published by We The People Living with AIDS/HIV of the Delaware Valley, Inc.
WISDOM pulls out of AACO needs assessment
Protease combo reduces viral load by 99.9%
Viracept available through expanded access
Study shows NTZ works against crypto diarrhea; ACT UP protests seizure of shipment;
New evidence that IL2 boosts immunity
Gel to help women prevent HIV transmission
Age at infection linked to disease progression
Two drugs said to protect against KS
Researchers develop cream to prevent herpes
WISDOM pulls out of AACO needs assessment
Women with Immune System Disorders Organizing and Meeting (WISDOM) -- the regional coalition of women living with HIV/AIDS -- has announced it will not participate in a planned HIV/AIDS needs assessment targeted to HIV+ lesbian women -- for which it had advocated for almost four years.
The city's AIDS Activities Coordinating Office (AACO) had announced needs assessment in early September after intense pressure from representatives of a variety of "underserved" populations affected by the HIV epidemic, who have claimed that their special needs have been ignored by the city's AIDS services system. Utilizing $100,000 from Title I Ryan White CARE Act supplemental funds, the Philadelphia HIV Commission had authorized AACO to seek the help of community organizations in conducting a needs assessment for six "special populations": lesbians, Asians and Pacific Islanders, low-income people in the city's Kensington/Fishtown neighborhoods, pregnant women, transgendered people, and incarcerated people.
In a letter to Philadelphia health commissioner Estelle Richman and AACO director Jesse Milan, WISDOM director Pam Ladds said that the funding for the needs assessment was inadequate to producing a realistic and useful result, especially among the divergent populations included. She also said that the time frame for building effective collaborative efforts among very different organizations and constituencies which AACO required for the project -- a total of five working days -- was too short for constructive partnerships to be developed among the groups interested in working on the needs assessment.
AACO had issued a Request for Proposals (RFP) for the project which required the implementation and "interpretation" of a needs assessment for all of the populations included, as well as the development of service enhancement and/or capacity building strategies targeting the underserved HIV/AIDS populations in the city. The assessment was aimed at evaluating the needs of people living with HIV/AIDS in the population groups, rather than developing prevention strategies, which were the subject of a separate needs assessment being conducted by the HIV Commission's HIV Prevention Community Planning Group.
AACO said that proposals received in response to the RFP would be reviewed by the city's controversial Resource Allocations Advisory Committee RAAC), which has been criticized for keeping its membership secret and for refusing to release details on how it conducts its deliberations. In her letter to the health department, Ladds also said that the long delays that are typically experienced in waiting for the all-volunteer RAAC to conduct its process also bring into question the seriousness of AACO's commitment to the needs assessment, since the entire process needs to be completed within the next six months.
Ladds noted that the five-day time frame allowed by AACO to build the required collaborations among the various groups interested in participating in the needs assessment was impractical. Groups representing the various constituencies "had no prior knowledge of each other's interest in applying" prior to a September 13th technical assistance session sponsored by AACO, she said, "limited information on relevant expertise, organizational structure or personalities. And we had five working days to accomplish this!"
Noting that most of the underserved populations were being helped by groups comprised almost solely of volunteers, she said that their ability to overcome all of these obstacles to planning the comprehensive collaboration AACO required was complicated by the fact that "most of us have not been able to give up our day jobs."
"WISDOM is a group with few financial resources," Ladds said. "The AIDS industry that allows AACO personnel to spend time attending meetings and constructing hoops for the rest of us to leap through, pays for their hours involved in this. WISDOM women, myself included, do not get paid to attend meetings, write grant applications, or spend hours getting to know how other groups work."
"Collaboration needs to be worked out carefully," Ladds said, "and five days is totally disrespectful of this process." She noted that the five-day turnaround time also fell within the Jewish holidays between Rosh Hoshanah and Yom Kippur, inhibiting others from fully participating in the process.
Ladds also criticized AACO director Jesse Milan for failing to take seriously the criticisms about the time line. "Milan's response, which was condescending and dismissive, was [delivered] in AACO's hallway," Ladds wrote. "The issue apparently didn't merit his real time and attention. He was sure we could 'manage' to do it."
