Antiretroviral Therapy of HIV: New Data From the 2007 International HIV Drug Resistance Workshop

Introduction

The XVI International HIV Drug Resistance Workshop was held in Barbados, June 12-16, 2007. This conference is consistently considered to be one of the best research meetings in the field of HIV therapeutics and provides a setting for presentation of important new data on new antiretrovirals, HIV pathogenesis, mechanisms and epidemiology of drug resistance, and new technologies for measurement of HIV drug resistance. Highlights of the conference are reviewed in this report.

Resistance to Integrase Inhibitors

Integrase inhibitors are a novel class of antiretroviral therapies under investigation in both therapy-experienced and therapy-naive patients. The lead compound in this class, raltegravir, is currently in phase 3 study, whereas a second integrase inhibitor, elvitegravir, has been evaluated in a phase 2b study. Given the need for new therapies with activity in patients with multidrug-resistant virus, data on resistance patterns associated with exposure to integrase inhibitors are of great interest

More here: http://www.medscape.com/viewarticle/561463

Experts Discuss Latest Drugs And Treatment To Stop HIV Replication

AIDS/HIV experts gathered in Sydney for day 3 of the 4th International Aids Society (IAS) Conference discussed the progress being made in research and treatment development for fighting the global pandemic. The main thrust of a new generation of HIV treatments appears to be stopping the virus from spreading among people, and from replicating itself inside a person, as well as attacking it directly, which was the main thrust of earlier treatments.

The day's plenary discussions focussed on three main areas: Male Circumcision, Gene Therapy and New Treatments.

In a session titled "Male Circumcision: From Research to Practice", Robert Bailey, of Professor of Epidemiology at the University of Illinois at Chicago and Research Associate at the Field Museum in Chicago, US, said that scientists now have "compelling evidence" that male circumcision reduces HIV transmission from women to men by around 60 per cent. Over 45 observational studies, three major clinical trials and several biological studies support this.

Bailey himself has conducted studies in Uganda, Kenya, Malawi and Zambia, and also in the US.

He described estimating models that show circumcision could help prevent millions of new HIV infections in sub-Saharan Africa. About 30 per cent of the world's males are circumcised, and in Africa this figure is 67 per cent. Circumcising more men in the high HIV prevalence areas would be very cost-effective and would have enormous impact, says Bailey.

In another session, Dr John Rossi who is Professor of Molecular Biology and Dean of the Graduate School of Biological Sciences at City of Hope's Beckman Research Institute in the US led a discussion titled "Use of Gene Therapy to Develop HIV Treatments".

Gene therapy is a cutting edge biotechnology that helps to fight disease by switching off the "bad" genes that promote it.

Rossi and colleagues working at his lab have found three small pieces of RNA, ribonucleic acid, that behave like gene inhibitors that stop HIV from replicating itself. They are developing a "virus vector" that will insert the DNA of the RNA inhibitors into patients. The RNA inhibitors target the virus directly, and an associated viral protein, and also block a site on cells that interact with HIV. The "triple construct vector" is now being tested in two different human trials by Rossi and his team.

A third plenary session dealt with the topic of "New Agents and Treatment Strategies". This was led by Dr Joseph Eron, who is Professor of Medicine in the Division of Infectious Diseases at the University of North Carolina at Chapel Hill School of Medicine in the US.

Eron said there is a lot of change in the field of HIV clinical care. Existing treatments are getting better and new classes of HIV drugs are appearing that work in completely new ways.

He said that more than 20 antiretroviral treatments were now working in the field, but he was most excited by a new type of drug called integrase inhibitors. Integrase inhibitors stop HIV getting into new cells. There are two drugs in development, one is already being trialled in Australia, Raltegravir. This drug is supposed to be more potent than existing drugs and showed fewer adverse events, said Eron. He also said such compounds now gave patients with resistant HIV strains real hope that their viral load could be suppressed to "undetectable levels".

