Bulletin of Experimental Treatments for AIDS, April, 1998
Liz Highleyman
This issue of BETA features articles about doctor-patient relationships, HIV vaccines and herbal medicine. There are many challenges associated with combination anti-HIV treatment. One is high cost. In this issue BETA presents an extensive chart of pharmaceutical company patient assistance programs for people who cannot afford HIV/AIDS drugs. Another major barrier to treatment is side effects. Also in this issue, BETA inaugurates a new Drug Watch section that spotlights new anti-HIV and opportunistic infection drugs. A later section contains news briefs related to women and HIV, including new results confirming the effectiveness of short-course AZT in reducing perinatal HIV transmission.
The 5th Conference on Retroviruses and Opportunistic Infections was held February 1-5 in Chicago. Several presentations focused on HIV reservoir or sanctuary sites in the body. Another widely reported topic was unusual side effects experienced by people taking combination anti-HIV therapy, including "protease paunch," "buffalo hump," high blood sugar levels, and high fat and cholesterol levels; different research teams gave frequency estimates for these side effects that ranged from 5% to 64%. Many presentations focused on new drugs and combination regimens, including double protease inhibitor combinations, and 4-drug, 5-drug and even 6-drug regimens. Results were also presented showing the effectiveness of triple combination therapy in children. Data were presented on hydroxyurea, an inexpensive cancer drug, that in combination with certain nucleoside analogs led to sustained undetectable blood viral load levels. Finally, several presenters discussed promising experimental drugs, including abacavir, efavirenz, amprenavir (141), FTC and zinc finger inhibitors. For more information, see the advocacy section and conference highlights.
Glaxo Wellcome announced on March 12 that its anti-HIV drug abacavir would be made available through an expanded access program. Abacavir (also known as 1592) was given the brand name Ziagen. The drug has shown promise in clinical studies when used as part of a combination regimen. The expanded access program makes the drug available to persons over 13 years of age who are on a failing anti-HIV regimen or cannot tolerate their current therapy, and who cannot construct a viable regimen without abacavir. The drug will be provided for free through physicians. An open-label study remains available for children under 13. People are encouraged, if possible, to combine abacavir with other drugs that they have not used previously. Abacavir is generally well tolerated, but 2-5% of patients experience an unusual hypersensitivity reaction. People who experience nausea and flu-like symptoms, possibly followed by a measles-like rash, should contact their doctor; once they stop taking abacavir, they should not restart the drug, since doing so may be life-threatening. See the advocacy section and conference coverage for details. For more information on the expanded access program or to enroll patients, physicians may call 800-501-4672.
In December, DuPont Merck announced that it was broadening the criteria for its expanded access program for efavirenz (Sustiva; also known as DMP-266), making the drug available to more people. Participants are eligible if they have ever had a CD4 T-cell count under 400 cells/mm3 (previously the cut-off was 50 cells/mm3), if their current anti-HIV regimen is failing, if they cannot tolerate their current regimen due to side effects and if their physician is not able to create a viable treatment regimen without efavirenz. For information or to enroll, call 800-998-6854. See the advocacy section for new safety information concerning birth defects in infant monkeys born to mothers receiving efavirenz.
In March, a panel of experts announced its decision to add the new soft-gel formulation of saquinavir (Fortovase) to the list of "preferred" therapies set forth in the federal government's Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents. When the revised guidelines were issued in November 1997, saquinavir was not included in the list of "preferred" protease inhibitors because the old hard-gel formulation (Invirase) has low bioavailability and the new more potent formulation had not yet been adequately studied. With the recent addition, saquinavir joins indinavir, nelfinavir and ritonavir as recommended protease inhibitors to be used in regimens that also include 2 nucleoside analog drugs.
The Food and Drug Administration (FDA) in February issued a warning about drug interactions and side effects associated with the prescription anti-allergy drug astemizole (Hismanal). Adverse events may include irregular heartbeat and anaphylactic shock. Astemizole should not be taken with any of the approved protease inhibitor drugs, with the antibiotic clarithromycin (Biaxin) or with serotonin reuptake inhibitors such as fluoxetine (Prozac).
The health care consulting company Scott-Levin recently released data showing how anti-HIV therapy is being used in the U.S. The "HIV Therapy Audit" gathered data from physicians who treat people with HIV. Results indicate that 70% of people being treated for HIV disease are receiving 3-drug therapy, while 23% are receiving 2-drug therapy, 5% are receiving 4-drug therapy and 2% are receiving monotherapy. The 3 most commonly used drug regimens are AZT/3TC/indinavir (18%), AZT/3TC (11%) and d4T/3TC/indinavir (8%). The audit found that 363,640 people with HIV sought treatment in the third quarter of 1997. Most visits (63%) occurred in doctors' offices, with another 16% in clinics and 11% in hospitals. Medicaid was the largest source of payment for drugs at 39%; HMOs paid for 21%, traditional fee-for-service insurance accounted for 14% and state AIDS Drug Assistance Programs (ADAP) paid for 12%.