Ladds also noted that the target groups for the needs assessment were identified "months ago," and that the funding has been available to the city since last April. "Why then have the applicants been set up either to fail or drive themselves crazy in an unrealistically short time frame," she asked. "Shotgun collaborations work about as well as marriages set up the same way," she said.
Ladds said that AACO's action leaves WISDOM "literally caught between the RAAC and a hard place. If we refuse to participate in what we experience as an abusive process we become 'uncooperative,' and we may sabotage an opportunity to obtain needed services for a population we have been screaming about for the last four years. If we do participate we have no choice but to be abused further."
Ladds blamed the poor planning on the needs assessment on the crisis mentality which still pervades the city's AIDS bureaucracy.
"We do no constructive long-term planning," she concluded.
"These data demonstrate not only the continued antiviral effect of this combination of two protease inhibitors, but also the enhanced activity of the combination over time," said investigator Calvin J. Cohen, M.D. of Community Research Initiative, New England.
The 12 week data presented today come from the first-ever study to examine the safety and efficacy of a combination of two protease inhibitors. The effect on disease progression and survival is unknown. Six week results from this trial were presented in July at the XI International AIDS Conference.
The multi-center, open-label study randomized approximately 136 patients to one of four different treatment arms. All patients had baseline CD4 cell counts of 100 - 500 prior to beginning the treatment regimens, and none had previous exposure to protease inhibitors.
In the first two treatment arms, patients received either 400 mg Norvir plus 400 mg Invirase twice daily or 600 mg Norvir plus 400 mg Invirase twice daily. After 12 weeks of treatment, the median viral RNA level declined 99.9 percent (2.97 logs), and the median CD4 cell count increased by 95 cells. The changes in these two treatment arms were similar.
In the third and fourth treatment arms, patients received 400 mg of Norvir plus 400 mg Invirase three times a day or 600 mg Norvir plus 600 mg Invirase twice daily. After six weeks of treatment, the median viral RNA level dropped by 99.3 percent (2.14 logs), and the median CD4 cell count increased by 75 cells. Again, the changes in the two treatment groups were similar.
"The response in both of these dosing regimens demonstrates that saquinavir and ritonavir appear to work synergistically," said Cohen. "These drugs interact in a way that clearly results in high therapeutic blood concentrations of both agents and increased antiviral activity."
The combined regimens were generally well-tolerated, with about seven percent of patients discontinuing. Most of these patients were in the three times daily 400 mg ritonavir/400 mg saquinavir regimen. Continuation of this treatment arm is under review. Tingling around the mouth, diarrhea, fatigue and nausea, the most commonly reported adverse events, were generally mild and transient in nature. Since Norvir interacts with some drugs when taken together, patients should discuss use of other medications with their doctor.
Renal deficiency linked to ritonavir
Meanwhile, physicians in France have reported three cases of reversible renal dysfunction associated with ritonavir use in HIV-infected patients.
Dr. Michel Duong of the Hospital du Bocage and colleagues describe three patients who presented with renal dysfunction within 10 and 12 days after the start of ritonavir therapy. In all patients, the French doctors report that creatinine levels returned to normal within 1 week of discontinuation of ritonavir therapy. In one patient, renal deficiency returned upon rechallenge with the drug.
Dr. Duong notes that renal abnormalities were observed in animals and crystalluria and kidney stones were described in the early phases of development of ritonavir.
"Notwithstanding the great benefit that protease inhibitor therapies have provided to many people, there unfortunately remain some people who are unable to avail themselves of these current treatments due to intolerance, contraindication or prior failure. Agouron is committed to supplying Viracept to these people whose need is the greatest," said Peter Johnson, president and chief executive officer. Agouron anticipates filing a New Drug Application (NDA) with the FDA in the first quarter of 1997, followed by equivalent regulatory submissions in Canada and Europe. An independent European expanded access program will follow later this year.
A toll free information service is available for physicians, health care professionals and people interested in the VIRACEPT Expanded Access Program. 1-800-621-7111 is available Monday through Friday from 8:00 a.m. to 6:00 p.m. EDT to answer calls. Calls placed before or after these hours will be returned during operating hotline hours, Agouron said.
The safety of VIRACEPT has been studied in more than 500 people who received drug either alone or in combination with nucleoside analogues. The most commonly reported side effects were mild or moderate diarrhea, headache and fatigue. Phase II/III clinical studies of Viracept are ongoing.
