Panel Backs AIDS Drug, Possible Carcinogen in Viracept, Breakthrough Antibiotic Treatment for TB

November 2, 2007
AIDS Reader

The AIDS Reader Vol 17 No 11, Volume 17, Issue 11

An independent advisory panel recommended accelerated FDA approval of Merck & Co's drug Isentress (raltegravir) for patients who have drug-resistant strains of HIV (Chong J-R. Los Angeles Times. September 6, 2007). If approved, Isentress would be the first in a new class of AIDS drugs, integrase inhibitors, that aim to prevent HIV from integrating into human DNA during the replication process.

Panel Backs AIDS Drug
An independent advisory panel recommended accelerated FDA approval of Merck & Co's drug Isentress (raltegravir) for patients who have drug-resistant strains of HIV (Chong J-R. Los Angeles Times. September 6, 2007). If approved, Isentress would be the first in a new class of AIDS drugs, integrase inhibitors, that aim to prevent HIV from integrating into human DNA during the replication process.

Clinical trials, which lasted 16 to 24 weeks, involved about 900 patients. In about 600 patients taking Isentress in a cocktail with other AIDS drugs, HIV was suppressed to undetectable levels in the blood of about 62% of the patients. Among the 282 patients taking a standard cocktail and a placebo, about 34% achieved undetectable levels of virus in the blood.

Some in the 11-member advisory panel were concerned with cancers and abnormal tissue growths seen in 13 patients taking Isentress. However, Merck and FDA officials said the rate of malignant neoplasms seen among the Isentress group is comparable to the rate in other patients infected with highly resistant HIV.

Malignant neoplasms in those taking Isentress included squamous cell carcinoma and lymphoma. None in the placebo group experienced malignant neoplasms during the trial. However, the FDA said the difference could be due to chance. An agency analysis suggested there was an unusually low number of malignant neoplasms in the placebo group, rather than a high number in the Isentress group. Several panel members recommended that Merck conduct a 5-year follow-up study of Isentress to confirm its safety.

"Overall, based on the data we've seen today, the risk-to-benefit ratio seems fairly favorable," said Dr Marshall Glesby, a panel member and codirector of Cornell University's HIV Clinical Trials Unit.

The FDA is not obliged to accept the panel's advice but usually does. [CDC HIV/Hepatitis/STD/TB Prevention News Update, Thursday, September 6, 2007]

[Editor's note: The FDA granted Insentress (raltegravir) tablets accelerated approval on October 12, 2007, for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in treatment-experienced adult patients who have evidence of viral replication and HIV-1 strains resistant to multiple antiretroviral agents.]

Pfizer Warns Health Care Professionals of Possible Carcinogen in Viracept
On September 10, the FDA announced that Pfizer Inc has notified health care professionals that its HIV drug Viracept contains traces of ethyl methanesulfonate (EMS), a potential human carcinogen (Associated Press. September 10, 2007). The FDA has asked Pfizer to limit the presence of EMS, a process-related impurity, in Viracept. Animal studies have indicated EMS is carcinogenic; however, no human-based data are available.

In June, drug-maker Roche recalled Viracept in Europe. Pfizer, which sells the drug in the United States, has not issued a recall here. Pfizer said testing has found EMS levels in its Viracept substantially lower than the levels that prompted the European recall by Roche.

Pediatric patients on stable HIV treatment plans may continue taking Viracept, but treatment-naive patients should not begin regimens that include Viracept until further notice. Pregnant women are advised not to start taking Viracept; those currently taking it should be switched to an alternative.

Pfizer is working with the FDA on measures to keep EMS at substantially lower levels. For more information, visit http://www.fda.gov/cder/drug/infopage/nelfinavir/default.htm. [CDC HIV/Hepatitis/STD/TB Prevention News Update, Tuesday, September 11, 2007]

Doctors Report Breakthrough Antibiotic Treatment for TB
In a study of more than 170 patients with tuberculosis (TB) in Rio de Janeiro, substituting moxifloxacin for ethambutol in combination therapy improved treatment outcomes and shortened the time to disease clearance (Santini JL. Agence France Presse. September 18, 2007). The Brazilian-US research team recently presented its data at the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy in Chicago.

Using moxifloxacin in standard combination therapy in place of ethambutol, scientists were able to increase active Mycobacterium tuberculosis clearance from 68% of patients to 85% and reduce treatment time from the typical 6 months to 4 months. Reducing the duration of TB therapy could improve treatment adherence rates, preventing the evolution of drug-resistant M tuberculosis. Moxifloxacin is also less expensive, a clear value for developing nations with high burdens of TB and HIV/AIDS.