Delegates were upbeat about the new drugs and genetic therapies, and a new word entered the discussion - "eradication". This is perhaps the first time that an HIV/AIDS conference has dared to use this word, eradication, in what appears to be more than a wishful sense.

FDA Panel To Review Merck's Antiretroviral Raltegravir In September

An FDA panel of experts will review Merck's experimental antiretroviral drug raltegravir in September, the agency announced on Wednesday, the AP/Yahoo! Finance News reports (AP/ Yahoo! Finance News, 7/11). Merck in June announced that FDA granted priority review status to raltegravir, an experimental integrase inhibitor. Raltegravir effectively decreases HIV viral loads after 24 weeks of use among HIV-positive people who have not responded to other treatments, according to a study published in the April 14 online edition of the journal Lancet. Raltegravir works by blocking an HIV enzyme called integrase. Integrase is one of the three enzymes necessary for HIV to replicate in the body, and integrase inhibitors stop HIV from inserting its genes into uninfected DNA. The other two enzymes necessary for viral replication, reverse transcriptase and protease, already are targeted by a variety of antiretroviral drugs.

Merck said that if the drug is approved, it will be used in combination with standard oral antiretrovirals by HIV-positive people who have developed resistance to their current treatments. The company said it will begin filing marketing applications outside the U.S. Raltegravir will be sold under the brand name Isentress (Kaiser Daily HIV/AIDS Report, 6/29).

According to documents posted to FDA's Web site, the panel plans to assess the safety and efficacy of raltegravir on Sept. 5 (AP/Yahoo! Finance News, 7/11).

"Reprinted with permission from http://www.kaisernetwork.org. You can view the entire Kaiser Daily Health Policy Report, search the archives, or sign up for email delivery at http://www.kaisernetwork.org/dailyreports/healthpolicy. The Kaiser Daily Health Policy Report is published for kaisernetwork.org, a free service of The Henry J. Kaiser Family Foundation . © 2005 Advisory Board Company and Kaiser Family Foundation. All rights reserved.

HIV confab: Progress in treatment, but access inadequate

More than 5,000 researchers, community advocates, and people with HIV gathered this week in Sydney, Australia, for the fourth International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention.

The IAS conference, which alternates every other summer with the International AIDS Conference, has traditionally focused more on the medical management of HIV AIDS disease.

While there were no major new treatment breakthroughs announced in Sydney, the overall mood was upbeat due to continued incremental improvements in therapy.

At the retrovirus conference in February, researchers announced promising results for two antiretroviral drugs from entirely new classes – the CCR5 inhibitor maraviroc (Celsentri) and the integrase inhibitor raltegravir (Isentress) – in highly treatment-experienced patients with extensive drug resistance. In Sydney, it was reported that both drugs also work well in people starting treatment for the first time.

With today's better drugs, experts are again discussing the benefits of early therapy. This approach was popular in the late 1990s, but fell out of favor due to unexpected long-term side effects. Today, however, the pendulum appears to be swinging back.

Conference co-chair Dr. David Cooper of Australia's National Centre in HIV Epidemiology and Clinical Research reignited another old debate when he suggested that new therapies might be able to completely eradicate the virus.

"Eradication was talked about when antiretroviral therapies became available in the mid-1990s, but went off the agenda because of the toxicity of the drugs," he said. "Now, with some of the newer drugs and newer strategies, it's back on the agenda again."

But Dr. Anthony Fauci, with the National Institute of Allergy and Infectious Diseases, who spoke at the conference's opening session on July 22, sounded a less optimistic note.

"You can stop [HIV] multiplying and keep someone quite well for many, many years," he told reporters. "But so far we haven't even come close to truly eradicating it in anyone."

But such debates remain largely irrelevant in developing countries, where millions of people with HIV/AIDS still go without needed treatment.

