In this issue:
S. Africa links deaths to nevirapine trial
Pfizer drops drug price after protest threat
Gays on PIs 'likely' to have unprotected sex
Protease inhibitors linked to accelerated bone mineral loss
Rapid CD4 loss linked to anal sex
New test identifies drug susceptibility in HIV strains
Mutation cited for potential Hep C defense
Some complications of HIV drugs puzzle doctors
Young adult men not receiving HIV prevention messages
FIGHT educational programs set
ACT UP Choir rehearsals weekly
The South African government is drawing a chorus of criticism for linking deaths in a clinical drug trial to an anti-AIDS drug that has proved highly effective in blocking mother-to-child transmission of HIV.
On April 5th, Health Minister Mantao Tshabalala-Msimang implied that N\nevirapine, a cheaper alternative to AZT, was connected to the deaths of five South African women during a trial of a cocktail of anti-AIDS drugs.
Researchers, drug companies and opposition politicians spoke out against Tshabalala-Msimang's comments. And on April 7th, the Medical Control Council, which Tshabalala-Msimang assigned to probe the deaths, said nevirapine was only one of five drugs used in the trial.
"The large numbers of patients experiencing toxicity was unexpected, and a conclusive cause and effect has not yet been established," council chairwoman Dr. Helen Rees told the SAPA news agency.
Investigators conducting completely separate trials in South Africa on the use of nevirapine to block mother-to-child transmission of HIV said they were confident the drug was safe for that purpose. And nevirapine manufacturer Boehringer Ingelheim said there was no conclusive proof that its product had been the cause of the deaths.
But company spokesman Kevin McKenna also said liver failure was a common side effect of taking nevirapine and there were warnings of that in the drug brochures.
"There is no doubt that the benefits of nevirapine outweigh the harmful effects," McKenna said.
President Thabo Mbeki's government has been engaged in a long-running battle with drug companies, accusing them of putting profits before lives. The government estimates about a tenth of South Africa's 42 million people are infected with HIV or AIDS.
AIDS activists and opposition politicians have criticized the government for not distributing the drug AZT to pregnant women to prevent transmission of HIV from mother to child. The government has said it can't afford the expensive drug, and lobbyists have called for nevirapine to be made available.
The clinical trial that sparked the controversy is being conducted on behalf of the U.S. company Triangle Pharmaceuticals at 16 sites around South Africa. It seeks to document the safety and efficiency of combinations of anti-retrovirals, including a new unregistered drug, Emtricitabine, in treating HIV disease.
During the trial, two women died from liver failure, one from pancreatitis, one from a central nervous system disorder and the fifth from causes yet to be determined, the Johannesburg newspaper Business Day quoted Triangle Pharmaceuticals as saying.
The 510 patients recruited for the trial all had advanced HIV, and serious liver complications were reported in 55 of them, the Medical Control Council said. One explanation was that there might be an interaction between Emtricitabine and either Nevirapine or another drug, Stavudine.
"Serious concerns were raised with Triangle Pharmaceuticals, Quintiles (the research organization monitoring the trial) and the principle investigator about the adequacy of the technical management of the study," Rees told SAPA. "As a result of these concerns, recruitment to the trial was stopped, and a detailed review of the study continues."
Advocates of the drug note its apparent efficacy and relatively low cost compared with zidovudine. In South Africa there are an estimated 1,700 new cases of HIV every day, with the infection rate highest among teenage girls. The country also has the highest incidence of rape in the world. But the government has incited domestic and international wrath by refusing to give zidovudine to HIV-infected pregnant women or rape survivors, citing conflicting scientific reports and the astronomical cost of the multidose drug.
It has further incensed the scientific world by inviting scientists who question the link between HIV and AIDS to the World AIDS Conference scheduled for July.