There is no consistently effective or approved therapy for cryptosporidiosis, caused by a microscopic protozoan parasite. Symptoms include profuse diarrhea, abdominal cramping, urgency, severe dehydration and weight loss. It is estimated that 15 to 20 percent of people with AIDS suffer from this condition. For them this diarrhea can be chronic, severe and often life threatening.
In people with normal immune function, cryptosporidiosis may be intense and prolonged, but usually is self-limited, lasting up to two to four weeks. However, it is estimated that 45 million people in the U.S. may be exposed to drinking water from systems contaminated with cryptosporidium. In 1993, an outbreak in Milwaukee caused illness in 400,000 and was linked to at least 100 deaths.
Small quantities of cryptosporidium were found in the Philadelphia water supply last year, but city health department officials claim that the levels were not sufficient to cause an outbreak. Recently, the city's AIDS Activities Coordinating Office (AACO) began reporting publicly the incidence of cryptosporidium infection in people living with HIV/AIDS in the city. In its June 30th AIDS epidemiology report, AACO noted that the city health department had received 138 reports of AIDS-related cryptosporidiosis since January of 1990, with only three cases being reported so far in 1996. The report said that by this time last year, twelve cases had been reported to the health department.
The Phase II NTZ trial included 28 patients with both AIDS and cryptosporidial diarrhea, who failed to respond to other therapies. These patients received up to 2,000 mg (milligrams) per day of NTZ for eight weeks. Results showed that 58 percent had a clinical response, with 50 percent having complete or partial reduction in bowel movement frequency, and 36 percent showing complete or partial reduction of cryptosporidial parasites. In addition, 32 percent of patients experienced reduction of both diarrhea and parasites.
Dr. Rosemary Soave, assistant professor of medicine at Cornell University, was the lead investigator of the study conducted at New York Hospital - Cornell Medical Center and the Kaiser Foundation Research Institute in San Francisco. "NTZ appears to have a favorable clinical effect on cryptosporidial diarrhea, and greater benefit may be obtained with longer treatment times and/or higher doses," she explained. "In addition, the drug was well tolerated and patient compliance was excellent. The findings of this study suggest that NTZ may represent a significant advance in the treatment of cryptosporidial diarrhea."
Interim results of an ongoing compassionate use study, in which access to NTZ was given to several hundred people, improvement was seen in the frequency of bowel movements and liquid stools beginning at the end of the first week. By the eighth week, the mean total stool frequency in 113 patients who received 500 mg twice a day declined by 50 percent. Mean liquid stool frequency declined by 65 percent. Moreover, body weight in these patients increased by approximately one pound per week during eight weeks of therapy.
"A Phase III study is planned to begin by year-end to more fully demonstrate the safety and effectiveness of NTZ," said Stephen Simes, Unimed president and CEO. "NTZ currently is approved for marketing in Mexico and has been designated an Orphan Drug by the U.S. Food and Drug Administration. We plan to submit results of the Phase III study to health authorities in the U.S. and other countries seeking approval to market NTZ as soon as they are available. This compound shows great promise for treating a condition where therapies are urgently needed.
Meanwhile, ACT UP/Philadelphia has lodged a protest with the U.S. Food and Drug Administration against a U.S. Customs Department decision to seize a shipment of NTZ on its way to the U.S. from abroad last June.
In a letter to Ronald Chesemore, Commissioner of the Office of Regulatory Affairs for the FDA, ACT UP member Julie Davids said that Customs officials had told ACT UP that "any Customs action in this area will depend entirely on the FDA approval determination for granting a waiver." She said that since early this summer, complaints about the seizure have been "passed back and forth" between the FDA and Customs with no action on the part of either agency to resolve the matter.
"This is not a matter of overlooking the law in order to save lives," Davids wrote. " It is
perfectly legal to import treatments from other nations for personal use. We are outraged that this shipment is being held while people are dying a horrible death from cryptosporidiosis."
"We are simply asking you to let this shipment reach its destination," Davids wrote, "so
it can be used by people suffering from cryptosporidiosis who have made an informed decision that it may be a possible treatment option. We are appalled that this situation has taken months to resolve, and can only hope that a swift resolution is at hand. If not, we are prepared to do whatever is necessary to resolve this injustice."
