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
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
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.
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
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
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
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.
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..."
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.
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.
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
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).
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
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.
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.
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
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.