Tshabalala-Msimang took a swipe at the world scientific community, accusing it of using South Africa as a dumping ground. "It is highly unlikely that all but a few South Africans will every derive any benefits from the drugs that are tested here, since once they are patented and registered they are marketed at prices that are unaffordable to us," she said. (Associated Press, Reuters)
ACT UP has canceled plans to take over Pfizer's world headquarters in New York in response to the drug giant's agreement to provide free fluconazole to people with AIDS-related Cryptoccocal meningitis in South Africa. Approximately 3.6 million people in South Africa are infected with HIV, and over 100,000 suffer from cryptoccocal meningitis, a brain infection that is fatal if left untreated.
US AIDS activists had mixed feelings in response to Pfizer's announcement.
"Pfizer has shown that it can respond when it feels the heat from people with AIDS," said Eric Sawyer of ACT UP New York. "But access for South Africa alone is not enough. Pfizer's market-driven genocide continues in poor countries like Guatemala and Kenya, where life saving therapy costs anywhere from ten to twenty dollars per day."
Fluconazole is effective in treating cryptoccocal meningitis, the most common AIDS-related systemic fungal infection, but the drug is currently priced at US$8.92 per pill in South Africa. In Thailand, where Pfizer does not have exclusive marketing rights, fluconazole costs only US$0.29 per pill. The average daily wage in South Africa is about US$7.00.
Pfizer's capitulation comes at the peak of an ongoing campaign led by the community-based coalition Treatment Action Campaign (TAC) of South Africa along with ACT UP, Doctors Without Borders, and other community organizations in the US. "This first step by Pfizer's must be extended to all other poor countries where people with AIDS are dying without access to fluconazole," said Joyce Hamilton of ACT UP Philadelphia. Pfizer reported $1.2 billion in profit from fluconazole sales worldwide in 1999.
US campaign escalation came two weeks ago when an angry mob of ACT UP activists stormed the office of Pfizer CEO William Steere, Jr., demanding the drug company concede to the South African activists and drop the price of fluconazole, or issue a voluntary license to allow people with AIDS to import generic fluconazole from a less expensive supplier. Today's letter from Pfizer addressed to TAC stated their plans to seek the advice and collaboration of the South Africa Ministry of Health "in a program to deliver Diflucan free of charge through appropriate medical specialists for South African HIV/AIDS patients suffering from Cryptococcal meningitis who cannot afford this treatment."
"Pfizer isn't out the woods yet-their track record with giveaway programs in the developing world is shoddy at best." said Asia Russell of ACT UP Philadelphia. "Without intense community scrutiny, Pfizer's program may devolve into nothing more than a public relations stunt."
Gays on PIs 'likely' to have unprotected sex
Gay and bisexual men who are HIV infected are three times more likely to have unprotected sex after protease inhibitor therapy is initiated than prior to protease therapy, according to data from the French SEROCO study.
Dr. Maureen Miller, now at the National Development and Research Institutes in New York, and colleagues at INSERM in Le Kremlin-Becetre, France, studied 191 HIV-infected patients. Of these, 81 were gay or bisexual men, 46 were heterosexual men and 64 were heterosexual women. Subjects were interviewed prior to starting protease inhibitor therapy and again after a mean of 13 months of therapy. The study results are reported in the March 10th issue of AIDS.
The researchers write, "The initiation of protease inhibitor therapy was not significantly associated with either an increase in the number of HIV-infected patients reporting anal or vaginal sex or with an increase in the number reporting unprotected sexual intercourse." In addition, Dr. Miller and colleagues found that after the initiation of protease inhibitor therapy there was no relationship between viral load and unprotected sexual intercourse.
Despite these overall findings, the researchers found that, "among gay or bisexual men, increases in unprotected sexual intercourse were observed, particularly with partners vulnerable to HIV transmission, whereas among both heterosexual men and women, non-significant decreases in unprotected sexual intercourse were observed."
