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).

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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."