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Issue #168: March 15, 1998
fastfax is available by fax in the 215 and 610 area codes at no cost, or by mail anywhere for $20.00 per year, by calling 215-545-6868, and by E-mail by contacting and type the message SUBSCRIBE in the message section. Sources for some information in this issue include AIDS, American Journal of Epidemiology, Archives of Internal Medicine, Journal of the American Geriatric Society, Journal of the National Cancer Institute, Reuters.Crypto drug presented to FDA for approval
Study supports using CD4 counts to predict illness
HIV skin diseases differ in men, women
Women live longer with experienced MDs
New test detects AIDS-related lymphoma
Sex, drugs increase as HIV route for older people
Crypto drug presented to FDA for approval
Unimed Pharmaceuticals has announced that the U.S. Food and Drug Administration (FDA) has officially approved a priority review for the New Drug Application (NDA) to market NTZ (nitazoxanide) for the treatment of cryptosporidial diarrhea in people with HIV disease.Only last year, the FDA sought to prevent the importation of NTZ for people with HIV affected by cryptosporidiosis, a bacterial infection sometimes found in tap water.
A crypto scare engulfed Philadelphia's AIDS community about three years ago, when tests of city water supplies indicated potentially threatening levels of Cryptosporidium parvum in the city's tap water. The city's AIDS Activities Coordinating Office issued several special alerts to the AIDS community offering advice on how to protect against crypto infection, and data on reported cases began to be publicly reported by the Health Department.
As of last September 30th, the Health Department reports that only five new cases of cryptosporidiosis have been reported in Philadelphia, as compared to nine for the first nine months of 1996. Since 1990, 155 cases of cryptosporidiosis have been formally reported in Philadelphia.
In immunocompromised patients, cryptosporidiosis is a serious medical condition that can be fatal without effective treatment. Unimed filed the NDA for NTZ on December 30, 1997. This NDA marked the first submission of a new drug application to treat the diarrhea associated with cryptosporidiosis.
"The compound was developed under an extremely aggressive plan which took only two years from Phase I to NDA filing," said Ronald L. Goode, Ph.D., president and chief operating officer of Unimed. "This priority review demonstrates the validity of Unimed's strategy to develop products that treat unmet therapeutic needs. For any company this is a remarkable achievement. For a company of Unimed's size, this is an extraordinary accomplishment."
An FDA priority review ensures that a NDA will be completely reviewed and acted upon within six months of receipt. Unimed expects the FDA to schedule an Advisory Committee Meeting in conjunction with their priority review. Given the immediacy of priority review and the Committee's recommendations, FDA clearance of NTZ could follow soon thereafter.
Cryptosporidiosis is caused by the relatively common, highly infectious water- and food-borne parasite, Cryptosporidium parvum. It is estimated that worldwide, 250 million to 500 million cases of diarrhea each year are due to cryptosporidiosis(1). The associated chronic diarrhea, as many as 15 to 20 liquid bowel movements per day, is debilitating and leads to chronic malabsorption of fluids and nutrients. Other common symptoms include abdominal cramping and pain, rectal urgency and bowel movements that awaken individuals from their sleep. For AIDS patients infected with this parasite, significant weight loss occurs and is often followed by death. Cryptosporidium parvum has been identified in municipal water supplies across the U.S. and has infected thousands of immunocompetent as well as immunocompromised people. In 1993, the parasite contaminated Milwaukee's water supply causing more than 400,000 cases of cryptosporidiosis, including more than 100 AIDS patients who died as a result.
"Many AIDS patients suffer from this potentially life-threatening diarrhea," said Rosemary Soave, M.D., Associate Professor of Medicine and Public Health, Cornell University Medical College, Division of International Medicine and Infectious Diseases. "If approved, NTZ will be the first and only drug that has a specific indication to help AIDS patients battle this debilitating condition which all too often leads to hospitalization and death."
Unimed holds an exclusive license to develop and market oral dosage forms of NTZ for human use in the U.S., Canada, Australia and New Zealand from Romark Laboratories.
