Government Cancels Testing of HIV Vaccine, Roche to Suspend HIV Research, New TB Drug Resistance Test, Topical Estrogen Protects Men

August 1, 2008

On Thursday, July 17, plans to conduct a large-scale test of an experimental therapeutic AIDS vaccine were canceled, the latest setback following last year’s failed Merck AIDS vaccine trial (Russell S. San Francisco Chronicle. July 18, 2008).

Government Cancels Testing of Experimental AIDS Vaccine; Large-Scale Study to Be Scaled Back After Similar Drug Failed
On Thursday, July 17, plans to conduct a large-scale test of an experimental therapeutic AIDS vaccine were canceled, the latest setback following last year’s failed Merck AIDS vaccine trial (Russell S. San Francisco Chronicle. July 18, 2008). The candidate vaccine was developed by the NIH, and it contained the same weakened cold virus that Merck had used in its vaccine, adenovirus type 5.

After months of debate whether to proceed with a large trial of the NIH’s candidate vaccine among 2400 volunteers, Dr Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, called it off in favor of a “smaller, leaner, meaner” one. The $63 million PAVE (Partnership for AIDS Vaccine Research) 100 study will now involve fewer volunteers and cost less than $45 million.

The NIH vaccine succeeded in laboratory studies with monkeys. In addition, rather than using bits of viral protein as the Merck candidate did, the NIH’s creation used bits of viral DNA, which could prove more powerful. However, among Merck trial participants, those previously exposed to adenovirus appeared to later acquire HIV at a higher rate than unexposed volunteers.

Fauci wants a smaller study to answer whether NIH-vaccine recipients who subsequently acquire HIV control the virus in their bloodstream better than peers given a placebo. Just how many volunteers will be needed to generate the data necessary to answer that question still has to be determined, said Dr James Kublin, director of the HIV Vaccine Trials Network, which was to have conducted PAVE 100. [CDC HIV/Hepatitis/STD/TB Prevention News Update, July 18, 2008]

Roche to Suspend HIV Research, Seeing No Advances
The Swiss pharmaceuticals company Roche Holding AG on Friday, July 11, confirmed that it is suspending research on HIV infection treatments because none in development shows any improvement over existing drugs (Seetharaman D. Reuters. July 11, 2008). The company will continue to support its molecular diagnostic tests and current treatments, such as enfuvirtide (Fuzeon).

On Wednesday, Roche sent an e-mail informing activists of the decision, saying it will “refocus our resources within virology on diseases in which we can deliver substantial improvements over existing medications,” according to Linda Dyson, a Roche spokesperson. Of its prospective treatments, the company “concluded that none would provide a true incremental benefit for patients compared to medicines currently on the market.”

If Roche identified a promising breakthrough related to HIV outside of its laboratories, however, the company said it would reassess its involvement. “Roche is a big company and they’ve been trying to get this right for many, many years,” said Peter Staley, founder of AIDSmeds.com, which tracks HIV news. “I don’t think it’s a sign of a serious problem in pharma’s commitment.” Roche’s HIV drug Fuzeon struggled because its cost, $25,000 per year, surpassed other drugs on the market, he noted. [CDC HIV/Hepatitis/STD/TB Prevention News Update, Monday, July 14, 2008]

New Drug Resistance Test Gives Hope to TB Fight
On Monday, June 30, the World Health Organization (WHO) unveiled a molecular test that will quickly allow doctors in poor countries to determine whether a patient’s tuberculosis (TB) is multidrug-resistant (MDR) (MacInnis L. Reuters. June 30, 2008). Created by Germany-based Hain Lifescience and Innogenetics, the diagnostic can return results in hours rather than requiring a month-long wait. The WHO, UNITAID, and the Foundation for Innovative New Diagnostics are partnering to ensure poor countries affected by the disease will receive the diagnostics and necessary support.

“We are capable now of making a diagnosis of MDR-TB within hours,” said Mario Raviglione, director of WHO’s Stop TB department.

Using only a saliva sample, the new test can show whether TB is treatable with the 2 main antibiotics used against the disease, isoniazid and rifampicin. Previously, the bacteria in the sample had to be incubated for as long as 60 days to test its susceptibility to various antibiotics. The quicker test will allow doctors to prescribe the right drugs needed in time to fight the bacteria. Using the wrong medications can exacerbate MDR-TB and lead to the deadlier extensively drug-resistant TB (XDR-TB). Hain is also working to develop a test for XDR-TB, the WHO said.