A study released in late January sheds new light on factors affecting adherence to complex anti-HIV treatment regimens. The study was conducted by the Center for AIDS Prevention Studies (CAPS) of the University of California at San Francisco. It included 114 participants, half of whom were people with HIV and half of whom were hotline operators, case managers and healthcare providers who counsel people about treatment. On the whole, patients and physicians make thoughtful decisions about anti-HIV therapy. Major deterrents to treatment include concerns about short-term and long-term side effects, skepticism about treatment effectiveness and a belief that one's health is currently good. Other reasons for not choosing treatment include a belief that drugs are too experimental, concerns about drug resistance, a preference for alternative or holistic therapy, and a belief that one could manage the disease on his or her own. Motivators to start treatment include worsening health status, seeing improvement in others using the drugs and better treatment information. People with HIV reported that their major sources of treatment information were physicians, specialized HIV publications and websites, support groups and other HIV positive people. CAPS director Thomas Coates, MD, identified 3 primary needs to help people with HIV/AIDS make the best possible decisions about treatment: "quality time for patients with physicians, more information about available therapies, and special outreach to women and minorities."
At the retrovirus conference and at an international conference on tuberculosis in Geneva, researchers presented data showing that a 2-month, 2-drug course of therapy is as effective as the standard 12-month regimen in preventing the development of tuberculosis in people with AIDS. The 5-year study included over 1,500 participants in the U.S., Mexico, Brazil and Haiti. Participants had AIDS and had been infected with the organism that causes tuberculosis as indicated by positive TB skin test results. One group received a 2-month regimen of rifampin plus pyrazinamide, while another received a 12-month course of isoniazid alone. The rate of active tuberculosis cases and deaths was similar in the 2 groups, but the 2-drug regimen was associated with fewer side effects and better adherence.
In January the Centers for Disease Control and Prevention (CDC) released its 1998 Guidelines for the Treatment of Sexually Transmitted Diseases. These guidelines, which were devised by a group of recognized experts in the field, supercede the 1993 guidelines. The new guidelines cover prevention, diagnostic testing and management of all major sexually transmitted diseases (STD) including genital ulcer disease, genital herpes, syphilis, human papillomavirus infection and hepatitis. The guidelines also discuss special issues related to pregnant women, adolescents and children. The CDC says that early STD detection and treatment could prevent most STD-related deaths. Several studies in the past few years have also shown that treatment of sexually transmitted diseases can substantially reduce HIV transmission. The guidelines are printed in the January 23, 1998 issue of Morbidity and Mortality Weekly Report and are available on the web at www.cdc.gov/nchstp/dstd/std98tg.htm.
Researchers at the Massachusetts Institute of Technology reported in the January 22 issue of Nature that an HIV gene appears to help the virus evade the host's immune system. Normally, virus-infected human cells display a molecule on their surface that alerts T-cells to eliminate the cell and the virus it contains. The new findings show that the HIV nef gene interferes with this display, allowing the virus to escape detection. These results may help explain why some people infected with HIV strains that are missing a functional nef gene experience less disease progression.
In related news, a study from Massachusetts General Hospital and Harvard Medical School (published in the November 21 issue of Science) revealed that a strong CD4 T-cell response is important in preventing HIV disease progression. Typically, deficits in CD4 cell function occur early in HIV disease. In contrast, researchers found that a group of study participants who remained asymptomatic and maintained normal CD4 cell counts despite using no anti-HIV therapy retained a strong HIV-specific T-cell proliferation response. The study results suggest that early anti-HIV treatment may keep the virus in check and prevent CD4 cell damage, and offer hope that if a vaccine could stimulate the CD4 cell response, it could keep HIV under control.
HCG-Related Substance May Act against HIV
Recent research indicates that a substance associated with human chorionic gonadotropin (hCG), a hormone that is produced during pregnancy and found in the urine of pregnant women, may be a potential therapy for HIV diseases. The substance was isolated by Robert Gallo and colleagues of the Institute of Human Virology in Baltimore, MD. The researchers have named the substance -- which they believe is a protein -- hCG-associated factor, or HAF. Earlier studies had shown that hCG caused Kaposi's sarcoma tumors to shrink and reduced blood HIV levels in some subjects. The new research indicates that it is in fact the associated factor HAF, rather than hCG itself, that seems to be responsible for these effects. HAF also stimulates red and white blood cell production. HAF will likely not be available as a drug for human use for at least 3 years. The research was reported in the April 1998 issue of Nature Medicine.