"Beyond the obvious value of healing patients more quickly, a shorter treatment time could also cut down on transmission of the disease to others and make it easier for health care workers worldwide, who are overwhelmed by large numbers of patients, to treat more people and to treat them faster," said lead author Richard Chaisson, professor at the Johns Hopkins University School of Medicine.

In another study involving M tuberculosis–infected mice, replacing rifampin and isoniazide with a moxifloxacin-rifapentine regimen shortened the time to M tuberculosis clearance from 6 months to only 10 weeks.

Contaminated, Fake AIDS Drugs Flood Black Market in Zimbabwe
On October 8, Zimbabwean Minister of Health David Parirenyatwa called on HIV/AIDS patients to buy their medicines only from registered pharmacies, clinics, and hospitals (Shaw A. Associated Press. September 9, 2007). Drug shortages linked to the country's economic crisis have resulted in AIDS drugs-some of them contaminated, fake, or diluted-being sold at flea markets and hair salons. "These fake drugs increase chances of one becoming resistant to treatment and it becomes even more expensive for that person to remain on treatment," the state-run Herald newspaper quoted him as saying.

Zimbabwe has the world's highest official inflation rate at 7634%. However, independent estimates put the figure closer to 25,000%, and the International Monetary Fund forecasts it will reach 100,000% by year's end. According to the Herald, the "prohibitive" cost of antiretrovirals (ARVs) has fueled the underground market.

In Zimbabwe, where approximately 3000 people die weekly of AIDS-related conditions, about 50,000 HIV-infected patients are receiving ARVs from government hospitals. Another 300,000 are in urgent need of treatment, the Herald said.

Because of the scarcity of hard currency, HIV/AIDS drug manufacturers in Zimbabwe cannot import enough raw materials. But even when local generics are available, their cost of about 5 million Zimbabwe dollars ($166 US) for a month's supply is far beyond the reach of most people. For instance, a teacher in a top government high school earns about 3 million Zimbabwe dollars ($100 US) per month. In addition, the country's unemployment rate hovers around 80%.

Zimbabwean HIV/AIDS patients live in constant fear of not being able to find or pay for their medicines, say support groups. Treatment interruptions along with poor nutrition make patients more vulnerable to tuberculosis and other opportunistic infections, advocates note.

Papua New Guinea AIDS Crisis May Mirror Africa's, UN Says
Tim Rwabuhemba, Papua New Guinea's coordinator for UNAIDS, said in an interview that the country's HIV/AIDS epidemic may mirror the crisis in Africa (O'Brien E. Bloomberg News. September 9, 2007). Infections are surging, and more than 75% of patients are unable to access AIDS drugs. "There is an urgent need for more HIV services across the board here," he said.

The nation of 6 million accounts for 90% of the Pacific region's HIV cases. It is 1 of 4 Asia-Pacific countries experiencing an AIDS epidemic, according to the UN. HIV appeared in Papua New Guinea in the early 1990s and has spread to the remote highlands, where villagers did not come into contact with Europeans until the 1930s.

AusAID, Australia's development agency, said more than half a million Papua New Guineans will be infected by 2025, resulting in a 13% drop in the available workforce and a 1.3% decline in the $15 billion economy. The agency estimates that in 20 years, 117,000 children will have lost their mothers to AIDS, and 70% of the country's hospital beds will be needed for HIV/AIDS patients.

Rwabuhemba cited the inaccessibility of rural regions and a shortage of supplies for testing and treatment as reasons why HIV has infected nearly 2% of the population, with new infections increasing mostly in the countryside. He said stigma and discrimination are challenges, and education programs have not had the desired effect. Rwabuhemba said he could not substantiate newspaper reports that AIDS patients in the Southern Highlands have been buried alive by their families when they become too sick to care for.

According to the UN, the number of HIV cases in Papua New Guinea have been growing at a rate of 30% a year since 1997. Rwabuhemba said heterosexual transmission is the most common means of infection. [CDC HIV/Hepatitis/STD/TB Prevention News Update, Friday, September 7, 2007]

Johnson & Johnson Says Prezista Matches Kaletra in HIV Trial
Johnson & Johnson's drug Prezista was as effective as Abbott Laboratories Inc's Kaletra in reducing HIV to undetectable levels in a population of treatment-naive patients, according to a new study (Pierson R. Reuters. September 18, 2007). The results of the late-stage trial were presented at the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy in Chicago in October.

Prezista was introduced last year as a treatment for adults who were not responding adequately to other HIV drugs. Based on the new data, the company plans to ask US regulators this year to approve it for patients starting HIV drug therapy, said company spokesperson Pam Van Houten.

