Microbicide Group to Test Merck Drug as Vaginal Gel; FDA Alerts Doctors to Prezista’s Possible Link to Liver Damage; FDA Reviewing Safety of Ziagen and Videx

May 2, 2008

“It’s a completely different mechanism of action to what we have currently under development and what the field has under development,” said Dr Zeda Rosenberg, IPM’s CEO. “It’s pretty early in the life cycle for HIV. Most of us feel that for a microbicide to be really effective, it has to get at the infection in its earliest time points.”

Group to Test Merck Experimental AIDS Drug as Vaginal Microbicide Gel
The International Partnership for Microbicides (IPM) announced that it has received permission to use Merck & Co's experimental HIV drug L'644 in testing as a potential vaginal microbicide. L'644 is a gp41 inhibitor that would block HIV from attaching to immune cells (Fox M. Reuters. March 11, 2008).

"It's a completely different mechanism of action to what we have currently under development and what the field has under development," said Dr Zeda Rosenberg, IPM's CEO. "It's pretty early in the life cycle for HIV. Most of us feel that for a microbicide to be really effective, it has to get at the infection in its earliest time points."

While condoms can protect men and women, in many countries a woman who insists on condom use can face rejection or violence. In contrast, a woman could take it on herself to use a microbicide gel or cream to prevent HIV infection. In sub-Saharan Africa, about 61% of adults with HIV are women, according to the Joint United Nations Programme on HIV/AIDS (UNAIDS). "L'644 is a peptide that would need to be injected to act as an effective antiviral," said Dr Daria Hazuda, vice president of scientific affairs for infectious disease at Merck Research Laboratories. "As such, it was not deemed to have a favorable profile for patient convenience." Merck, therefore, is not developing L'644 as a drug to treat HIV infection.

IPM has agreements with other drug firms to develop microbicides, said Rosenberg. Other microbicide candidates include Merck's L'167/CMPD167 compound, a CCR5 blocker; Pfizer's CCR5 inhibitor maraviroc; Gilead Sciences's tenofovir, in collaboration with Bristol-Myers Squibb; and Johnson & Johnson's Tibotec Pharmaceuticals's dapivirine. [CDC HIV/Hepatitis/STD/TB Prevention News Update, Friday, March 14, 2008]

FDA Alerts Doctors to Prezista's Possible Link to Liver Damage, Deaths
On Friday, March 21, US health officials warned doctors that Johnson & Johnson's HIV drug Prezista (darunavir) could be linked to liver illness and death in some patients (Associated Press. March 21, 2008). Original studies found that drug-induced hepatitis developed in 0.5% of patients taking Prezista, the new FDA-approved labeling for Prezista states. Since the drug's 2006 approval, the FDA says it has received more reports of hepatitis, some fatal, mostly in patients with advanced HIV infection who took many medications. For more information, visit www.fda.gov/cder/drug/infopage/darunavir/default.htm. [CDC HIV/Hepatitis/STD/TB Prevention News Update, Monday, March 24, 2008]

Advocating for Rectal Microbicides
At the Microbicides 2008 conference in New Delhi last month, International Rectal Microbicides Advocates (IRMA) issued a report on the status of research in the field of rectal microbicides and priorities for the upcoming years. Titled, "Less Silence, More Science," IRMA's report noted that only $7 million a year is being spent to study rectal microbicides. Most of that support, which is about 3% of the microbicide portfolio, comes from the NIH. IRMA called for a 5-fold boost in research funding, to $35 million, by 2010 and for expanding the sources of financial support (Roehr B. Bay Area Reporter. March 6, 2008)

Despite the perception that only gay men are interested in a rectal microbicide and that heterosexual men and women do not engage in anal sex, studies in the United States and the United Kingdom show that 10% to 35% of heterosexual women have experienced anal sex.

For biological reasons, HIV transmission is much more efficient through the rectum than the vagina, so the difficulties of protection through a rectal microbicide would be presumably greater. There are also more than just scientific barriers to the development of a rectal microbicide. "Anal sex is a highly stigmatized behavior. People who are doing it don't want to talk about it, they lie about it, policymakers don't want to say it," and those who fund studies do not want to talk about it, said Jim Pickett, IRMA's chairperson and director of advocacy at the AIDS Foundation of Chicago.

Last year, IRMA conducted an online survey about the use of lubricants during anal sex. Among the 8945 respondents, about 88% were male, 64% lived in North America, and almost 20% of surveys were taken in Turkish.