In an interview with Reuters Health, Dr. Miller said, "I think there is a risk that we may see another little epidemic of HIV, particularly among gay men. This is based upon data from both France and here. In San Francisco, [the Centers for Disease Control and Prevention] found an increase in anal rectal gonorrhea. Over the past decade there has been a real dramatic decline in gonorrhea incidence and prevalence, and now that is on the rise, indicating that people are having sex without condoms."
As to reasons for this increase after therapy, Dr. Miller said that gay and bisexual men "may have felt safer, they may have felt healthier and felt like becoming sexually active again, maybe after strictly a period of oral sex."
The researchers believe that a new HIV prevention message is essential. Dr. Miller noted, "There are two different messages. For HIV-negative people, basically you have to work at it to stay negative. You should really continue using condoms. HIV-positive people should also be using condoms to prevent transmission. It has not been proved that therapy prevents transmission." (Reuters)
Protease inhibitors linked to accelerated bone mineral loss
There is an excess prevalence of osteopenia and osteoporosis among HIV-infected men receiving protease inhibitors, according to findings published in the March 10th issue of AIDS.
Decreased bone mineral density was rarely seen in HIV-infected patients prior to the use of protease inhibitors, note Dr. Pablo Tebas and colleagues from Washington University School of Medicine, St. Louis, Missouri. They studied 112 men, of whom 60 were HIV-infected patients receiving HAART that included protease inhibitors, 35 were HIV-infected patients not receiving protease inhibitors and 17 were HIV-negative.
Dual energy X-ray absorptiometry was used to assess bone mineral density of the whole body, lumbar spine and proximal femur. The investigators found that the subjects receiving protease inhibitors had a relative risk of 2.19 for osteopenia and osteoporosis according to World Health Organization definitions, compared with the other two groups.
The researchers also report that "subjects receiving protease inhibitors had greater central:appendicular adipose tissue ratios than the other two groups," but this did not correlate with bone mineral density. Hence, they suggest that bone mineral loss and body fat redistribution are independent side effects of protease inhibitor therapy.
Rapid CD4 loss linked to anal sex
A five year study of 937 HIV-positive men receiving little or no anti-retroviral treatment has shown that men who had any unprotected receptive anal intercourse (RAI) and who were thus exposed to semen had more rapid CD4 cell declines than men who avoided unprotected RAI.
The study followed men recruited to the MACS cohort between 1984 and 1985, and tracked their sexual behavior and CD4 counts during the period before anti-retroviral treatment became widespread, in order to get the purest possible information on the potential negative effects of unprotected RAI.
Most men reported only one or two RAI partners during the twelve months prior to their rapid CD4 cell loss, but this level of U-RAI was in itself associated with greater CD4 cell loss than avoidance of unprotected anal intercourse. Men who reported any U-RAI during the previous twelve months were twice as likely to experience a CD4 cell decline compared to men who avoided U-RAI. The risk of CD4 cell loss increased with each U-RAI partner reported during the previous 12 months. People who reported 8 or more RAI partners during the previous 12 months were at four times greater risk of experiencing a rapid CD4 decline during that period.
Paradoxically, men who consistently reported a high number of RAI partners throughout the study period were at much lower risk of rapid CD4 decline, a finding that the research group cannot explain. They suggest that these individuals (numbering less than 4% of the cohort) may have been naturally more resistant to the effects of HIV infection, as evidenced by their relative lack of CD4 decline.
The study cannot determine whether the cause of the CD4 decline was re-infection with HIV, exposure to other sexually transmitted infections, or some immunosuppressive effect of semen itself. Recreational drug use did not affect the rate of CD4 cell loss, and the only sexually transmitted infections analyzed were syphilis and gonorrhea. An episode of either of these infections increased the risk of a rapid CD4 decline by around 70% in any 12 month period.
The study cannot provide any information about the effects of U-RAI in individuals currently taking anti-retroviral treatment since too few men in the study received anti-retroviral treatment, and the effects of this treatment would have been modest in any case. (aidsmap.com)
New test identifies drug susceptibility in HIV strains
A new test developed by scientists at ViroLogic, Inc., can be used to determine the susceptibility of HIV-1 in infected patients' plasma to protease and reverse transcriptase inhibitors.