In the current trial, one group of patients received the protease inhibitor (PI) Prezista in an experimental 800-mg once-daily dose, along with Abbott's older PI Norvir (ritonavir) and Truvada. Manufactured by Gilead Sciences Inc, Truvada contains 2 NRTIs. The other group of patients received Kaletra, which combines Norvir with the PI lopinavir and Truvada.

The Johnson & Johnson researchers said 84% of the Prezista patients had achieved undetectable HIV levels after 48 weeks, compared with 78% of the Kaletra patients.

Ilke Arici, an Abbott spokesperson, said the trial "does not reflect a real-life scenario." She said the study's design was inconsistent with the way doctors prescribe treatment. Many study patients, she said, were given the soft gel formulation of Kaletra, which she said is not as effective as the tablet version usually prescribed in the United States. Van Houten responded that most of the Kaletra patients were switched to tablets when they became available.

Van Houten also noted that the Prezista dosage administered, 800 mg once a day, was lower than the twice-daily 600-mg dosage the label recommends. The lower dosage was given, she said, on the theory that it would be adequate for treatment-naive patients without resistance to HIV drugs. [CDC HIV/Hepatitis/STD/TB Prevention News Update, September 19, 2007]

AIDS Cocktails Preserve Brain, Study Finds
A new study shows AIDS drug cocktails appear to curb HIV-associated brain damage, researchers said (Reuters. October 8, 2007).

In addition to damaging the immune system, HIV can attack the brain and nerves. Before the introduction of drug cocktails known as HAART, about 20% of HIV-infected patients developed dementia. However, not all of the drugs used in these combinations get into the brain, so it was not known how much HAART helped.

Dr Asa Mellgren of Sweden's Goteborg University and colleagues studied 53 male and female HIV-infected patients. Their cerebrospinal fluid was tested, and then the patients were given HAART for 1 year. Before treatment, 21 patients had high levels of neurofilament light protein, which is believed to indicate brain damage.

Three months into HAART, the high levels of the protein dropped to normal levels in almost half of the patients. After 1 year, just 4 patients still had high neurofilament light protein levels, the researchers reported.

"This type of treatment appears to halt the neurodegenerative process caused by HIV," said Mellgren. "This study confirms that neurofilament light protein serves as a useful marker in monitoring brain injury in people with HIV and in evaluating the effectiveness of HAART."

The study, "Antiretroviral Treatment Reduces Increased CSF Neurofilament Protein (NFL) in HIV-1 Infection," was published in Neurology. 2007;69:1536-1541. [CDC HIV/Hepatitis/STD/TB Prevention News Update, Tuesday, October 9, 2007]

Study Sees Differences in How US Hispanics Get HIV
Differing patterns of HIV transmission among US Hispanics suggest the need for more tailored prevention messages targeting this community, federal officials said (Dunham W. Reuters. October 11, 2007).

A CDC report based on data from 33 states in 2005 found an association between how Hispanics become HIV-infected and where they were born. Infection through male-to-male sexual contact was more common among those born in South America (65% of HIV cases), Cuba (62%), and Mexico (54%) than among Hispanics born in the United States (46%), the report said. More Hispanics born in the Dominican Republic (47%) or Central America (45%) became infected through high-risk heterosexual sex than did US-born Hispanics (28%).

Puerto Rico-born Hispanics had a greater proportion of HIV infections due to injection drug use (33%) than did those born in the United States (22%). In addition, immigrant injection drug users (IDUs) born in Cuba, Mexico, and Puerto Rico reported less HIV knowledge than did US-born IDUs, the report found.

"In terms of the prevention messages, if you are looking at Hispanics, you can't look upon them as a monolithic group. You have to think about the various subcategories," said Dr Ken Dominguez, a CDC epidemiologist and coauthor of the report.

The report's findings are attributed in part to cultural and socioeconomic differences among Hispanic subgroups. "We're a very diverse community," agreed Dennis deLeon, president of the Latino Commission on AIDS in New York.

For Hispanic males, the main mode of HIV transmission was male-to-male sex (61%), followed by heterosexual sex (17%) and drug injecting (17%). For Hispanic women, 76% were exposed to HIV through heterosexual sex and 23% through drug injecting, the CDC reported.

Hispanics, who make up 14% of the US population, face disproportionate HIV infection rates, trailing blacks with the second-highest rate among all US racial and ethnic groups, the report noted. "The rate of HIV diagnosis for Hispanic males is about 3 times higher than the rate among white males. And for Hispanic females, it's about 5 times higher than among white females," said Dominguez.

The report, "HIV/AIDS Among Hispanics - United States, 2001-2005," was published in Morbidity and Mortality Weekly Report. (2007;56:1052-1057). [CDC HIV/Hepatitis/STD/TB Prevention News Update, Friday, October 12, 2007]

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