GMHC Treatment Issues 1994 Mar 1; 8(1): 1
The First National Conference on Human Retroviruses and
Related Infections was held on December 12-16, 1993 in
Washington, DC. The conference provided an impressive array of
researchers in a somewhat intimate surrounding. Much of the
program focused on HIV antivirals, immune therapies, and basic
science. More limited attention was focused on HIV- related
opportunistic infections. With the International Conference on
AIDS being held in Japan this year and scheduled to become a
biannual affair thereafter, many believe that this annual
conference will become increasingly important. In this issue,
Treatment Issues provides an overview of the conference. Next
month, we will provide comprehensive analysis of the oral
ganciclovir studies that were reported at the conference.
AZT Resistance: A Marker for Progression?
Resistance to AZT may predict more rapid disease progression.
In a subset of ACTG 116B/117, which studied the effects of ddI
in patients with less than 200 CD4 cells who had taken AZT for
more than sixteen weeks, it was found that those who had
entered the study with a high level of AZT resistance were
three times more likely to progress to another opportunistic
infection (OI) or death. In addition, those who had a high
level of AZT resistant virus also did not seem to benefit from
switching to ddI.
This poor showing was of great concern to conference
participants. It gave a clear indication that the presence of
AZT-resistant HIV in the body really translates into poorer
physical health, even when an individual switches to another
drug. But the reason for this observation eluded the experts.
A two-and-a-half hour roundtable discussion on the issue could
only conclude that AZT-resistance must somehow be a sign that
the virus has gained other abilities, such as greater
mutability, that help it to quickly respond to challenges
posed by drug therapy or immune defenses.
Benefits Seen in Switching to ddI
Switching from AZT to ddI did cause a significant increase in
CD4 cells in a study conducted by the Canadian HIV Trials
Network. Two hundred thirty two patients who had been on AZT
for greater than six months were randomized to either ddI (334
mg daily if body weight less than 60kg, 500mg daily if more)
or continued AZT (600 mg daily). Sixty percent of those
enrolled were asymptomatic, the balance had either ARC or
AIDS. Patients given ddI had an average increase of 47 CD4
cells at four weeks and 90 CD4 cells at 24 weeks, compared to
those given AZT. This statistically significant increase lasted
for greater than 36 weeks. Interestingly, benefits in switching
to ddI occurred in patients with both syncytium inducing (SI)
or non-syncytium inducing (NSI) stains of virus. SI virus
promotes a "clumping together of immune cells" that causes
cell death and has been linked to more rapid disease
Searle's HIV Protease Inhibitor
One way to get around the problems posed by resistance to AZT
and related drugs is to find a therapy that attacks a
different, more vulnerable point in the virus's lifecycle. A
new class of treatments that received considerable attention
at the conference is protease inhibitors. Protease inhibitors
block the assembly of HIV particles as they bud out from an
infected cell. A comprehensive report on protease inhibitors
will appear in next month's Treatment Issues. Companies
currently developing protease inhibitor include
Hoffmann-LaRoche, Merck & Co. and Searle/Monsanto. Researchers
at the Retrovirus Conference presented data on SC-52151,
Searle's lead HIV protease inhibitor compound.
They reported that SC-52151 is estimated to have a "single-
dose oral bioavailibility of greater than 20 percent." In a
press conference , Martin Bryant of Searle compared this to
Hoffmann-LaRoche's lead protease inhibitor compound, RO-31-
8059, which he reported is 4 percent bioavailable. He also
characterized the Roche drug as "at the cusp of the dose
response curve," implying that higher doses of Roche's drug
may be more beneficial than those now being tried. Dr. Bryant
further reported that, in terms of toxicity from animal studies
and single-dose safety studies in humans, SC-52151 is "very
In regard to viral resistance, Bryant thought that
simultaneous resistance to different protease inhibitors may
be more difficult for HIV to achieve. Test tube studies of
other protease inhibitor compounds have reported that viral
resistance may develop at a slower pace than with nucleoside
analogues such as AZT, ddI and ddC.
A dose escalating study, using a 100mg, 300mg, 500mg, and 1
gram single dose of SC-52151 is underway. The company expects
to begin enrolling 60 patients in a Phase I trial in the
Spring of 1994. In terms of production, Searle's drug requires
ten to twelve steps compared to Roche's 24 steps (we hope that
this means that the drug is so much easier to produce and that
trials will be quicker and more forthcoming).
Measuring HIV Viral Load
Significant attention was focused on new methods to measure
HIV viral load. A rapid, accurate, and relatively inexpensive
means of measuring viral burden is critically important to the
study of new anti-HIV therapies. Such a test would also
provide physicians with guidance as to whether existing
therapies are benefiting individual patients. One particular
test which caused some excitement was the branched DNA assay
(Quantiplex) developed by Chiron Corp., a California-based
biotechnology company. This test measures HIV RNA using
branched DNA signal amplification technology.
Researchers at San Francisco General Hospital and Chiron
reported that this test is precise and amenable to routine
laboratory use for measuring HIV RNA in plasma. Using the
branched DNA assay, levels of HIV were found to be
significantly higher, in general, in HIV-infected patients
with low CD4 counts. Another study suggested that the branched
DNA assay may be useful in predicting progression to AIDS.
