Research Initiative Treatment Action (RITA!); Vol 5, No. 2 April 1999
The Wall Street Journal reported on the increasing number of patients who have failed their drug regimens after having an undetectable viral load for several years. (Wall Street Journal, B1, 02/01/99) The article cites several cases of patients who have responded well to initial therapy and then suddenly stop responding. The reasons for the failures are not understood and have baffled doctors. Subsequently, at the 6th Conference on Retroviruses and Opportunistic Infections, 1999 (6th CROI) in Chicago, the latest reports on an early cohort of patients using indinavir (Crixivan), zidovudine (Retrovir) and lamivudine (Epivir) were presented. These patients have been on this drug regimen for 148 weeks. Of those still on the study only 67% remain below the level of detection as compared to early results in which 90% had become undetectable.
In a letter to The New England Journal of Medicine (340:5, p. 392,1999) doctors from Japan reported two cases of hemophilic, HIV-infected patients who developed renal atrophy after long-term use of indinavir. Symptoms resolved after nelfinavir (Viracept) was substituted for indinavir, but the size and shape of the kidneys did not change.
Dr. Alice Stek of the University of Southern California School of Medicine reported on a study of HIV-infected pregnant women who used received protease inhibitor therapy during pregnancy. At a meeting of the Society for Maternal and Fetal Medicine in San Francisco, scientists conducting this study found no premature births or birth defects in the 32 HIV-uninfected infants born to these mothers. (A study finding complications with the use of combination therapy was summarized in RITA!, 5:1, p. 19, 1999.)
Researchers at the University of Texas Medical Branch at Galveston report in the Archives of Internal Medicine that saliva appears to kill HIV-infected mononuclear leukocytes. Saliva is devoid of many of the salts that normally are present in bodily fluids. The lack of salt inactivates the HIV-infected white blood cells. It should be noted that despite these findings cases of HIV transmission through oral sex are still reported.
Three enzymes commonly present in the tears and saliva of pregnant women have been found to have anti-HIV properties. In an article in the Proceedings of the National Academy of Sciences (96:2678, 1999) scientists from New York University identify human urinary lysozyme C, human Rnase A and urinary Rnase U as being able to destroy and stop the replication of HIV-1. The scientists speculate that these naturally occurring substances may be used against HIV and are less toxic than current therapies.
The U.S. Food and Drug Administration has given approval for the clinical testing of an investigational new drug for the treatment of HIV/AIDS. The drug, called HE2000, is the product of Hollis-Eden Pharmaceuticals, Inc., a San Diego-based pharmaceutical company. The mechanism of action of the drug is to block certain cellular enzymes and in the words of the company, "starve" the virus of certain necessary components and prevent replication. Targeting a cellular component rather than a viral component avoids the problem of resistance through mutation. Cellular proteins do not mutate and therefore represent a stable target for therapy. This drug is in early development and its effect in humans has yet to be established. Clinical trials of this drug will conducted in four cities across the country, including a site in Houston at the office of Joseph C. Gathe, Jr., MD, telephone number 713.526.9821.
The U.S. Food and Drug Administration announced on March 1, 1999 the approval of a new 333 mg. strength capsule of the protease inhibitor indinavir. This new strength formulation will allow for flexibility when indinavir is prescribed at a higher 1000 mg every eight hours rather than the standard 800 mg dose. In addition, the standard 400 mg capsules will now be available in single unit dose (blister) packages. The single unit dose will allow for smaller quantities to be dispensed or stored. The flexibility in storage and dispensing is intended to help pharmacists in institutional centers such as hospitals, Veteran Administration and military medical centers, prisons and long-term care facilities.
The U.S. Food and Drug Administration has approved for marketing the Amplicor HIV Monitor Ultrasensitive Test manufactured by Roche Molecular Systems, Inc. The new ultrasensitive test can measure down to 50 copies of HIV RNA. In addition, Roche has instituted the Amplicor patient assistance program to assist those unable to pay for the test and having inadequate insurance to cover the expense. The patient assistance program can be reached at 1.888.TEST.PCR (1.888.837.8727).