According to "Missing the Target #4," a new report from the International Treatment Preparedness Coalition released on July 18, wealthy country governments and international donors are failing to provide free or low-cost anti-HIV drugs for all who need them throughout the developing world.

"With fewer than one-third of people living with HIV in low- and middle-income countries having access to life-saving medications, and still fewer with access to proven prevention services such as condoms and sterile syringes, the goal of universal access by 2010 must remain a priority," said IAS President Dr. Pedro Cahn. "Science has given us the tools to prevent and treat HIV effectively. The fact that we have not yet translated this science into practice is a shameful failure."

On the prevention front, more data support adult male circumcision as part of a comprehensive HIV prevention strategy. But women-controlled prevention technologies have seen recent setbacks, including a higher rate of new HIV infections in a large trial of the UsherCell vaginal microbicide and no protective benefit in a recent study of cervical diaphragms.

While much attention has focused on HIV-positive women and children in poor countries, men who have sex with men still account for a large proportion of people living with or at risk for AIDS worldwide. But these men are often ignored, marginalized, or subject to violence due to the stigma surrounding homosexuality in many parts of the world.

To address this issue, the American Foundation for AIDS Research this week launched a new initiative to reduce the spread of HIV among MSM in developing countries.

"For too long, squeamish and homophobic governments have failed to provide even the basic tools for MSM to protect themselves from HIV," said AmFAR's Kevin Frost. "Only one in 20 MSM globally have access to appropriate services."

To redress this shortcoming, the new initiative – funded in part by Elizabeth Taylor and the MAC AIDS Fund – will work to empower local grassroots organizations, advocate for better policies, and research gaps related to MSM, many of whom may not self-identify as "gay" or "bisexual."

Several New HIV Treatment Options to Be Available Over Next 12 Months

Several new treatment options for patients with HIV could become available over the next year as manufacturers advance regulatory submissions for new antiretroviral drugs.

The European Medicines Agency’s (EMEA) Committee for Medicinal Products for Human Use (CHMP) recently issued a positive opinion for Pfizer’s entry inhibitor Celsentri (maraviroc) based on data that showed the product was superior to standard optimized antiretroviral therapy.

The CHMP opinion recommends approval of Celsentri for use in combination with other antiretroviral therapies in treatment-experienced patients when the presence of CCR5-tropic HIV-1 is detectable. The company received an approvable letter from the FDA for the product last month.

Development of other HIV medicines advanced recently as well. Johnson & Johnson submitted a new drug application (NDA) for its investigational non-nucleoside reverse transcriptase inhibitor (NNRTI) etravirine, or TMC125, being developed by subsidiary Tibotec Therapeutics.

Abbott announced the recent submission of global regulatory filings for a new, oral pediatric dosage form of Kaletra. The submissions are under priority review by the FDA and accelerated review by the EMEA, Abbott said.

Merck expects FDA action on its NDA for integrase inhibitor Isentress (raltegravir) in mid-October, the firm said in June. The application requests approval of the use of Isentress in combination with other antiretrovirals for treatment-experienced HIV patients where there is evidence of virus-replication.

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.
ADVERTISEMENT (article continues below)

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."

Elimination of HIV from body within eight years if treatment starts just after infection

American researchers are suggesting that commencing antiretroviral treatment soon after infection with HIV could eradicate the infection within eight years. Their study, which involved seven patients, is published in the June 15^th edition of the Journal of Infectious Diseases. The investigators found that the reservoir of resting, HIV-infected CD4 cells fell by 50% every five months of HIV therapy and they estimated that the pool of cells latently infected with HIV would be eradicated in 7.7 years.

But the authors of an accompanying editorial are rather sceptical. They highlight the slower rate of viral decay seen in four of the patients in the study, and suggest that the persistence of just a few HIV-infected cells would potentially be enough to reignite infection with HIV should therapy be discontinued. The authors of the editorial also note that there is a slight chance that HIV could persist in cells other than CD4 cells, or in tissue.