In addition, phase III clinical trials are currently underway for Androgel and Androgel-DHT for the treatment of HIV wasting. The company plans to file an NDA with the FDA for Androgel(TM) and Androgel-DHT(TM) in the near future.
Meanwhile, a new paper in the February issue of the American Journal of Epidemiology reinforces earlier recommendations that people with compromised immune systems should boil their tap water.
Their contentions conflict with an analysis of a massive waterborne outbreak of Cryptosporidium infection in Wisconsin, in which a multicenter team of epidemiologists found that, in general, HIV-positive individuals were not more likely to become infected compared with HIV-negative individuals.
"However, once infected, the duration and severity of illness was greater in HIV-infected persons, especially if the CD4 count was less than 200," the Wisconsin researchers said.
New York-based epidemiologists, however, say that Cryptosporidium parvum in tap water, even at low levels, represents an important exposure route for this pathogen.
Although waterborne transmission of C. parvum has been linked to outbreaks of cryptosporidiosis, the role of tap water in endemic disease is uncertain, Dr. Joseph F. Perz and colleagues at Columbia University in New York explained. Therefore, they evaluated the potential role of tap water in C. parvum transmission using a risk assessment model. Based on a "plausible" C. parvum concentration of 1 oocyst per 1,000 liters, they calculated the resulting rates of infection and of clinically apparent disease in populations with and without AIDS.
Dr. Perz's team estimated the median annual risk of infection in a non-AIDS population to be about 1 in 1,000, "...while in the AIDS subgroups the predicted risk was 2 in 1,000." In adults without AIDS, only 3 of every 10,000 infections would result in cryptosporidiosis, but in AIDS patients the majority of infections would produce disease.
Applying these figures to the New York City population, the authors estimate there would be a total of 6,000 infections per year attributable to tap-water exposure. This would result in 34 cases of cryptosporidiosis in the AIDS subgroup and 6 in the non-AIDS subgroup. Since there is no proven treatment for cryptosporidiosis, they write, their analysis "...supports recommendations for clear general advisories to immunocompromised persons regarding the avoidance of unboiled tap water."
Dr. Perz's team notes that the number of cases of cryptosporidiosis reported in New York City and elsewhere in the US has declined since the end of 1996. This may reflect "...a decline in the number of Cryptosporidium infections in the AIDS population and/or that outcomes are less severe." They suggest that decreased susceptibility to infection might be attributed to the availability of improved combination antiretroviral therapies.
Study supports using CD4 counts to predict illness
In an era where most doctors and people living with HIV disease have grown more dependent on viral load counts to determine their risk of active illness, a new British study has reaffirmed that AIDS-defining illnesses can, to some extent, be predicted by monitoring patients' CD4 lymphocyte levels, according to a report in the March 9th issue of the Archives of Internal Medicine. These data are useful in identifying individuals who will benefit most from disease-specific prophylaxis, the research group has reported.For example, individuals with CD4 lymphocyte counts above 50 cells per microliter have a low incidence of cytomegalovirus (CMV) infection and Mycobacterium avium-intracellulare complex (MAC) infection, Dr. Brian Gazzard of St. Stephen's Clinic in London and colleagues report. Conversely, Kaposi sarcoma, Pneumocystis carinii pneumonia and esophageal candidiasis may occur in patients with a wide range of CD4 cell counts.
Dr. Gazzard and members of the Royal Free/Chelsea and Westminster Hospitals Collaborative Group evaluated 4,883 HIV-positive patients seen over a period of about 13 years. Median follow up was a little under 28 months, and close to 4,000 AIDS-defining illnesses occurred in more than 1,700 patients for whom CD4 cell counts were measured.
Dr. Gazzard's group reports that "the incidence of each AIDS-defining illness increased as the CD4 lymphocyte count declined." They also noted "...considerable differences in the CD4 lymphocyte count at which different AIDS-defining illnesses occur." In addition to the relationship between MAC and CMV infection and lower CD4 cell counts, they also found that "...diseases such as lymphomas and tuberculosis...typically occur at higher CD4 cell counts."