The test "may be useful in facilitating the selection of optimal treatment regimens for patients who have failed prior therapy or drug-naive patients infected with drug-resistant virus," Dr. Christos J. Petropoulos, and colleagues in San Francisco, California, suggest in the April issue of Antimicrobial Agents and Chemotherapy.
The new test utilizes resistance test vectors labeled with a luciferase gene and protease and reverse transcriptase sequences derived from HIV-1 isolates. Complete results from the automated test can be obtained in 8 to 10 days, according to the report.
The new test "can rapidly, accurately and reproducibly measure the susceptibility of HIV-1 to all currently available antiretroviral drugs," Dr. Petropoulos and colleagues report. "The assay is intended to aid physicians in the selection of more efficacious treatment regimens," and may also be of use in screening new agents for activity against resistant strains of HIV-1, they conclude.
Studies are in progress to assess the clinical utility of the new assay. (Reuters)
A study testing the effectiveness of flu vaccination in people with HIV was recently published in the journal Annals of Internal Medicine. In this study, 102 people with HIV were divided into two groups, one of which received the flu vaccine while the other received a placebo or dummy shot.
The researchers reported that flu was later confirmed in ten people who received the placebo, but not in anyone who received the flu vaccine. In terms of respiratory symptoms (like runny nose and sore throat), 23 (49%) of the people who received the placebo shot got these symptoms, compared with 16 (29%) of those who took the flu vaccine.
Earlier studies have sometimes found that flu vaccines temporarily increase HIV viral load. For this reason, the researchers measured subjects' T-cell counts and viral loads when they started the study and at one month and three months after vaccination. The results showed no significant differences between people who took the flu vaccine and those who took the placebo shot. The overall conclusion of the researchers was that "routine influenza vaccination benefits patients with HIV infection." It is important to note that only thirteen people in this study had T-cell counts below 200, and the results may not necessarily be applicable to people with low T-cell counts.
Mutation cited for potential Hep C defense
People who carry unusual genes that protect them against HIV infection may also be protected against the CCR5 C virus, according to researchers at North Shore University Hospital and the State University of New York at Stony Brook.
About five years ago, scientists in New York City discovered a genetic mutation in some people of European descent that made their cells impervious to most types of HIV infection.
Under normal circumstances, the HIV uses CCR5 receptors to gain entry to cells. But gene mutations carried by people in this group were found to produce defective receptors on the surfaces of immune system cells that do not allow the virus to take hold.
If people in this group inherit the mutation from one parent, or are heterozygous, they may be infected, but are less likely to contract AIDS. If they are homozygous, meaning they inherited the mutation from both parents, HIV cannot infect their cells except in rare cases when the virus spreads using other receptors.
Now Dr. Mark Kaplan and his North Shore University Hospital colleagues have discovered that this same mutation seems to protect against the usually dangerous hepatitis C virus.
Those with the CCR5 mutation had a significantly lower overall viral load of hepatitis C than normal patients, Kaplan said yesterday in an interview, and they were more than twice as likely to spontaneously clear hepatitis C from their bodies.
"We don't know why the is a good thing to have," Kaplan said. "Maybe it protects against infection from a lot of other things, too."
Kaplan's study focused on 79 Long Island-based patients who were infected with both HIV and hepatitis C. Twenty percent of the group inherited the CCR5 mutation from one parent.
After presenting his findings at the seventh Conference on Retroviruses in San Francisco, Kaplan said they had a woman with the mutation who had "been an IV-drug user for a couple of decades and never got HIV or hepatitis C, even though she's been sexually active and shared needles with partners who have died of both diseases."
"I used to think my long-term survivors were hanging on because I was doing such a good job of caring for them," Kaplan said. "But all of them are [CCR5 mutation] heterozygotes."