Treatment with potent combination anti-HIV therapy has lowered the rate of several opportunistic infections (OI). Various presentations at the retrovirus conference reconfirmed this trend. Results from a study of patients at an HIV outpatient clinic in New Orleans showed decreases in the incidence of Pneumocystis carinii pneumonia (PCP), Mycobacterium avium complex (MAC), cytomegalovirus (CMV) disease, toxoplasmosis and cryptococcal meningitis. Decreases in the rates of CMV disease, cryptosporidiosis, toxoplasmosis, MAC and bacterial pneumonia were seen at the Johns Hopkins HIV Clinic in Baltimore. Researchers at San Francisco General Hospital reported dramatic declines in OI incidence. Between 1994 and 1997, incidence of cryptococcal meningitis fell 63% (from 27 cases in 1994 to 10 cases in 1997), PCP incidence decreased 71.4% (from 224 to 64 cases), MAC incidence fell 83.5% (from 165 to 27 cases) and CMV incidence declined 93.8% (from 48 to 3 cases). Overall, the largest declines were seen in OI that affect the most severely immuncompromised people.
At the same time, there were reports of cases in which effective anti-HIV treatment appears to worsen manifestations of certain OI. Some physicians have seen MAC-associated lymph node swelling and fever in people who have recently started anti-HIV therapy, and others have seen unusual eye inflammation in people with CMV retinitis. Researchers suggest that these reactions may be the result of heightened immune system activity due to successful anti-HIV treatment.
According to the CDC, the number of AIDS deaths in the U.S. fell by 44% in the first half of 1997, from 21,460 deaths in January-June 1996 to 12,040 in January-June 1997. The absolute number of AIDS cases decreased for the first time in 1997. Accidents, rather than AIDS, are now the leading cause of death for young adults aged 25-44.
The national decline reflects death rate decreases in several cities and states. In New York City, 5,000 people died of AIDS in 1996 compared to 2,600 in 1997, a decline of 48%. In Philadelphia, the AIDS death rate fell 24% from 1996 to 1997; in contrast to most other localities, the most pronounced decline occurred among African-Americans. In Maryland, the number of AIDS-related deaths decreased 43%, from 1,182 deaths in 1996 to 611 deaths in 1997. Florida saw a similar 42% decline for the first half of the year. Chicago noted its first ever decline in AIDS deaths among women and African-Americans.
In California, the AIDS death rate fell 60% in the first 6 months of the year, from 2,788 deaths in January-June 1996 to 1,112 deaths in January-June 1997. State officials attribute the decline to new treatments, and credit the state's effort to provide anti-HIV drugs to all who need them through the state AIDS Drug Assistance Program.
The decline in AIDS deaths is due primarily to potent new combination anti-HIV therapy. Harold Jaffe, MD, of the CDC said, "The very favorable trends we are seeing appear to us to be very much the result of improved treatment. We have very little evidence that they are due to improved prevention." The CDC also reported that people who were receiving potent 3-drug regimens that included a protease inhibitor had an 86% lower risk of death due to AIDS than those who were not taking any anti-HIV drugs.
On January 27, San Francisco mayor Willie Brown hosted the Mayor's Summit on AIDS and HIV. The summit was the first meeting of its kind in the city, and was attended by politicians, community-based service providers, researchers, health care providers, advocates for people with HIV/AIDS and concerned members of the public. Participants discussed many aspects of the epidemic, including prevention, adherence to new anti-HIV regimens, access to treatment, insurance coverage, mandatory testing and names reporting, housing, workplace entry and re-entry, and medicinal marijuana. Working groups focused on the various issue areas met for 6 months prior to the summit and prepared a lengthy report which contains some 175 policy recommendations. Copies of the report are available by calling 415-554-6657.
Liz Highleyman is Assistant Editor of BETA.
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Copyright © 1998 - Bulletin of Experimental Treatments for AIDS (BETA). Reproduced with permission. BETA is published four times a year by the San Francisco AIDS Foundation. All rights reserved. Noncommercial reproduction is encouraged. Subscription lists are kept confidential. Call 415.487.8060; FAX: 415.487.8069. Mailing Address: P.O. Box 426182, San Francisco, CA 94142-6182. beta@sfaf.org http://www.sfaf.org/beta.html
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