The researchers also observed an "...increasing incidence of MAC in patients diagnosed as having HIV in more recent years, but found no evidence of an increase in cytomegalovirus infections." In contrast to previous reports, they found that women had a "significantly reduced" risk of esophageal candidiasis when compared with men.
Overall, these data provide "...important information about the incidence of AIDS-defining illnesses across a wide range of CD4 lymphocyte counts, enabling disease-specific prophylaxis to be targeted at the most appropriate population."
Few of the subjects in this study had received treatment with protease inhibitors, which have been reported to substantially alter patterns of HIV disease progression, Dr. Gazzard's group adds. They therefore believe that "...it will be of great interest to compare the median CD4 lymphocyte counts at which AIDS-defining illnesses occur in patients who take protease inhibitors, and to confirm the declining incidence of opportunistic infections."
HIV skin diseases differ in men, women
Women with HIV infection are less likely than HIV-infected men to develop virus-related skin diseases, such as warts, according to preliminary results presented at the American Academy of Dermatology meeting in Orlando, Florida.
Up to 21% of HIV-positive men have warts compared with 1.5% of HIV-positive women, reported Dr. Paradi Mirmirani, of the University of California, San Francisco. Women also have a lower prevalence of AIDS-related skin diseases such as Kaposi's sarcoma and herpes simplex than men, though the reason why is unclear.
The study included 332 HIV-positive women and 89 HIV-negative women who were recruited from the San Francisco Bay-area HIV and methadone clinics, outreach programs, and living centers. Not surprisingly, women with HIV had a higher prevalence of skin diseases compared with women without HIV, Mirmirani said.
More than half of the women (57.8%) with HIV had abnormal skin exams compared with 40.2% of women without HIV. Intravenous drug use was the only independent predictor of an abnormal skin exam in the HIV-positive group, Mirmirani said.
The researchers compared their data with that from 10 studies of men with dermatologic complications of HIV. More than 40% of men have Kaposi's sarcoma compared with 0.4% of women, nearly half of men (49%) have seborrheic dermatitis -- a chronic inflammatory skin disease -- compared with 4.3% of women, and 22% of men have herpes simplex infections compared with 4.3% of women. Almost three quarters of men have xerosis (dry skin) compared with 12.7% of women. The incidence of bacterial infection is more evenly distributed between men and women.
The study is one arm of the Women's Interagency HIV Study. The multicenter longitudinal study, funded by the National Institutes of Health, includes six sites nationwide with approximately 2,000 participants, Mirmirani said. She will soon begin to analyze the data from the other five sites and plans to finish putting together the entire study by early 1999, she said.
Women live longer with experienced MDs
A multicenter team has reported that HIV-positive women have a 50% better chance of survival if they receive care at a clinic that is experienced in treating HIV infection than in one with less experience.These findings, published in the March 5th issue of AIDS, confirm previous reports that women with AIDS who are treated by experienced providers have more favorable outcomes.
Dr. Christine Laine of Jefferson Medical College in Philadelphia reviewed the records of women with AIDS who were enrolled in the New York Medicaid program between 1986 and 1992. Data included records from 117 clinics in New York, which is the state with the largest number of HIV-positive women in the US. Dr. Laine's group evaluated the survival time for 887 women following a diagnosis of AIDS.
"Previous research in this area calculated experience by collecting self-reports from doctors who estimated the number of HIV infected patients they had treated," Dr. Laine commented in a Thomas Jefferson University press release. "Using Medicaid records, we counted the number of patients with HIV treated at each clinical rather than relying on providers' rough estimates."
Dr. Laine's group found no survival differences among the women treated between 1989 and 1990. However, beginning in 1991 the relative hazard of death for patients in high-experience clinics was 0.53 compared with patients in low-experience clinics. After making adjustments for clinical and demographic variables, they found that "...71% of patients in high experience clinics were alive 21 months after diagnosis compared with 53% in low experience clinics.".
These findings support those reported by Kitahata et al., the researchers point out, in which a similar relationship was found between provider experience and patient survival for a cohort of homosexual men with AIDS.
An unexpected finding was that survival was positively associated with methadone treatment and pregnancy. Dr. Laine's group suggests that closer medical follow-up and/or better access to care may explain these relationships.