Current HIV treatment strategies have been unable to eradicate HIV infection. This is mainly because of the persistence of reservoirs of HIV, particularly a pool of HIV-infected resting CD4 cells.

As eradication of HIV is not possible as long as these latent infected cells persist, investigators wished to determine the half-life of these reservoirs. Such information could, they hope, help develop HIV-eradication strategies involving the use of newer, more potent antiretroviral drugs such as integrase inhibitors.

Investigators therefore closely monitored seven patients who had initiated HIV therapy shortly after they contracted with infection.

The seven individuals commenced HIV therapy an average of seven months after they experienced an HIV seroconversion illness and had their infection diagnosed. All were prescribed antiretroviral therapy consisting of at least one protease inhibitor with two nucleoside reverse transcriptase inhibitors. The mean duration of HIV therapy was 40 months and all the patients achieved and maintained an undetectable plasma vital load.

Tests showed that the reservoir of latently infected cells decayed in all the patients and the investigators calculated that it fell by an average of 50% every 4.6 months. They therefore estimated the complete elimination of HIV-infected resting CD4 cells in an average of 7.7 years.

“The present study demonstrates that decay of the latent viral reservoir does occur in resting CD4 T-cells in patients in whom antiviral therapy was initiated during the early phase of HIV infection”, write the investigators.

They believe that their finding could have significant clinical implications, particularly “regarding the design of future therapeutic strategies aimed at eradicating HIV. Although ongoing HIV infection cannot be ruled out in individuals who began antiviral therapy early in HIV infection, it would be of considerable interest to pursue evidence for the possibility of eradicating HIV in such individuals whose duration of therapy has reached [eight years].”

They note that they will be able to examine this hypothesis in a sizeable population. Potent anti-HIV therapy became available in 1996 and there will soon be a significant number of patients who started treatment soon after infection and have maintained viral suppression for a protracted period.

They also plan to use Merck's new integrase inhibitor raltegravir (Isentress) and the Roche fusion inhibitor enfuvirtide (Fuzeon) in future patients, in order to increase the speed at which viral load declines during the initial phase of treatment, in the hope that this will reduce the pool of infected cells and thus shorten the period of treatment required for the pool to decay. The drugs will also be used in patients already under study.

The authors of an accompanying editorial are somewhat more cautious. They note “a close examination of the data suggests that, at least in 4 of the patients studied, a second, slower phase of viral decay appears to exist.” They add that the persistence of just “a few infected cells…may be enough to reignite infection.” Furthermore, “the possibility exists that HIV may rarely persist in cells other than resting CD4 T-cells or that circulating resting cells somewhat underrepresent infection in resting cells in the tissue.”

Studies showing the presence of HIV in cerebrospinal fluid and the central nervous system are also highlighted by the editorial’s authors, who also point to evidence of the persistence of HIV in lymphoid tissue in the gut.

Antiretroviral therapy can mean that HIV-infected individuals enjoy a normal prognosis. Therefore, the authors believe that the “bar for improving over current therapies is high.” HIV treatment is becoming more potent, but not at the cost of added inconvenience or toxicity, consequently “therapies that attempt to eradicate HIV must avoid undue risk and toxicity."

Reference
Chun T-W et al. Decay of the HIV reservoir in patients receiving antiretroviral therapy for extended periods: implications for eradication of virus. J Infect Dis 195 (online edition), 2007.

Margolis DM et al. Eliminating persistent HIV infection: getting to the end of the rainbow. J Infect Dis 195 (online edition), 2007.