Hepatitis C is primarily spread through contaminated blood, needles or medical equipment. It causes severe liver cirrhosis and has been linked to liver cancer. There is no cure. And even though some patients have undergone liver transplantation, doctors say the microbe can resurface and trigger infection in the new liver.
There are 36,000 new hepatitis C infections reported yearly in the United States, according to the Centers for Disease Control and Prevention in Atlanta, with 8,000 to 10,000 deaths per year.
Overall, it's estimated that 3.9 million Americans have the disease.
Numerous studies to be presented at the Retrovirus also show that liver disease caused by Hepatitis C is a major new threat to HIV patients.
Dr. Thomas O'Brien of the National Cancer Institute, meanwhile, expressed some caution about Kaplan's results. He said he has been studying hemophiliacs who became infected with both viruses through contaminated blood transfusions.
In his population, the CCR5 mutation does not appear to be protective against hepatitis C, O'Brien said. And he noted that he has seen homozygous CCR5 mutation in hepatitis C-infected individuals.
But Kaplan said he expects further study will support an association between the mutation and hepatitis C survival.
Some complications of HIV drugs puzzle doctors
AIDS researchers and doctors acknowledged at the Retrovirus conference that they were puzzled by some of the side effects of HIV drugs, which include odd accumulations of fat, raised cholesterol and a tendency to osteoporosis.
But they said no single drug, or even class of drugs, is to blame for the complications -- which should come as a relief to pharmaceutical companies that have been desperate to prove that their particular drugs are safe.
Researchers said they were redoubling efforts to find out just what is causing the side effects, and whether they represent a change in metabolism that could raise the risk of heart disease for HIV patients.
One thing is clear -- people who have taken drug cocktails for the longest time are most at risk of the complications, which include lipodystophy - marked by "buffalo humps" of fat growing on the back and a wasting away of fat in the limbs and face -- raised blood cholesterol and loss of bone mass.
"These changes were seen first in people on the edge, in the checkout queue, before HAART," David Cooper of the University of New South Wales in Australia told a news conference.
HAART, or highly active antiretroviral therapy, is the name for the mixtures of two different classes of drugs now keeping many HIV patients in the developed world alive and healthy.
"It turns out that these two classes of drugs, nucleoside reverse transcriptase inhibitors (RTIs) and protease inhibitors, both cause metabolic disturbance," Cooper said.
The first patients to go on HAART had been heavily treated with RTIs, which were starting to lose their effectiveness, and they were saved when protease inhibitors were introduced.
"This is the group that seems to be the worst affected by lipodystrophy," Cooper said.
He said their symptoms could have been caused by the old RTIs, by the new ones added to their regimes, by the protease inhibitors or, most likely, by a combination of all of them.
Carl Grunfeld of the University of California San Diego said the problems were linked to two RTIs -- lamivudine and stavudine. But he said they both came out at the same time as the protease inhibitors and many people just happened to have been put on the new drugs at that time.
"We should not be rushing to implicate any drugs," he said.
Lamivudine, also known as Epivir or 3TC, is made by Glaxo-Wellcome while stavudine, known as D4t or Zerit, is made by Bristol-Myers Squibb.
Grunfeld said how long a person had been infected and how long they had taken the drugs, as well as age, were all factors. "In a sense, it may in part be a product of the success of the therapies," he said. People were living long enough to suffer from the natural indignities of aging.
"One of the symptoms is that your belly gets bigger, and part of normal aging is your belly gets bigger," he said.
Grunfeld said this so-called "protease paunch" is probably a different syndrome from lipodystrophy.
He also said about 20 percent of patients taking HAART in his study could be classified as having osteoporosis. They were not the same patients who had the odd fat distributions.
Several researchers reported on how patients had higher levels of LDL or "bad" cholesterol, higher levels of triglycerides and lower levels of HDL or "good" cholesterol. (Reuters)
Compared with adolescents, young adult men in the United States are less likely to receive information about preventing HIV infection and sexually transmitted diseases (STDs), national survey findings suggest.