"The results of our study suggest that physicians and health professionals who treat a certain illness frequently may do it better," Dr. Laine continued in the university release. "This is especially true in regards to HIV management and treatment, since therapy is advancing so rapidly."
New test detects AIDS-related lymphoma
Studies show that as HIV-infected patients are surviving longer with improved combination antiretroviral therapies, more are developing a type of brain tumor called primary central nervous system lymphoma (PCNSL).Now, many cases of this AIDS-related cancer can be diagnosed by identifying Epstein-Barr virus (EBV) DNA in cerebral spinal fluid, according to Italian researchers.
PCNSL is often difficult to distinguish from Toxoplasma encephalitis --a common complication of AIDS, say the researchers in a report in the March 4th issue of the Journal of the National Cancer Institute (JNCI). Because of the similarity between the two disorders, a brain biopsy has been required to confirm diagnosis. However, Dr. Antonella Cingolani of Catholic University in Rome, Italy, and colleagues report that a minimally invasive diagnostic approach using EBV DNA "...is a sensitive and highly specific diagnostic marker of AIDS-PCNSL."
Cingolani's group evaluated 122 HIV-positive patients who had brain lesions. They tested the clinical usefulness of detecting EBV-DNA in the patient's cerebral spinal fluid, which was obtained from most of the patients (90 subjects) by lumbar puncture.
The researchers found that this method was highly sensitive and specific for detecting lymphoma in these patients. They estimated that about 63% of the patients with PCNSL would have been correctly diagnosed and 76% of patients without lymphoma would have been identified using this method.
"This study provides strong evidence that measurement of cerebral spinal fluid EBV-DNA can be a useful tool in the diagnosis of AIDS-related PCNSL," according to Dr. Robert Yarchoan and colleagues at the National Cancer Institute. Current approaches are limited, and this test "...has the potential of representing an important diagnostic advance," they write in an accompanying editorial.
The need for a less invasive diagnostic technique for AIDS-PCNSL had been acute, according to a JNCI News report in the same issue. Brain biopsies are impractical in some AIDS patients, Dr. Alexandra Levine of the University of Southern California explains. Many AIDS patients are frail, and some neurosurgeons are reluctant to perform a brain biopsy because of potential risk to the surgical team.
Therefore, if treatment for toxoplasmosis fails, patients are often treated for lymphoma. "In my personal experience, this is one of the only settings where you sometimes end up treating a cancer without a pathological diagnosis," Yarchoan adds. "It gnaws at your stomach."
Sex, drugs increase as HIV route for older people
HIV infection in older adults has been thought to be transmitted primarily through blood transfusions, but a report in the February issue of the Journal of the American Geriatric Society indicates that this is no longer the case.Dr. Helen X. Chen of the Union Memorial Hospital in Baltimore evaluated 321 cases of AIDS diagnosed in patients who were 60 years of age or older. This reflects about 2.7% of the total number of AIDS cases reported in Maryland from 1981 through 1994.
Dr. Chen's group found that the overall "...incidence of AIDS in older patients has remained fairly constant since 1987 in Maryland." Pneumocystis carinii pneumonia was the most common indication of AIDS among the older adults, but AIDS-wasting, candidiasis and HIV encephalopathy were also common.
"Transfusion was the primary cause of exposure of 32% of the older people with AIDS," they report. But over the last few years, Dr. Chen's team observed that "...sexual transmission and drug abuse have been implicated more frequently." Among the older adults, 12% of HIV-positive individuals had no reported risk factors for HIV infection, compared with 4% of the younger HIV-positive individuals.
"Many people choose to die of AIDS rather than have it identified officially, and more older than younger patients are likely to make this decision," Dr. Margaret Terpenning of the University of Michigan in Ann Arbor comments.
"The effectiveness of various campaigns that point out the risk of AIDS to older people should be evaluated," Dr. Terpenning continues. Approaches that include posters and talks in senior centers, and other educational strategies may be effective. Other areas concerning AIDS prevention in older adults that need attention include patient resistance to HIV testing, the feasibility of preventive vaccine trials and improvements in physician-patient communication.
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