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Gay Men's Health Crisis
ICAAC Overview: Anti-Viral and Miscellaneous Reports
Derek Link
November 1, 1993
GMHC Treatment Issues 1993 Nov 1; 7(10): 2

The 33rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), held October 17 to 20, 1993 in New Orleans, is the premier infectious disease conference and includes numerous HIV-related presentations. This article reviews anti-HIV presentations and miscelleneous clinical reports from the 1993 ICAAC. A review of opportunistic infection research reports at ICAAC will appear in an upcoming issue.

Nuceoside Analogues Several new anti-HIV nucleosides were presented at ICAAC. FCU (935U83) is new nucleoside analog under development by Burroughs Wellcome, a North Carolina-based drug company. In test tube experiments, FCU is one-ninth as potent as AZT, but 1300-fold less toxic. FCU is active in vitro against both AZT- and ddI- resistant viral strains. According to the company, a phase I, twelve-patient pharmacokinetic study of FCU is completed and is now being analyzed. Efficacy studies, including a study of FCU-ddI combination, are planned for Europe, Australia, and the U.S.[1] Several studies were presented that suggest pharmacokinetic (i.e the way drugs move through and are eliminated by the body) differences with anti-HIV drugs in various populations. The Veterans Adminstration AIDS Cooperative group presented a study of AZT pharmacokinetics in white and black men. Eighteen men (nine white/nine black) received 200 mg AZT orally and intravenously. Intravenous, but not oral AZT appeared to have different pharmacokinetic profiles in the two groups. However, the groups were not matched by age (whites ranged from 41 to 68 years versus 30 to 47 for blacks), confounding the analysis of racial differences.[2] Bristol Myers Squibb, a New York-based drug company, presented toxicity data from the D4T expanded access program. As of September 26, 1993, 9165 patients were enrolled in the program: 95 percent of participants are white, 85 percent male, and 55 percent had fewer than 50 CD4 cells. Neuropathy has been the most common reported toxicity, seen in 63 cases. Nausea and vomiting, chills, and diarrhea were the next most common toxicities with fifteen, thirteen and twelve reported cases each respectively.[3] D4T and ddI can be given in combination without additional toxicities or altered pharmacokinetics, according to a pilot study performed by Bristol Myers. Ten HIV-infected men received ddI, d4T or the combination of both on successive days for one week. No difference was found in the pharmacokinetic profile of the combination compared to that of each individual compound.[4] The antacid buffer in ddI tablets does not affect the absorption of isoniazid (INH), according to a Canadian study. In this phase II study, twelve healthy volunteers received INH plus a ddI placebo tablet (containing the antacid found in the active medication) and INH alone. Plasma levels of INH were the same when given alone or with the ddI-antacid.[5] Reverse Transciptase Inhibitors Atevirdine (ATV) is a new reverse transcriptase inhibitor under development by Upjohn, a Michigan-based drug company. Resistance to ATV was examined in a phase I study of sixteen patients who received ATV and AZT for six to 28 weeks. Nine patients received drug for sixteen weeks or longer. Viral isolates from five of these patients remained ATV-sensitive. Isolates from four patients were ATV-resistant (one at six weeks, the others after twelve to 24 weeks of therapy.) Upjohn investigators are optimistic about this data since other non-nucleoside reverse transcriptase inhibitors induce resistance after only two to six weeks on therapy.[6] Researchers from Hoffmann-LaRoche, a New Jersey-based drug company, presented data on using benzodiazapene compounds as inhibitors of HIV reverse transcriptase. Roche originally developed these compounds as tat inhibitors, although they also act against HIV reverse transcriptase in the test tube. Roche dropped its tat inhibitor program earlier this year due to problems with their lead compound, RO-24-7429, and new research which casts doubt on tat's role in HIV's life cycle. Roche researchers suggest that other benzodiazapene compounds with anti-RT activity may "prove useful as single agents or in combination..."[7] Other Anti-Viral Therapies Gossypol is a cotton seed extract used as a contraceptive agent in China that has anti-HIV-activity in test tubes. Researchers from New York and Mexico conducted a phase I study of the drug in nineteen HIV-infected Mexican patients. Doses ranged from 20mg/day to 80mg/day. Doses under 50mg/day were well tolerated; higher doses caused reversible polyneuritis, hypokalemia (low levels of potassium), and hepatitis. No hematologic or renal toxicities were seen at the lower doses. Transient liver enzyme increases occurred at the lower doses, but resolved despite continued treatment. CD4 counts increased in three patients, remained unchanged in nine patients, and decreased in seven patients. Gossypol is also being investigated as a potential virocide (like nonoxynol-9) that may reduce HIV transmission during sexual intercourse.[8] SC-49483, manufactured by GD Searle, an Illinois-based drug company, is a prodrug of N-Buytl DNJ, an anti-HIV compound that produced significant gastrointestinal toxicities in phase I studies. The new pro-drug was evaluated in a 30 patient phase I study. SC-49483 was administered in single doses of 1.25g, 2.5g and 5g. After administration, only N-Butyl DNJ was detected in plasma samples, indicating that SC-49483 is effectively transformed into the active compound in the body. Oral bioavailability of N-Butyl DNJ was approximately 30 percent with the prodrug. No serious toxicities, including GI toxicities, were reported in the study.[9] Researchers from Applied Genetics, a Long Island-based company, report the development of transgenic mice which can be used as a model of HIV activation. When agents which are known to activate HIV in cell culture, such as ultraviolet light, were applied to the mice, increased HIV activity occurred, measured by genetic tests. However, when a liposomal formulation of vitamin E and vitamin C were topically applied to the mice, HIV activation was prevented. The authors suggest that the transgenic mice may be a useful means of measuring anti-HIV activity and that liposomal formulations of vitamin E and C may be worthy of study.[10] Mycoplasma and HIV The presence of mycoplasma DNA in the blood of HIV-infected patients is transient and not prognostic, according to a report from the Naval Medical Research Institute. Co-infection with Mycoplasma fermentans appears to increase the pathogenicity of HIV-infection in cell culture, leading some researchers and advocates to speculate that mycoplasma may be a necessary co-factor in disease progression. Using PCR techniques, this study identified six patients with detectable mycoplasma and seventeen patients without. Patients were followed for eighteen to 24 months and repeat PCR samples were obtained. Mycoplasma infection did not develop in the seventeen patients with no evidence of infection at baseline. Furthermore, all six mycoplasma- positive patients became negative for mycoplasma on repeat testing (only one mycoplasma-positive patient received antibiotics with anti-mycoplasma activity.) CD4 cell declines and disease progression were the same in both groups: one mycoplasma patient progressed to AIDS (1/6) during the study period compared with three mycoplasma-negative patients (3/17).[11] Colony Stimulating Factors G-CSF and GM-CSF have similar efficacy, but G-CSF is significantly better tolerated, according to a Belgian study that compared the two colony stimulating factors as acute salvage therapy in advanced HIV-infected individuals with neutropenia. Neutropenia refers to abnormally low levels of neutrophils, a type of white blood cell which fights bacterial infections. Twenty-four patients with an absolute neutrophil count below 1,000 were enrolled; twelve patients in each arm. All twelve patients who received G-CSF (1mcg/kg/day, subcutaneously) and nine of twelve who received GM-CSF (1mcg/kg/day, subcutaneously) had a hematologic response after three days of therapy. However, ten adverse events were reported in the GM-CSF arm, and only one in the G-CSF arm.[12] Smoking and HIV Smoking does not increase progression to AIDS or death, but may alter the clinical course of HIV disease, according to an observational study of 5113 HIV-infected patients. Current smokers, ex-smokers, and non-smokers were followed in the observational database of the Community Programs for Clinical Research on AIDS (CPCRA), a large, federally-funded research network. Participants were more likely to stop smoking as disease progression occurred. Current smokers were more likely to develop oral candidiasis and oral hairy leuloplakia, but less likely to develop cytomegalovirus disease. Heavy smokers (greater than one pack a day) were more likely to develop bacterial pneumonia compared with light smokers, non-smokers or ex-smokers. Finally, ex-smokers were more likely to develop PCP than non-smokers.[13] Flu Vaccine and HIV Influenza vaccination does not increase viral load in HIV- infected individuals, according to a study by Steigbigel and colleagues. The investigators followed ten patients who were given the vaccine. HIV viral load was measured by p24 antigen levels and quantitative plasma viremia. The authors found no evidence of increased HIV activation after immunization by either measurement.[14] HIV-Genital Ulcer Disease HIV-infection itself may cause genital ulcer disease (GUD) in infected women, according to a research team from Cornell Medical Center and Memorial Sloane Keterring Cancer Center, both in New York City. The researchers followed 307 women, with an average CD4 count of 197, for over twenty months. Of 42 new ulcers that were identified, 23 ulcers (55 percent) had no identifiable etiologic agent, leading the investigators to speculate that "HIV may play a local role in causation." The remaining nineteen lesions were caused by herpes simplex, cytomegalovirus, Chlamydia, Gardnerella Vaginalis, and two "unusual herpetic lesions."[15] Azithromycin Dr. Rosemary Soave, of Cornell Medical College in New York City, presented a study of oral azithromycin for cryptosporidiosis. The study randomized 90 patients with cryptosporidiosis to receive azithromycin 900mg/day or placebo for three weeks. Differences in bowel movement frequency, parasite shedding in stool, and overall clinical response between the azithromycin and placebo groups were not statistically significant. Plasma levels of the drug were analyzed in thirty-three patients. Azithromycin was poorly absorbed in many patients, according to the investigators. Patients who had detectable serum levels of azithromycin appeared to have a clinical response.

