Integrase Inhibitor Raltegravir as Effective as Efavirenz-Based Therapy in Naive HIV-Infected Patients: Presented at IAS

Close to 90% of patients treated with either the novel integrase inhibitor raltegravir or the standard-of-care non-nucleoside reverse transcriptase efavirenz were able to suppress HIV to undetectable levels, researchers said here at the 4th International AIDS Society (IAS) Conference on HIV Pathogenesis, Treatment and Prevention.

However, Martin Markowitz, MD, Clinical Director, Aaron Diamond AIDS Research Center, New York, New York, said that treatment with raltegravir -- which is still awaiting approval by the US Food and Drug Administration -- caused fewer adverse effects in the patients during the 48-week trial.

Dr. Markowitz and colleagues enrolled 198 treatment-naive patients and randomized them to one of four doses of raltegravir -- 100, 200, 400, and 600 mg twice a day -- or to 600 mg a day of efavirenz. Both treatments were administered with tenofovir and lamivudine.

Regardless of the study dose, it took about 4 weeks for about 90% of patients to reach a viral load of less than 400 copies of HIV RNA per milliliter of blood, he said. In contrast, patients on efavirenz took between 8 and 12 weeks to reach the same level.

"The FDA application for raltegravir is for its use in patients who have had previous antiretroviral treatments but have not been able to suppress viral levels to undetectable," Dr. Markowitz said. "The studies we presented here in Sydney are exploring the possibility of using the drug early in treatment."

In the study, Dr. Markowitz noted, there was no difference in the proportions of patients who reached low levels of HIV by the end of the study. Also, the proportion of patients who experienced treatment failure -- defined as nonresponse or a rebound in viral load -- was 3% for both raltegravir and efavirenz.

The major difference between the drugs, he said, was in the side effects, with raltegravir being "more benign." There were no dose-related toxicities.

The most common side effects were the known central nervous system events of efavirenz -- abnormal dreams, dizziness, and headache -- and those were higher in the efavirenz arm.

Raltegravir also appears to be neutral with respect to changes in lipids, Dr. Markowitz said.

The study was sponsored by Merck, which is developing raltegravir. Merck has filed for approval of raltegravir with the FDA. A hearing is scheduled for September 5, 2007.


[Presentation title: Rapid Onset and Durable Antiretroviral Effect of Raltegravir (MK-0518), a Novel HIV-1 Integrase Inhibitor, as Part of Combination ART in Treatment-Naive HIV-1 Infected Patients: 48-Week Data. Abstract TUAB104]

Can switcing off genes fights HIV without drugs?

THE newest generation of HIV drugs are so potent they can almost eradicate the virus in those who are infected, scientists say.

AIDS researchers have outlined the latest cutting edge treatments, including a new class that appears to dramatically limit the effects of the disease.

Also showing promise is an experimental therapy in which HIV genes in infected cells are "switched off", effectively allowing sufferers to control their condition without drugs.

An American HIV specialist Dr Joseph Eron told the International AIDS Society conference in Sydney there were more than 20 antiretroviral treatments on the market, but most excitement was being generated by a new class of drugs called integrase inhibitors.

These drugs work differently in that they block the HIV virus from infecting new cells. Two drugs are being developed with one, Raltegravir, already available for trials in Australia. Data presented at the congress shows the medication, to be put forward for licensing in the US in September, is more potent than its predecessors and has fewer side effects.

Used in combination with a cocktail of the best drugs available, it was found to be far superior for treating HIV in people who have become resistant to other medications. "There is now an opportunity for even our most treatment-experienced patients to become fully suppressed, to get their viral load to these undetectable levels," said Dr Eron.

Geneticists, too, have come up with new ways to fight the disease. HIV gets into human genes and damages the cells by producing more HIV. A molecular biologist, John Rossi, and colleagues at the City of Hope Beckman Research Institute in California have worked out how to turn off this HIV gene, potentially allowing the disease to be controlled for long periods without drugs.

Professor David Cooper, director of Australia's National Centre for HIV Epidemiology and Clinical Research, said drug and genetic developments had put eradication in the spotlight. "These new drugs, new strategies mean we are talking about eradication … and that's very exciting."

Merck's HIV drug acts fast against virus

Merck's investigative AIDS drug raltegravir -- sold as Isentress -- did as well as the standard of care treatment for new patients, say U.S. doctors.

About 90 percent of all the patients treated with either raltegravir of efavirenz -- marketed as Sustiva -- were able to suppress HIV to undetectable levels.

In a report at the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention in Sydney, Martin Markowitz, clinical director of the Aaron Diamond AIDS Research Center in New York, said that treatment with raltegravir -- awaiting approval by the U.S. Food and Drug Administration -- caused fewer adverse side effects in the patients during the 48-week trial.