Merck's Antiretroviral Raltegravir Found To Reduce Viral Loads Among HIV-Positive People With Drug Resistance

Merck's integrase inhibitor raltegravir effectively decreases HIV viral loads after 24 weeks of use among HIV-positive people who have not responded to other treatments, according to a study published in the April 14 online edition of the journal Lancet, AFP/Yahoo! News reports (AFP/Yahoo! News, 4/13). Raltegravir, formerly known as MK-0158, works by blocking an HIV enzyme called integrase. Integrase is one of the three enzymes necessary for HIV to replicate in the body, and integrase inhibitors would stop HIV from inserting its genes into uninfected DNA. The other two enzymes necessary for viral replication -- reverse transcriptase and protease -- already are targeted by a variety of antiretrovirals (Kaiser Daily HIV/AIDS Report, 2/28). For the study, Beatriz Grinsztejn of Merck Research Laboratories in Westpoint, Pa., and colleagues divided 178 HIV-positive people into four groups. Participants in three groups received different doses of raltegravir, ranging from 200 milligrams to 600 milligrams, and the fourth group received a placebo. All four groups also took a basic "background treatment," according to AFP/Yahoo! News. The study found that after 24 weeks, HIV viral loads dropped below a measurable threshold of 50 copies per milliliter in 65% of the patients taking the drug, nearly five times as many as the placebo group. The study also found that immune system responses substantially improved. Pedro Cahn and Omar Sued of the Department of Clinical Research at the Fundación Huesped in Buenos Aires, Argentina, in an accompanying Lancet commentary wrote that raltegravir "showed unprecedented levels of virological efficiency," adding that the treatment "achieved virological suppression even in patients with limited options." According to Cahn and Sued, "If no long-term, unexpected side effects or resistance issues emerge, raltegravir will have a major role in salvage therapy, particularly in combination with another new drug" (AFP/Yahoo! News, 4/13). Merck has announced that it will apply for FDA approval in the second quarter of 2007 (Kaiser Daily HIV/AIDS Report, 2/28).

Isentress (raltegravir, Isentress): HIV Treatment Information

What is Isentress?

Isentress is an experimental integrase inhibitor being developed by Merck & Company.

After HIV's genetic material is deposited inside a cell, its RNA must be converted (reverse transcribed) into DNA. A viral enzyme called integrase then helps to hide HIV's DNA inside the cell's DNA. Once this happens, the cell can begin producing genetic material for new viruses. Integrase inhibitors, such as Isentress, are designed to block the activity of the integrase enzyme and to prevent HIV DNA from entering healthy cell DNA.

Isentress will need to be used in combination with other drugs. Clinical trials will evaluate its effect in combination with other drugs, including those currently approved for the treatment of HIV.

Merck has announced that it has initiated an expanded access program (EAP), called EARMRK, for Isentress. The program provides the drug, free of charge, to HIV-positive people with limited treatment options. This is defined as people who: 1) have HIV resistance to at least one drug in all three classes of oral HIV drugs, 2) are failing their current regimens, and 3) require a new drug to which their HIV may not be resistant. For more information on the EARMRK program, call 1-877-EARMRK1 or review Merck's EARMRK website.

What is already known about Isentress?

The Isentress dose being studied in phase III clinical trials is 400mg taken by mouth twice a day.

Isentress might interact with other medications, including those used to treat HIV. It is important that your personal physician and/or the research nurse or study investigator be aware of all drugs you are taking, including those you buy without a prescription.

Isentress holds promise for HIV-positive patients who have taken other anti-HIV drugs in the past. Because Isentress targets HIV differently than currently available drugs, chances are that most people living with the virus—regardless of their treatment history—will likely benefit from using Isentress.

What do we know from clinical trials of Isentress?

Results of a two-part phase II study have been presented. The first part of the study enrolled 35 HIV-infected patients who had not received other anti-HIV medications in the past. The patients received one of four doses of Isentress twice a day (100mg, 200mg, 400mg, or 600mg) or placebo without any other anti-HIV medications. After ten days of treatment, viral loads were reduced in all patients receiving Isentress by 1.7 to 2.2 log (approximately 98%).

