a second line treatment.

Berger told UPI that 71 percent of patients who received Prezista were able to suppress their virus -- often containing resistant strains of HIV -- to undetectable levels compared with 60 percent of the patients on Kaletra. "That difference was highly statistically significant," Berger said. Side effects were generally mild in both groups, and led to few discontinuations of treatment.

"Kaletra is considered the gold standard as a second line treatment," he said. "I now think we have a practice-changing result with these trial results."

In a commentary in the Lancet, Bernard Hirschel and Thomas Perneger from Geneva Hospital in Switzerland, chided the DUET authors for producing two duplicative studies instead of pooling the virtually identical results into one paper that appears to show even better results for patients receiving etravirine - in that these patients had a reduced risk of clinical events, death or hospitalization.

"People care whether they get sick and die, and rather less whether their laboratory results are normal," they wrote.

The doctors also suggested that even while HIV/AIDS is being turned into a chronic disorder when medication is available rather than a death sentence, it is still encouraging to see advances are still possible with new drugs.

Non-nucleoside reverse transcriptase inhibitors and protease inhibitors represent two classes of a rapidly expanding arsenal of weapons that prevent replication of HIV. To date, however, no vaccine has been developed against the disease that has killed more than 25 million people worldwide in the past 25 years and still infects 40 million today. There is no cure for the disease, requiring life-long treatment.

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