1 Daluge SM, et al. Program Abstract 41. 33rd ICAAC 1993.

2 Simberkoff M, et al. Prgram Abstract 325. 33rd ICAAC 1993.

3 Anderson R, et al. Program Abstract 684. 33rd ICAAC 1993.

4 Stewart M, et al. Program Abstract 720. 33rd ICAAC 1993.

5 Gallicano K, et al. Program Abstract 719. 33rd ICAAC 1993.

6 Demeter LM, et al. Program Abstract 45. 33rd ICAAC 1993.

7 Connell E, et al. Program Abstract 40. 33rd ICAAC 1993.

8 Koll B, et al. Program Abstract 687. 33rd ICAAC 1993.

9 Smith M, et al. Program Abstract 715. 33rd ICAAC 1993.

10 Morey, JD, et al.Program Abstract 1265. 33rd ICAAC 1993.

11 Frank D, et al. Prgram Abstract 562. 33rd ICAAC 1993.

12 Hermans P, et al. Prgram Abstract 697. 33rd ICAAC 1993.

13 Burns D, et al. Program Abstract 566. 33rd ICAAC 1993.

14 Steigbigel RT, et al. Program Abstract 1271. 33rd ICAAC 1993.

15 Laguardia KD, et al. Program Abstract 1169. 33rd ICAAC 1993.

16 Soave R, et al. Program Abstract 405. 33rd ICAAC 1993.