The second part of the study enrolled 198 HIV-positive people, including 30 participants enrolled in part one of the study. The patients were to take one of the four doses of Isentress or Sustiva® (efavirenz). All patients in the study also received Viread® (tenofovir) and Epivir® (lamivudine). After 24 weeks of therapy, 85% to 95% of patients taking the Isentress regimen saw their viral loads reduced to less than 50, regardless of which dosing group they were in. In the Sustiva group, approximately 92% of patients experienced viral load reductions to less than 50. CD4 cell counts increased in all patients after 24 weeks or treatment. This study will follow patients for a total of 48 weeks.

A phase IIb study enrolled 178 HIV-positive participants, most of whom had evidence of resistance to drugs in three available classes (NRTIs, NNRTIs, and PIs). Patients were randomly assigned to one of three doses of Isentress (200, 400, or 600mg twice daily), or placebo, in combination with a regimen of currently approved anti-HIV drugs. After 24 weeks of treatment, up to 67% of the patients receiving Isentress (most notably those receiving 600mg twice daily) had viral loads below 50, compared to 14% of the patients who took placebo.

Phase III studies of Isentress have been started. An expanded access program (EAP) was initiated in September (see above and below).

What is known about side effects?

In the two phase II studies reported to date, Isentress therapy was generally well tolerated. The most common side effects included diarrhea, nausea, vomiting, fatigue, dizziness, headache, flushing, itching, and injection-site reactions (among patients taking Fuzeon®). However, these side effects were also seen in patients receiving placebo. The only possible treatment-related toxicity of concern was a patient in the two-part phase II study taking 600mg Isentress group. He was required to discontinue therapy due to significantly increased liver enzymes.

Additional data from studies evaluating the safety of Isentress are needed.

Who should not take Isentress?

It is not known whether Isentress will harm an unborn baby. It is very important to treat HIV/AIDS during pregnancy to reduce the risk of infecting your baby. Talk to your doctor about your treatment options.

It is not known whether Isentress passes into breast milk and what effect it may have on a nursing baby. To prevent transmission of the virus to uninfected babies, it is recommended that HIV-positive mothers not breast-feed.

Merck's Integrase Inhibitor Gets a Name: Raltegravir

Merck unveiled a new name for its integrase inhibitor, raltegravir, along with 16-week data on a pair of phase 3 clinical trials at the 14th Conference on Retroviruses and Opportunistic Infections.

The first-in-class compound is a small molecule that blocks an early stage in the HIV lifecycle, the integration of the virus into host cell DNA. The drug formally was known as MK-0518.

The Benchmrk 1 and 2 studies respectively enrolled 350 and 349 patients with triple-class drug failure defined as genotypic/phenotypic resistance to 1 or more drugs in each of the 3 classes and HIV RNA viral load of more than 1000 copies/mL. The typical patient was a man in his mid-40s, with a CD4+ cell count of about 150 cells/µL, and a viral load of 4.5 logs HIV-1 RNA, said David Cooper, MD, the Australia National HIV Center, who led the Benchmrk 1 study.

Background therapy was optimized and patients were randomized 2:1 to receive 400 mg of raltegravir twice daily or placebo. The 16-week interim analysis was built into the 48-week study at the request of European regulatory authorities.

Combined interim analysis of the 2 studies found that 79% of patients receiving raltegravir plus optimized background therapy (OBT) suppressed the virus below 400 copies/mL at week 16 compared with 43% of those receiving placebo plus OBT. "There were good CD4 count responses of around 100 cells, and a viral load response of 2 logs," said Dr. Cooper. Adverse effects were comparable between the 2 groups.

Dr. Cooper was particularly excited that the study allowed use of drugs that were still experimental at that time as part of OBT, in this instance, darunavir (subsequently approved), which was available through expanded access. Roughly 20% of patients in the slightly earlier study incorporated darunavir into their regimen and that increased to about 50% in the second study that started a bit later.

