Popular HIV drug may cause memory declines

Johns Hopkins study suggests the commonly prescribed anti-retroviral drug efavirenz attacks brain cells The way the body metabolizes a commonly prescribed anti-retroviral drug that is used long term by patients infected with HIV may contribute to cognitive impairment by damaging nerve cells, a new Johns Hopkins research suggests. Nearly 50 percent of people infected with HIV will eventually develop some form of brain damage that, while mild, can affect the ability to drive, work or participate in many daily activities. It has long been assumed that the disease was causing the damage, but Hopkins researchers say the drug efavirenz may play a key role. People infected with HIV typically take a cocktail of medications to suppress the virus, and many will take the drugs for decades. Efavirenz is known to be very good at controlling the virus and is one of the few that crosses the blood-brain barrier and can target potential reservoirs of virus in the brain. Doctors have long believed that it might be possible to alleviate cognitive impairment associated with HIV by getting more drugs into the brain, but researchers say more caution is needed because there may be long-term effects of these drugs on the brain. "People with HIV infections can't stop taking anti-retroviral drugs. We know what happens then and it's not good," says Norman J. Haughey, Ph.D., an associate professor of neurology at the Johns Hopkins University School of Medicine. "But we need to be very careful about the types of anti-retrovirals we prescribe, and take a closer look at their long-term effects. Drug toxicities could be a major contributing factor to cognitive impairment in patients with HIV." For the study led by Haughey and described online in the Journal of Pharmacology and Experimental Therapeutics, researchers obtained samples of blood and cerebrospinal fluid from HIV-infected subjects enrolled in the NorthEastern AIDS Dementia study who were taking efavirenz. Researchers looked for levels of the drug and its various metabolites, which are substances created when efavirenz is broken down by the liver. Performing experiments on neurons cultured in the lab, the investigators examined the effects of 8-hydroxyefavirenz and other metabolites and found major structural changes when using low levels of 8-hydroxyefavirenz, including the loss of the important spines of the cells. Haughey and his colleagues found that 8-hydroxyefavirenz is 10 times more toxic to brain cells than the drug itself and, even in low concentrations, causes damage to the dendritic spines of neurons. The dendritic spine is the information processing point of a neuron, where synapses — the structures that allow communication among brain cells — are located. In the case of efavirenz, a minor modification in the drug's structure may be able block its toxic effects but not alter its ability to suppress the virus. Namandje N. Bumpus, Ph.D., one of the study's other authors, has found a way to modify the drug to prevent it from metabolizing into 8-hydroxyefavirenz while maintaining its effectiveness as a tool to suppress the HIV virus. "Finding and stating a problem is one thing, but it's another to be able to say we have found this problem and here is an easy fix," Haughey says. Haughey says studies like his serve as a reminder that while people infected with HIV are living longer than they were 20 years ago, there are significant problems associated with the drugs used to treat the infection. "Some people do seem to have this attitude that HIV is no longer a death sentence," he says. "But even with anti-retroviral treatments, people infected with HIV have shortened lifespans and the chance of cognitive decline is high. It's nothing you should treat lightly." HIV and AIDS CE Course ### The study was supported by grants from the National Institute on Alcohol Abuse and Alcoholism (AA0017408), the National Institute of Mental Health (MH077543, MH075673 and MH71150), the National Institute on Aging (AG034849) and the National Institute of Neurological Disorders and Stroke (NS049465). Other Hopkins researchers involved in the study include Luis B. Tovar y Romo, Ph.D.; Lindsay B. Avery, Ph.D.; Ned Sacktor, M.D.; and Justin McArthur, M.B.B.S., M.P.H. For more information: http://www.hopkinsmedicine.org/neurology_neurosurgery/research/jhu_nimh/researchers

Phase III trial of dapivirine ring begins in Africa: New HIV prevention approach for women