No response to the ACT UP letter had been received by the fastfax deadline.
New evidence that IL2 boosts immunity
Doctors for the first time have used low doses of a cancer-fighting drug to boost the immune system of people infected with HIV without any apparent side effects.
The research, published in the Proceedings of the National Academy of Sciences, was based on a six-month study of 16 patients using interleukin 2 (IL 2).
Scientists in the past year have made remarkable strides in developing antiviral drugs that suppress the production of HIV in humans. Those drugs target the virus. The interleukin research attempted to give them an ally by marshaling the body's own immune system defense.
Larger-scale controlled studies are needed, as are studies to determine how IL 2 works best in combination with antiviral AIDS drugs. But the researchers at New York Hospital-Cornell Medical Center were very encouraged by the initial findings.
"In the entire history of medicine, we really have not been able to stimulate the immune system. We can suppress it -- for transplants, allergies and autoimmune diseases. But we didn't know how to turn it up," lead researcher Dr. Kendall Smith told Reuters in a telephone interview. "But we achieved that this shows the proof of concept."
Smith said the idea was to use IL 2, with the other new "cocktails" of AIDS drugs, "to treat people as early as possible, before they've had much immune system damage."
IL 2 may also hold promise for people who are already sick from AIDS. The anti-viral drugs may reduce HIV levels in their blood, but "this may help the immune system in coming back," Smith said.
Interleukin 2 is a hormone that is a natural part of the immune system. Identified in the 1970s, it is used in chemotherapy against some cancers. But chemotherapy requires large doses and patients often have terrible side effects.
Other scientists are experimenting with chemotherapy-style IL 2 treatments for AIDS, giving large doses in the hospital for about five days at a time. The treatment is costly and the side effects can be severe.
In contrast, Smith's subjects gave themselves daily shots of small doses of IL 2, much like diabetics give themselves insulin. They did not have to go to the hospital and could continue normal daily school and work activities.
The idea was to see how low a dose would be effective in raising the number of CD-4 cells in the bloodstream. The CD-4 count is an indicator of how healthy HIV-infected people are, how well they can stave off the virus's killer effects.
The subjects had no AIDS symptoms yet and had CD4 counts of between 200 and 500 -- well below normal but not "advanced" AIDS. On average, they had been HIV-infected for seven years.
Smith's team found that doses measured at 125,000 IU was too low. There were no significant side effects but there were no benefits either. At 500,000 IU, the side effects started, including low-grade fever, muscle aches and a "general bad feeling," he said.
But at 250,000 the patients' CD-4 counts rose steadily, a mean of 27 or 28 cells each month, and they had no side effects.
"The results from this study indicate that asymptomatic HIV-individuals can self-administer IL 2 safely and without any detectable toxicity for six months," the scientists wrote. "Expanded clinical trials of low dose IL 2 are now warranted."
Procept believes its PRO 2000 antiviral compound is well suited for development as a female-controlled topical product to help prevent HIV infection. Laboratory studies have shown that PRO 2000 is active against a wide range of HIV strains from both the developed and developing world. It is also active against other STD pathogens, such as herpes simplex virus type 2, a cause of genital lesions which are believed to be a portal for HIV entry. Easily prepared and stable, the company believes that it will be possible to manufacture sufficient quantities of PRO 2000 to meet anticipated worldwide demand.
On September 7, Procept presented preclinical data on its PRO 2000 topical gel formulation at the First Annual Meeting of Dr. Robert Gallo's Institute of Human Virology in Baltimore. The gel was shown to be well tolerated in a rabbit vaginal irritation study, and did not induce skin sensitization in guinea pigs. PRO 2000 topical gel was also shown to be compatible with latex condoms. Procept plans to begin Phase I clinical studies in healthy female volunteers by the end of 1996.
Donna E. Shalala, U.S. Secretary of Health and Human Services, announced at the XI International Conference on AIDS in Vancouver that the National Institutes of Health and the Centers for Disease Control and Prevention will spend $100 million over the next four years to speed development of such products. "Today, too often, women must rely solely on their male partner for protection from HIV. And in too many cases that means no protection at all", she said. Development of topical microbicides has also been endorsed by the British Medical Research Council, and the Joint United Nations Program on HIV/AIDS.