Benchmrk 2 lead investigator Roy Steigbigel, MD, from the University of Stony Brook in New York, said that 61% of patients with no active drug other than raltegravir achieved a viral load below 400 copies/mL. However, the drug requires the support of one or more active drugs to sustain viral suppression.

In the patients who added enfurvitide or darunavir for the first time as part of OBT, viral load dropped below 400 copies/mL in 90%, while 98% of those who received both drugs for the first time achieved a viral load less than 400 copies/mL, he said.

Resistance to raltegravir can develop along 2 different pathways, at positions 155 and 148 of the HIV integrase. They are associated with clusters of other mutations, Dr. Cooper said. "My understanding is that there is no cross resistance" with any of the approved classes of drugs. He cautioned against reading any clinical relevance into these findings because of the relatively small number of patients and short duration of use of the drug.

John Mellors, MD, vice chair of the conference scientific committee, was rhapsodic in declaring the significance of these data. He said at a CROI news conference that he moderated, "When HAART initially came out, the response [of <400>

Dr. Mellors was elated to see comparable rates of suppression of viral load below 400 copies/mL in this highly treatment-experienced population. He said, "This is really a remarkable development."

According to Daniel Kuritzkes, MD, "What clinicians need to be doing with their experienced patients is assessing patients' clinical status carefully and not leap to introduce any one of the new drugs until they are convinced they can put together a fully active regimen," Dr. Kuritzkes is director of AIDS research at Brigham and Women's Hospital in Boston, Massachusetts. He was not involved in the trial.

That may mean using an expanded access program or holding off until the drug becomes available. Dr. Kuritzkes said, "You really need to use these drugs in combination, whenever possible."

Merck is enrolling treatment-naive patients into phase 3 trials. The company anticipates submitting 24-week data on treatment-experienced patients to the US Food and Drug Administration later this year, with approval coming by the end of 2007.

Raltegravir - New HIV drug shows promise

A new drug called raltegravir shows promise in combating drug-resistant HIV, concludes an international study in The Lancet medical journal. HIV is the virus that causes Aids.

Raltegravir belongs to a new class of drugs called integrase-inhibitors, which block an enzyme essential for HIV to replicate itself, BBC News reported.

The study included 178 patients with advanced HIV who failed to respond to the antiretroviral drugs they'd been taking for about 10 years. The patients were assigned to take their usual drugs plus either raltegravir or a non-medicinal placebo.

After 24 weeks, patients taking raltegravir showed a 98 percent drop in the amount of HIV genetic material in their blood, compared to a 45 percent drop among the placebo group. Those taking raltegravir also showed a significant boost in the number of CD4 cells, an indication of immune response, BBC News reported.

"This drug has the potential to become an important component of combination treatment regimens...for patients failing current therapies with multidrug-resistant virus and limited treatment options," wrote the study's authors at Merck Research Laboratories in Pennsylvania. – (HealthDayNews)

New anti-AIDS drug aimed at the global market

Shanghai Target Drug Pharmaceutical Co., Ltd. and Australia's Avexa Limited have signed an agreement on international cooperation in Shanghai to promote follow-up studies of a new entry-inhibitor HIV drug, TD0232.

According to the agreement, China has the intellectual property rights to the drug, but will share the rights to any new intelligence that emerges during follow-up research and development. It also has full manufacturing and distribution rights to the drug in China, (including Hong Kong, Macao and Taiwan regions). Avexa is bearing the costs of the study, and has full rights to markets outside China.

In 2003, scientists discovered a number of drug molecules that they believed capable of fighting HIV and applied for an international patent. In June 2003, the Shanghai Institute for Biological Sciences under the Chinese Academy of Sciences and the Shanghai Institute of Organic Chemistry pooled their knowledge of the molecule. They entered an agreement with Shanghai Fudan-Zhangjiang Bio-Pharmaceutical Co., Ltd. to establish the Shanghai Target Drug Pharmaceutical Co., Ltd. to promote follow-up study of the new drug. Preclinical trials have revealed that the drug is equally as effective as other, similar types of drugs available.