One surprising finding is that many people used saliva for anal sex, regardless of condom or lubricant use. That would need to be factored into the study of microbicides. An earlier Internet survey finding that many people douche before and/or after anal sex would also need to be taken into account. [CDC HIV/Hepatitis/STD/TB Prevention News Update, Thursday, March 13, 2008]

FDA Approves Only 1 HIV Home Test Kit
The FDA recently issued a reminder to consumers that there is only 1 FDA-approved home testing kit for HIV (Miami Herald. February 2, 2008).

Numerous unapproved HIV tests are being marketed, the agency said, and promise results in the home in 15 minutes or less. Some makers even claim FDA approval or that their facilities are agency-licensed. The only approved test is marketed as "The Home Access HIV-1 Test System" or "The Home Access Express HIV-1 Test System." These require users to collect a blood specimen that is sent to a laboratory for analysis. No FDA-approved HIV test kit allows results to be interpreted at home, regulators said. For more information, visit www.fda.gov/consumer/updates/hivtestkit012908.html. [CDC HIV/Hepatitis/STD/TB Prevention News Update, Monday, February 4, 2008]

University of North Carolina-Chapel Hill, Harvard Team Up on Inhaled TB Vaccine
Scientists have developed an experimental tuberculosis (TB) vaccine that is administered as an inhaled fine powder. The standard vaccine must be refrigerated and reconstituted in medical-grade water before being injected. These requirements can limit immunization efforts in developing countries where people often live far from medical facilities and have neither clean water nor electricity.

The scientists reformulated the existing TB vaccine and tested it on guinea pigs, and they found that it protected the animals better than the conventional injected vaccine (Fisher JP. News and Observer. March 15, 2008). Just 1% of lung and spleen tissue taken from animals vaccinated with the inhaled vaccine and then exposed to TB showed contamination with Mycobacterium tuberculosis, compared with about 5% of lung and 10% of spleen tissue from animals given the standard injected vaccine.

If the vaccine were to be approved, it would likely be administered to adults via a simple tube inhaler that looks like a plastic drinking straw. Once the tube is pierced, patients would breathe in while holding it in their mouth. According to Tony Hickey, one of the scientists at the University of North Carolina, infants could receive the vaccine via a modified pacifier. "You can have the baby essentially suck on it and blow the powder into the back of the throat," he said.

The next step for the research team is to test the safety of the vaccine in humans and then conduct clinical trials. Hickey said plans are under way to test it as soon as next year in South Africa, where TB is highly prevalent.

The research was supported by a Grand Challenge Grant from the Bill and Melinda Gates Foundation. The full report, "Immunization by Bacterial Aerosol," was published in Proceedings of the National Academy of Sciences. 2008;105:4656-4660. [CDC HIV/Hepatitis/STD/TBPrevention News Update, Friday, March 28, 2008]

FDA Reviewing Safety of Ziagen and Videx
On Thursday, March 27, the FDA said that it is evaluating the safety of the HIV drugs Ziagen (abacavir) and Videx (didanosine) after a large study showed patients receiving either drug had an increased risk of myocardial infarction (MI) compared with patients receiving other HIV drugs (Richwine L. Reuters. March 27, 2008). The notice is part of the FDA's effort to give the public early warnings about potential safety concerns before officials have reached any final conclusions. "Until this evaluation is complete, health care providers should evaluate the potential risks and benefits [of each drug]," the FDA said on its Web site.

Analysis of data from the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study, an evaluation of the long- and short-term effects of HIV drugs on more than 33,000 patients, prompted the concerns. Researchers examining the MI risk associated with NRTIs found that patients taking either Ziagen or Videx "had a greater chance of developing a heart attack than patients taking other medications," the FDA said.

The risk of MI did not seem to increase over time, and "the effect was not seen 6 months after stopping the drugs," the FDA said. The agency said that it believes the D:A:D analyses are still incomplete, and researchers have yet to evaluate any MI risks associated with the NRTIs Viread (tenofovir) and Emtriva (emtricitabine).

The makers of Ziagen and Videx, GlaxoSmithKline and Bristol-Myers Squibb, respectively, say their own analyses of clinical safety databases reveal no increased risk of MI. However, the FDA said those analyses are
inconclusive.

To view the FDA's statement, visit http://www.fda.gov/cder/drug/early_comm/abacavir.htm. [CDC HIV/Hepatitis/STD/TB Prevention News Update, Friday, March 28, 2008]