Age at infection linked to disease progression
An individual's age at the time of HIV seroconversion influences the rate of disease progression, regardless of how the person was exposed to the virus, according to a new study.
Specifically, Italian researchers found a strong tendency for more rapid development in older subjects. However, they found no evidence of differences in rate of development of AIDS by exposure category.
Dr. Patrizio Pezzotti of Rome and colleagues in the HIV Seroconversion Study group determined the rate of development to AIDS in a longitudinal study of more than 1,100 subjects with known dates of seroconversion. Participants included individuals infected with HIV by injection drug use, homosexual sex or heterosexual sex. Over a follow-up of almost 6 years, 225 individuals developed AIDS. Age at seroconversion was strongly associated with progression to AIDS among all of the subjects and this age effect was of similar size in each exposure category and in men and women. This suggests that age was of fundamental importance in the pathogenesis of HIV.
Dr. Pezzotti believes these results also suggest that any comparisons of disease progression among subjects who were infected with HIV by different exposures should be interpreted with caution if the effects of age are not taken into account.
Two drugs said to protect against KS
A British study has confirmed that the anti-herpesvirus drugs foscarnet and ganciclovir appear to have a protective effect against the development of Kaposi's sarcoma in HIV-positive people. Acyclovir, however, does not.
Given the recent identification of a new herpesvirus, human herpesvirus-8, associated with Kaposi's sarcoma, researchers in the United Kingdom investigated the use of anti-herpesvirus drugs and the occurrence of Kaposi's sarcoma in a large unselected group of people with AIDS.
Dr. Amanda Mocroft of the Royal Free Hospital School of Medicine and colleagues found that among some 3600 patients with HIV who have been followed for more than 4 years, 16.2% developed Kaposi's. After adjustment for other factors, treatment with foscarnet and ganciclovir were associated with a decreased risk, with relative hazards of 0.39 and 0.38, respectively. Conversely, acyclovir was associated with a relative hazard of 1.10 for developing Kaposi's sarcoma.
Dr. Mocroft explains that previous data on this association have been conflicting, but that the present study has the benefit of a considerably longer follow-up period, and adds weight to the argument for a protective effect.
Researchers develop cream to prevent herpes
American researchers have announced that they have developed a cream made from human bile acid which can prevent genital herpes and has the potential to combat most sexually transmitted diseases.
The breakthrough in fighting genital herpes, a disease estimated to afflict 55 million Americans, is part of a $2 million search for new "microbicides", easy-to-use creams or gels to protect people against of sexual diseases, including potentially AIDS.
Doctors at Cincinnati's Children's Hospital Medical Center announced their findings at the 36th Interscience Conference on Antimicrobial Agents and Chemotherapy sponsored by the American Society for Microbiology.
The researchers, focusing on preventing sexual diseases in women as a strategy to protect fetuses and newborns from infection with syphilis, herpes, gonorrhea or chlamydia, reported a high success rate.
They said cholic acid, a bile acid produced by the body that plays a role in human digestion, provided 80 percent protection against infection from genital herpes, caused by the herpes simplex virus type 2.
"We'd like to get the protection rate up to 90 percent, either by reformulating the substance or combining it with other substances that have antiviral activity," said Shirley Reising, who directed the study.
"Eventually, we may have a formulation that prevents all or most sexually transmitted diseases," she said.
Another multinational study reported at the same conference that the topical cream penciclovir effectively reduced the lesions, pain and contagion of cold sores from the herpes simplex virus type 1.
Professor G. Wayne Raborn of the Penciclovir Topical Collaborative Study Group, University of Alberta, Edmonton Canada said studies conducted at 43 centers in Europe, Canada and Singapore confirmed results of similar studies conducted at 31 centers in the United States.
"Penciclovir cream is the first topical antiviral treatment to convincingly impact the clinical course of recurrent cold sores by affecting the multiple signs and symptoms, including pain resolution, lesion duration and cessation of viral shedding," said Raborn.
An estimated 20-25 percent of the world's adult population suffers from cold sores (herpes simplex labialis).
Penciclovir cream, manufactured by SmithKline Beecham, has been approved in Britain and was launched in June under the brand name Vectavir. The product is under review by the U.S. Food and Drug Administration.