Raltegravir May Be Safe, Effective in Treating Multidrug-Resistant HIV

The HIV-1 integrase inhibitor raltegravir (MK-0518) is safe and effective in treatment-experienced patients with multidrug-resistant virus, according to the results of a phase 2, randomized controlled trial study reported in the April 14 issue of The Lancet.

"Raltegravir (MK-0518) is an HIV-1 integrase inhibitor with potent in-vitro activity against HIV-1 strains, including those resistant to currently available antiretroviral drugs," write Beatriz Grinsztejn, from the Evandro Chagas Clinical Research Institute/Oswaldo Cruz Foundation in Rio de Janeiro, Brazil, and colleagues from the Protocol 005 Team. "The aim of this study was to assess the safety and efficacy of raltegravir when added to optimised background regimens in HIV-infected patients."

HIV-infected patients eligible for this multicenter, triple-blind, dose-ranging study had HIV-1 RNA viral load higher than 5000 copies/mL, CD4 cell counts greater than 50 cells/μL, and documented genotypic and phenotypic resistance to at least one nucleoside reverse transcriptase inhibitor, one nonnucleoside reverse transcriptase inhibitor, and one protease inhibitor. The main outcome measures were change in viral load from baseline at week 24 and safety; analysis was by modified intention-to-treat.

Of 179 patients eligible for randomization, 44 patients were randomized to oral treatment twice daily with raltegravir 200 mg, 45 to raltegravir 400 mg, 45 to raltegravir 600 mg, and 45 to placebo. One patient in the 200-mg group did not receive treatment and was therefore excluded from analysis.

Median duration of previous antiretroviral treatment was 9.9 years (range, 0.4 - 17.3 years), and mean baseline viral load was 4.7 ± 0.5) log₁₀ copies per mL. Of 4 patients who discontinued because of adverse events, 3 (2%) were in the raltegravir groups and 1 patient (2%) was in the placebo group.

Of 41 patients who discontinued because of lack of efficacy, 14 (11%) were in the raltegravir groups and 27 (60%) were in the placebo group. Mean change in viral load from baseline at week 24 was –1.80 (95% confidence interval [CI], –2.10 to –1.50) log₁₀ copies/mL in the 200-mg group, –1.87 (95% CI, –2.16 to –1.58) log₁₀ copies/mL in the 400-mg group, –1.84 (95% CI, –2.10 to –1.58) log₁₀ copies/mL in the 600-mg group, and –0.35 (95% CI, –0.61 to –0.09) log₁₀ copies/mL in the placebo group. At all doses, raltegravir had a safety profile similar to that of placebo, with no dose-related toxicities.

"In patients with few remaining treatment options, raltegravir at all doses studied provided better viral suppression than placebo when added to an optimised background regimen," the authors write. "The safety profile of raltegravir is comparable with that of placebo at all doses studied."

Raltegravir is manufactured by Merck & Co, which employs 4 of the authors. Some of the other authors report various financial relationships with Merck & Co, Abbott, Roche, GlaxoSmithKline, Bristol-Myers Squibb, Tibotec, Virgo, Boehringer Ingelheim, and/or Pfizer.

In an accompanying editorial, Pedro Cahn and Omar Sued, from the Fundación Huesped in Buenos Aires, Argentina, call these results "encouraging."

"Raltegravir showed a good safety profile and high potency in naive and experienced patients, achieving virological suppression even in patients with limited options," Drs. Cahn and Sued write. "If no long-term unexpected side-effects or resistance issues emerge, raltegravir will have a major role in salvage therapy, particularly in combination with another new drug. 48-week data for naive patients are eagerly expected. Should these data show similar efficacy to efavirenz-based regimens, raltegravir could be considered as a new option to build into initial regimens for highly active antiretroviral therapy."