In combination with efforts to reduce the cost of second-line TB drugs, the WHO said the initiative could help boost the worldwide rate of appropriately diagnosed and treated MDR-TB from 2% to 15%.

The WHO and partners will provide Lesotho with laboratory equipment and training to use the test first, Raviglione said. Other countries to receive the diagnostics and support are Azerbaijan, Bangladesh, the Democratic Republic of the Congo, Ethiopia, Georgia, Indonesia, Ivory Coast, Kazakhstan, Kyrgyzstan, Moldova, Myanmar, Tajikistan, Ukraine, Uzbekistan, and Vietnam. [CDC HIV/ Hepatitis/STD/TB Prevention News Update, July 1, 2008]

Topical Estrogen Protects Men From Infection
A study by researchers at the University of Melbourne found that application of the female hormone estrogen to the penis could create a “living condom,” potentially shielding men from HIV. Dr Andrew Pask and Professor Roger Short conducted laboratory tests on the estrogen cream Oestriol, which is currently used to treat prolapse in women. Applying estrogen cream to the vulnerable inner foreskin, they found they could boost the body’s natural defenses against HIV (Best C. Australian Associated Press. June 4, 2008).

Estrogen cream works by quadrupling the thin layer of keratin, a defensive protein, in the skin. “By using keratin, we can increase the body’s natural defense, and then the virus can’t physically inject itself through that barrier to infect the cells underneath,” said Pask.

Circumcision provides some protection from HIV and estrogen cream fills the gap, Pask said, providing a barrier against the virus in uncircumcised men. The hormone could potentially be a simple, inexpensive, and effective guard against HIV that would be applied once a week in cultures where circumcision and safe sex are not practiced, said Pask. Eventually, it could have applications in condoms and lubricants. The concept will be tested next in clinical trials in Africa.

The paper reporting the study results, “Topical Oestrogen Keratinises the Human Foreskin and May Help Prevent HIV Infection,” was published in the journal Public Library of Science ONE. 2008;3:e2308. doi:10.1371/journal.pone.0002308. [CDC HIV/Hepatitis/STD/TB Prevention News Update, July 7, 2008]

HIV Birth Witnessed
For the first time, US researchers have observed the assembly of HIV in real time, they recently reported in Nature. Using total internal reflection microscopy, a technique developed at Rockefeller University, scientists could see the surface of an infected cell and watch the processes of HIV replication (BBC Focus. May 28, 2008).

Rockefeller’s Sanford M. Simon and colleagues were able to see the thousands of molecules assembling to form a single HIV particle as well as HIV’s separation from the cell wall. The genesis of a single virus particle took 5 to 6 minutes.

The capacity to observe cell surfaces may help scientists learn more about the processes that occur there and aid in fighting HIV disease.

The full report, “Imaging the Biogenesis of Individual HIV-1 Virions in Live Cells,” was published online ahead of print in Nature. 2008. doi:10.1038/nature06998. [CDC HIV/Hepatitis/STD/TB Prevention News Update. June 13, 2008]

Drug Regimen Halves Passage of HIV From Mother to Child in Milk
Researchers at the Johns Hopkins Bloomberg School of Public Health have found that an extended AIDS drug regimen can cut by 50% an HIV-positive mother’s risk of transmitting the virus to her infant during breastfeeding (Kohn D. Baltimore Sun. July 10, 2008).

Of the 500,000 babies who contract HIV each year from their mothers, half are infected through breastfeeding. To counter this risk, nearly all HIV-positive mothers in Western nations feed their infants formula. But in the developing world, conditions such as poverty and the lack of clean water often make formula feeding impractical. And because of its many health benefits, breastfeeding has been shown to increase overall infant survival rates, even when the mother is HIV-infected.

To prevent mother-to-baby transmission, most infants born to HIV-positive mothers in the developing world receive 1 dose of nevirapine shortly after birth. The new study, based in Malawi, expanded this regimen.