Carolyn H. Bradner, a student at the University of Chicago Pritzker School of Medicine, and colleagues reviewed longitudinal data from the National Survey of Adolescent Males, which was first administered in 1988. The investigators obtained additional information on 1,290 subjects from the original cohort, who were between the ages of 22 and 26 at the time of follow-up.
Overall, 30% of the subjects received no information on HIV or STDs, other than from media sources, the researchers found. In contrast, there is "nearly universal coverage of HIV and sex education for high school students," they report in the January/February issue of Family Planning Perspectives.
The team also found that "22% of men surveyed discussed disease prevention topics with a health provider in the last year, 48% attended a lecture or read a brochure, 51% spoke to a partner, friend or family member, and 96% heard about AIDS or STDs from the media."
Factors associated with receiving more information included being black or Hispanic and having had an HIV test or a physical examination in the past year. Subjects who reported having a discussion about HIV or STDs with a parent or healthcare professional were also more likely to have received more information.
"While it is gratifying that black and Hispanic males are receiving prevention messages, it is of concern that white males with similar sexual histories and socioeconomic status are substantially less likely to receive this information," Bradner's group writes. These differences are especially pronounced regarding HIV or STD information obtained from healthcare professionals. "Forty-two percent of black males got medical advice, compared with 17% of white males."
Because rates of sexual activity are much higher in young men than in adolescents, the authors point out that HIV and STD prevention messages directed at this subgroup should actually be stronger. (Reuters, Family Planning Perspectives)
FIGHT educational programs set
Philadelphia FIGHT's monthly "Information You Need To Live" seminar will take place on Tuesday, April 11, 2000 at the Bluemle Building of Thomas Jefferson University Hospital, located on the corner of 10th and Locust Streets. The topic is, "Metabolic Abnormalities: Body Weight Changes". The speaker is Donald Kotler, MD, Professor of Medicine at St. Luke's-Roosevelt Hospital. Topics include, "What does "lipodystrophy" mean? Why are some people experiencing changes in body shape and labwork? What are the latest theories on these changes? Do we know it is caused by protease inhibitors or other anti-HIV drugs? How can we predict who may have these troubling side effects or conditions?
Does switching drugs help? Can exercise and dietary changes reverse these conditions?" Find out the answers to some of these and more questions about body weight changes. Admission is free. Starting at 6:30pm there will be a small reception and the presentation is from 7:00pm-9:00pm. This training counts 2 hours toward the Case Management Coordination Project continuing education requirements for Ryan White Year 10. For more information, call (215) 985-4448.
FIGHT's Frontline Information Series will take place on Wednesday, April 26, 2000. It will be held at St. Luke's & the Epiphany Church, located at 330 S. 13th St., 13th Street between Spruce and Pine Streets. The topic is "Patient/Providers: How to Partner With Health Care Staff". The speakers are Erika Aaron, CRNP, of Partnership Practice, MCP/Hahnemann University and Suzanne Willard, CRNP, of Partnership Practice, MCP/Hahnemann University. A health center doesn't have to be confusing or intimidating. This program will help HIV service providers and people with HIV identify skills they can use to create a great working relationship with health care staff. The presentation will also cover who different staff are and what they do.
Bring specific issues to discuss and use the resources of the group to find solutions. The seminar is from 3:oopm-5:00pm. Admission is free and refreshments will be served. This training also counts 2 hours toward the Case Management Coordination Project continuing education requirements for Ryan White Year 10. For more information, call (215) 985-4448.
ACT UP Choir rehearsals weekly
The ACT UP Philadelphia Choir, which is a group of AIDS activists who have joined together to fight the AIDS crisis through "songs of protest and hope," holds rehearsals every Monday evening from 5 to 6 pm at the Church of St. Luke and the Epiphany, 330 South 13th Street. For more information, call Jonathan at 215-917-2717.