WASHINGTON, D.C., July 24, 2012 – A large clinical trial testing the long-term safety and effectiveness of a new approach for preventing HIV in women – a vaginal ring used once a month – is now underway in Africa, researchers announced today at the XIX International AIDS Conference (AIDS 2012)Alcoholism and Drug Abuse Counselors Continuing Education ASPIRE – A Study to Prevent Infection with a Ring for Extended Use – is a Phase III trial evaluating a vaginal ring that contains dapivirine, a potent antiretroviral (ARV) drug originally developed to treat HIV. The ring slowly releases dapivirine to cells inside the vagina throughout the one-month period that it's worn, potentially giving women discreet, long-acting protection against HIV transmitted through sex. Nearly 3,500 women in Africa will take part in ASPIRE, which is being led by the Microbicide Trials Network (MTN) and funded by the National Institute of Allergy and Infectious Diseases and the National Institute of Mental Health, which are part of the U.S. National Institutes of Health. The Makerere University-Johns Hopkins University Research HIV Clinical Trial Unit in Kampala, Uganda this week began screening women interested in joining the study. A second site, the Emavundleni Research Center at the Desmond Tutu HIV Foundation, University of Cape Town, South Africa, should be ready to screen potential participants next week. The MTN hopes to conduct ASPIRE at a total of 17 sites in Malawi, Uganda, South Africa, Zambia and Zimbabwe. A second trial, The Ring Study, is being conducted in parallel with ASPIRE. The Ring Study is being led by the International Partnership for Microbicides (IPM), which developed the dapivirine ring, and will involve about 1,650 women. IPM has already enrolled more nearly 400 participants at trial sites in South Africa since the study launched in April. The Ring Study will also be conducted in Rwanda and is expected to start there in August. The two sister studies are the first effectiveness trials of a vaginal ring for HIV prevention. Vaginal rings, which are flexible products that fit comfortably high up inside the vagina and are seldom felt by either partner during sex, are already used in many countries as a way to deliver hormonal contraception. ASPIRE and The Ring Study are also the first large-scale prevention trials involving an ARV other than tenofovir or a tenofovir combination. For this reason, and because it is used for a month at a time, the dapivirine ring is seen as an alternative to tenofovir gel used daily or at the time of sex, and oral pre-exposure prophylaxis (PrEP), which involves the use of a daily ARV tablet – tenofovir or Truvada (tenofovir plus emtricitabine). "As a field, we must continue to develop new strategies for HIV prevention. No single approach will be right for every person. In the same way there is a range of effective choices when it comes to birth control, women must have multiple effective options for HIV prevention," explained Jared Baeten, M.D., Ph.D., of the University of Washington in Seattle, who is leading ASPIRE with Thesla Palanee, Ph.D., of the Wits Reproductive Health and HIV Institute (WRHI) in Johannesburg, South Africa. "The most effective HIV prevention product can only work if it's used consistently. The recent PrEP and microbicide studies have taught us that using a product every day can be challenging for many people. A sustained delivery product like a vaginal ring can release an antiretroviral drug in the vagina over an entire month following a single insertion. We think this will be an attractive option for many women, and we hope that women in ASPIRE will like the ring and use it consistently," added Sharon Hillier, Ph.D., principal investigator of the MTN, which is based at the University of Pittsburgh School of Medicine and Magee-Womens Research Institute. ASPIRE is designed to enroll approximately 3,476 HIV-negative women between the ages of 18 and 45 who will be randomly assigned to use either the dapivirine ring or a placebo ring that looks the same but contains no active drug. Participants will be instructed how to insert and remove the ring, which they will replace every four weeks over the course of the one to two years they are in the study. All participants will receive ongoing HIV risk reduction counseling, condoms and diagnosis and treatment of sexually transmitted infections (STIs). The results of ASPIRE, which are expected late 2014 or early 2015, together with results of The Ring Study, as well as smaller, supporting studies, will form the basis of an application that IPM plans to submit to regulatory authorities seeking approval of the dapivirine ring for widespread use. "Through IPM's partnership with MTN and NIH, we are able to conduct two pivotal studies in parallel and get the answers we need quickly," said Zeda Rosenberg, Sc.D., chief executive officer of IPM, a nonprofit product development partnership based in Silver Spring, Md. "Regulators usually require results of two large-scale Phase III trials, along with data from other supporting studies, to approve a product for use. This unique collaboration aims to help us make dapivirine ring available as quickly as possible to women in developing countries if it is proven effective and safe for long-term use." Of the more than 34 million people living with HIV, half are women; and women account for 59 percent of adults with HIV in sub-Saharan Africa, where unprotected heterosexual intercourse is the primary driver of the epidemic. Young women are especially vulnerable; women ages 15 to 24 are up to five times more likely to become infected with HIV than young men. Efforts to promote abstinence, monogamy and the use of male condoms have not been enough to stop the HIV epidemic nor are these practical methods in many settings. IPM is developing dapivirine for use as a microbicide through a royalty-free licensing agreement with Janssen R&D Ireland (previously Tibotec Pharmaceuticals), one of the Janssen pharmaceutical companies of Johnson & Johnson. Dapivirine, also known as TMC-120, belongs to a class of ARVs called non-nucleoside reverse transcriptase inhibitors (NNRTIs) that bind to and disable HIV's reverse transcriptase enzyme, a protein that HIV needs to make copies of itself. In addition to the Uganda and Cape Town, South Africa sites, ASPIRE will be conducted at the following MTN-affiliated trial sites, pending all necessary approvals: In Malawi – the University of North Carolina Clinical Research Site in Lilongwe and the College of Medicine-Johns Hopkins University Research Project at Queen Elizabeth Central Hospital in Blantyre; in South Africa – the Medical Research Council of South Africa in KwaZulu-Natal (seven sites), the eThekwini site for the Centre for the AIDS Programme in Research in South Africa (CAPRISA) in Durban; WRHI in Johannesburg; in Zambia – the Centre for Infectious Diseases Research in Zambia in Lusaka; and, in Zimbabwe – the University of Zimbabwe-University of California, San Francisco HIV Prevention Trials Unit in Harare (three sites). ### More information about ASPIRE is available at http://www.mtnstopshiv.org/news/studies/mtn020 and about The Ring Study at http://www.ipmglobal.org/the-ring-study. About the Microbicide Trials Network The Microbicide Trials Network (MTN) is an HIV/AIDS clinical trials network established in 2006 by the National Institute of Allergy and Infectious Diseases with co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Mental Health, all components of the U.S. National Institutes of Health. Based at Magee-Womens Research Institute and the University of Pittsburgh, the MTN brings together international investigators and community and industry partners who are devoted to preventing or reducing the sexual transmission of HIV through the development and evaluation of products applied topically to mucosal surfaces or administered orally.