Researchers divided 3016 breastfeeding infants into 3 groups. Babies in the first group received a single dose of nevirapine; babies in the second group received nevirapine for 14 weeks; babies in the third group received nevirapine and zidovudine for 14 weeks. HIV infections through breastfeeding dropped by half in the second and third groups, and the infants showed no adverse effects from the longer treatment.

Dr Taha E. Taha, a study coauthor, said plans are under development to roll out the treatment in Malawi and elsewhere. Because international aid subsidizes the cost of nevirapine and zidovudine in much of sub-Saharan Africa, “the cost is not the major barrier,” Taha said. “The logistical barriers will be key.”

Dr Brooks Jackson, an AIDS expert at the Bloomberg School of Public Health, agreed, noting that 30% of HIV-positive African mothers still do not receive nevirapine during labor, even though this intervention was proved 9 years ago to halve viral transmission.

Further studies are planned to assess the effect of extending infants’ antiretroviral treatment for 6 months or longer.

The report of the study, “Extended Antiretroviral Prophylaxis to Reduce Breast-Milk HIV-1 Transmission,” was published in the New England Journal of Medicine. 2008;359:119-129. [CDC HIV/Hepatitis/STD/TB Prevention News Update, July 10, 2008]

Gels to Protect Women From HIV May Help Men More
Microbicide gels that use antiretroviral drugs to fight HIV infection could do more to protect men from getting HIV from women than the reverse, researchers said recently. And women could end up with drug-resistant virus if they become infected anyway, computer models show (Fox M. Reuters. July 7, 2008).

“Paradoxically, although microbicides will be used by women to protect themselves against infection, they could provide greater benefit to men,” wrote Sally Blower of the University of California–Los Angeles and colleagues.

Blower and David Wilson of the University of New South Wales in Sydney, Australia, presumed the drugs could be systemically absorbed and, like any other monotherapy, could cause HIV to become drug-resistant. In addition, the mathematical model they used took into account inconsistent microbicide users and the possibility of a microbicide that is only partially effective. The model incorporated data from ongoing microbicide trials, what is known about how HIV develops drug resistance, and how consistently people use condoms or would use such a product.

“What we found out that was interesting or surprising or paradoxical was that under some conditions males would actually benefit a lot more than females,” Blower said.

The full report, “The Paradoxical Effects of Using Antiretroviral-Based Microbicides to Control HIV Epidemics,” was published online ahead of print in the Proceedings of the National Academy of Sciences U S A. 2008. doi:10.1073/pnas.0711813105. [CDC HIV/Hepatitis/STD/TB Prevention News Update, July 9, 2008]

Merck, FDA Expand Gardasil Warnings
On June 12, Merck & Co and the FDA expanded the packaging language describing possible adverse reactions to the human papillomavirus (HPV) vaccine Gardasil (Fagan A. Washington Times. July 10, 2008).

On its Web site, the FDA said the updated warnings “reflect reports received” after the vaccine came to market in 2006. The revised notice says that females receiving the injections may experience joint and muscle pain, fatigue, physical weakness, and general malaise.

Karen Riley, a spokesperson for the FDA, said the updated language has “nothing to do with” the reports of serious adverse effects related to the vaccine. Rather, she said, the updates were made on Merck’s request and deal with possible mild symptoms. “The bottom line is that we have not seen any safety signals in the adverse events other than [fainting]. We continue to look at these reports.”

On June 30, the conservative group Judicial Watch released a study saying that a government database had collected 8864 cases of Gardasil-related health problems, including fainting, numbness, seizures, paralysis, and as many as 18 deaths.

Amy Rose, a spokesperson for Merck, said she lacked conclusive answers about the recent changes but has no “reason to believe it was anything other than a routine update.”

Government and Merck officials study all reports of adverse events linked to Gardasil, and “from the data we have seen to date, the vaccine is safe and effective,” said Curtis Allen, a spokesperson for the CDC who said his own daughter has been vaccinated with Gardasil.

While Judicial Watch cited 18 deaths, Allen said that the CDC knows of only 17. Of these, he said, the government has determined that 8 were unrelated to Gardasil; 3 are under review; and the rest were inconclusive. Officials at the FDA, Merck, and the CDC maintain that the vaccine is safe and effective.

To read the updated packaging information for Gardasil, visit http://www.fda.gov/cber/label/gardasilLB.pdf.