Markowitz also told United Press International that treatment with raltegravir resulted in a faster reduction of virus than with efavirenz.

Raltegravir, if approved by the Food and Drug Administration, would be the first in a new class of drugs known as integrase inhibitors. Integrase is one of the three key enzymes required by the virus to replicate. Efavirenz attack the reverse transcriptase enzyme; other HIV drugs attack the protease enzyme.

"Isentress will be reviewed by the FDA in an advisory committee hearing Sept. 5," Lynn Kenny, a Merck executive, told UPI.

"The FDA application for raltegravir is for its use in patients who have had previous antiretroviral treatments but have not been able to suppress viral levels to undetectable," Markowitz said. "The studies we presented here in Sydney are exploring the possibility of using the drug early in treatment."

Regardless of the study dose, it took only about four weeks for patients to reach an undetectable viral load. In contrast, patients on efavirenz took between eight and 12 weeks to reach the same level.

Second Generation Drug Effective Against Resistant HIV Strains, New Trials

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 drug patient to expect to attain undetectable levels of HIV.
http://www.medicalnewstoday.com/articles/76185.php

Second-Generation HIV Drug Treats Resistant Virus

Results from a highly anticipated clinical study show that an experimental drug suppressed the human immunodeficiency virus (HIV) to undetectable levels in people with highly drug-resistant forms of the pathogen. The drug, TMC125 (etravirine), is the first of its kind in nearly a decade and is one of three new drugs capable of treating drug-resistant HIV that the Food and Drug Administration (FDA) is expected to approve this year.

The new drugs offer the hope of treatment to perhaps thousands of HIV patients who have stopped responding to other medications, says William Towner, medical director of the Kaiser Permanente HIV/AIDS research trials program and member of the study team, which reported its findings online today in The Lancet. By keeping the virus at undetectable levels, researchers believe they can slow the spread of drug-resistant varieties.
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The phase III study tracked 591 U.S. patients whose infections were resistant to the most common types of antiretrovirals, the medications used to treat HIV. Along with their preexisting regimens they were given the recently approved drug TMC114 (darunivir) as well as either TMC125 or a placebo. After 24 weeks, virus levels were undetectable—defined as less than 50 copies per milliliter of blood—in 62 percent of patients receiving TMC125, compared with 44 percent that received only the other drugs.

Tibotec, the company that developed TMC125 and darunivir, sponsored the trial and was involved in analyzing the data.

Drug manufacturers have developed more than 20 antiretroviral compounds since 1987 when the antiretroviral drug AZT came to market. All but one fall into one of three categories—either nucleoside or nonnucleoside reverse transcriptase inhibitors or protease inhibitors—based on the part of the virus they target.

Combining drugs from multiple classes into so-called cocktails makes it harder for the rapidly mutating virus to evolve resistance, but adding a single drug to a failing cocktail quickly breeds resistance to it, too. And when a member of one class fails it can take the rest along with it. A single mutation renders HIV immune to the three existing nonnucleoside transcriptase inhibitors.

TMC125 is a new, fourth member that picks up where the others leave off. When combined with darunivir and a third drug, it led to undetectable virus in 82 percent of 82 patients, according to the study.

"This is the first example that a second generation of this class can actually be part of a new regimen," says HIV researcher Eric Daar of the Los Angeles Biomedical Research Center and the David Geffen School of Medicine at U.C.L.A.

The development of protease inhibitors in the mid-1990s first made it possible to bring the virus to undetectable levels, but additional drugs trickled in one at a time, Towner says. "For many years we've had to make this hard choice" when a cocktail fails, he says. "Do we add the one [new] drug and burn our bridges … or do we wait for two drugs?"

Earlier this year phase III results came in for two other new drugs, Pfizer's maraviroc and Merck's raltegravir, each of which is the first in a new antiretroviral category and leads to undetectable levels of drug-resistant virus in about half of studied cases. All three compounds have been submitted for FDA approval.

They would join the second-generation protease inhibitors darunivir and Pfizer's tipranivir, both approved in the last two years. "This is the second coming of HIV medical therapy," Towner says. "That's what makes [TMC]125 so exciting."

Daar says there is no recent tally of multidrug-resistant HIV but he estimates that tens of thousands may harbor such infections. Towner says that in his clinical practice in Los Angeles, 15 to 20 percent of his 300-plus HIV patients have a highly resistant virus. "It hasn't exploded into a wildfire yet,'' he says, "but the potential exists."

Doctors and patients will never apply medications perfectly, Towner says, hence the existence of multidrug-resistant HIV. But with new cocktails on the horizon, he adds, "the hope would be that in a sizeable number of patients we could avoid any drug resistance."