In a letter to The Lancet, (353:9155, 1999) Dr. Henrik Nielsen of Aalborg Hospital in Denmark reported four cases of women who developed anemia as a result of abnormally profuse or prolonged menstrual flow, a condition called hypermenorrhea. All four women were taking a ritonavir (Norvir) -containing regimen. Two women were taking a ritonavir and saquinavir (Fortovase) regimen; another was combining ritonavir with zidovudine (Retrovir) and lamivudine (Epivir); and another was taking ritonavir, stavudine (Zerit) and lamivudine. Two of the women required blood transfusions.
Scientists at the National Cancer Institute have found that genetic diversity in what are called HLA Class I genes can account for slower progression in HIV disease. HLA Class I genes are responsible for marking cells with a molecule to signal to the immune system that the cell is infected. A marked cell is then killed by a CD8 cell called a cytotoxic T lymphocyte (CTL). There are three types of HLA Class genes designated as A, B or C. Each human inherits two of each type of gene. The pairing of the genes determines the level of diversity. With this many genes a person could have as many as six unique combinations or as few as three. Scientists found that persons with the greatest number of non-matching gene pairs progressed slowest to AIDS (6 to 12 years). Those with the greatest number of matched pairs tended to develop AIDS in three or less years. In addition, they determined that persons with paired copies of two of the gene forms—B35 and Cw04—tended to progress to AIDS most rapidly.
The active ingredient in St. John's Wort is a compound called hypericin. For some time hypericin has been touted as a natural antidepressant and an anti-HIV therapy. A recent article (Annals of Internal Medicine, 130:510, 1999) warns that hypericin causes significant phototoxicity and has no antiretroviral activity. The article reviewed the results of a phase I study where thirty HIV-infected subjects with CD4 T cell counts of less than 350 were given various doses of hypericin orally or intravenously. Antiviral activity was measured by changes in HIV p24 antigen level, HIV titer, viral load and CD4 T cell counts. Of the 30 patients enrolled, 16 discontinued treatment early because of toxic effect. Nineteen percent had a positive HIV p24 antigen response; there was no change in viral titers; no change in viral load at week 8; and a median decrease of 10 CD4 T cells from baseline to week 8.
According to an article in USA Today (14A, 03.16.99) approximately 300,000 Americans received blood transfusions tainted with hepatitis C between 1988 and 1992. Of these, 100,000 individuals have not been notified of their possible infection. The editors note that only now is an organized effort being made to notify those at risk. They report that the notification process will not complete until 2001.
The Journal of Infectious Diseases Online (179:3, p. 612, 1999) reports on the use of a fusion protein vaccine for the treatment of genital warts. In a study of 25 patients a vaccine consisting of human papillomavirus 8L2E7 with Alhydrogel was reported to be well tolerated and resulting in the production of serum antibodies against papillomavirus in all subjects. Nineteen of the patients evidenced antigen specific T cell responses. Five subjects completely cleared warts within 8 weeks. Those subjects who did not clear the warts with the vaccine alone were offered conventional therapy. No recurrences were seen in the 13 persons who cleared the warts by means of the vaccine or through conventional therapy. Further studies will be required to confirm efficacy.
At a satellite symposium at the 12th International Conference on Antiviral Research in Jerusalem, scientists presented data on Gilead's anti-HIV drug, adefovir dipivoxil. A four-week study compared 60 mg daily of adefovir against placebo in 47 treatment-naïve, HIV-infected patients. Participants had viral loads greater than 5,000 copies and CD4 T cell counts greater than or equal to 150 cells. After four weeks the mean decline in viral load in the adefovir arm was -0.25 log as compared to an increase of +0.08 log in the placebo arm. In a separate study adefovir doses of 60 mg and 120 mg were included in triple combination drug regimens. In the 60 mg adefovir + triple drug combination arm of the study 42% of the patients achieved levels of viral load below the limit of quantification. In the 120 mg adefovir + triple drug combination arm 33% of patients achieved levels of viral load below the limits of detection. Gilead's concern with the nephrotoxicity (kidney toxicity) of the drug has led the manufacturer to establish the lower dose of adefovir as equally efficacious as the higher dose. The lower dose resulted in a reduction of 30 to 50% of the incidence of nephrotoxicity in patients.
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Copyright © 1999 - Research Initiative Treatment Action (RITA!). Reproduced with permission. RITA! is published by The Center for AIDS. Contact Thomas Gegeny, MS, ELS, Editor, RITA! for permission to reproduce RITA!. tom@centerforaids.org. http://www.centerforaids.org
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