In this study, researchers examined 62 gay men from the
Multicenter AIDS Cohort Study (MAC) in whom HIV seroconversion
had been documented. They then compared those who had
progressed to AIDS rapidly (median 3.8 years) with 44
non-progressors (median of 5.6 years of follow-up). It was
found that persistently high levels of HIV during the first
two years after seroconversion, as measured by the branched
DNA assay, strongly predicted both rapid CD4 decline and
progression to AIDS.
If these results are confirmed by other studies, the branched
DNA test is likely to be a considerably simpler and less
expensive means of measuring HIV viral load than the PCR test
(Polymerase Chain Reaction). In addition, Chiron researchers
reported that branched DNA technology can be used to detect TB
bacteria in sputum samples within 24 hours. Of 74 TB
culture positive samples, 73 or 98.7 percent were also
positive with the branched DNA test. Moreover, the assay does
not cross react with other mycobacteria, such as MAI. The
researchers conclude that branched DNA assay is a rapid,
sensitive and specific method for direct detection of TB
bacterium in clinical specimens.
Underestimating Herpes Infections
Herpes Simplex (HSV) infections among HIV-infected gay men may
be substantially underestimated, according to researchers from
the University of Washington in Seattle. A total of 45
HIV-positive/HSV-positive and ten HIV-negative/HSV-positive
gay men were followed with daily viral cultures of the mouth,
rectum and urethra for 60 days. Among HIV-positive patients
the median CD4 cell count was 364. Overall, 68 percent of
HIV-positive people and 40 percent of HIV-negative people had
evidence of reactivated HSV infections. Among HIV-positive
patients, Herpes Simplex Virus 2 (HSV-2) was cultured on 9.7
percent of the days, compared to less than 1 percent of the
days in HIV-negative patients. The authors conclude that
herpes reactivation, especially of HSV-2, is frequent and has
been seriously underestimated in HIV-positive individuals.
Acyclovir for HIV
Acyclovir use was associated with a survival benefit in
patients with AIDS, according to a retrospective study
conducted as part of the Multicenter AIDS Cohort (MAC)
Study. In the study, researchers looked back at 786 HIV-
positive gay men who began AZT prior to an AIDS diagnosis. Of
these, 515 subsequently took acyclovir, an anti-herpes
therapy. These patients were followed semi-annually. It was
found that the reported use of Acyclovir did not correlate
with progression to AIDS). However, the drug was significantly
associated with a survival benefit. This survival benefit was
seen in patients who began acyclovir therapy after an AIDS
diagnosis. Dose, constancy, and timing of acyclovir were also
examined. The median dose used was 600 to 800mg per day.
Higher doses of acyclovir did not seem to effect survival, but
the use of the drug for a longer, uninterrupted period of time
was associated with longer survival. The researchers concluded
that acyclovir was significantly associated with survival, if
used after an AIDS diagnosis, but not if taken pre-AIDS.
Interestingly, acyclovir use did not seem to prevent
development of cytomegalovirus (CMV), a type of herpes virus.
It should be noted that this study was not designed to
determine whether acyclovir can be of benefit as a treatment
for HIV-disease. It was a retrospective ("look back") study
and participants were not randomized to receive either
acyclovir or placebo. Another conference presentation, by the
Houston Immunological Institute, described a small study
that directly compared AZT to AZT plus acyclovir. Over twelve
months time, three out of five of those taking AZT alone
(average T-helper cell count: 154) began to test positive for
HIV core protein (p24) in their blood compared to none of the
thirteen people taking the two drug combination (average T-
helper cell count: 166). Testing positive for p24 is
considered a sign of disease progression.
An earlier British study showed that acyclovir provided a
survival benefit in people with AIDS. In addition, ACTG 063, a
controlled study comparing AZT with and without acyclovir, is
ongoing. Preliminary data from this trial may be available
sometime in the first quarter of 1994.
Human Herpes Virus-6 and HIV
A number of presentations discussed Human Herpes Virus-6
(HHV-6) and how it may interact with HIV. In a plenary talk
focusing on many aspects of HIV disease. Dr. Robert Gallo of
the National Cancer Institute reported that HHV-6 may play a
role in HIV disease progression. According to Dr. Gallo,
HHV-6, is one of the few viruses that like HIV, binds to the
CD4 receptor. Dr. Gallo suggested that Foscarnet, an anti-CMV
therapy, should be evaluated as a therapy for HHV-6. In
addition, researchers from The Medical College of Wisconsin
reported that HHV-6 is more destructive to macrophages than
HIV, that HHV-6 and HIV show synergistic destruction of
Based on these findings and on reports showing that HHV-6 can
cause pneumonitis and bone marrow suppression in bone marrow
transplant patients, the researchers conducted autopsies of
nine patients who died of AIDS in order to see whether HHV-6
could be identified. They were able to quantify HHV-6 in one
patient with CMV pneumonitis and one with HHV-6 pneumonitis.
They suggested that HHV-6 may be more common in the tissues of
PWAs than CMV and may appear later in disease. Like Dr. Gallo,
the Wisconsin researchers believe that HHV-6 is susceptible to
antiviral agents. However, they concluded by stating they were
still unsure as to whether HHV-6 is "just another viral
infection that jumps on the bandwagon" or, perhaps, pathogenic
"co-factor" which significantly enhances HIV disease
Expanding HIV-Specific "Killer Cells"
Dr. Judith Lieberman of New England Medical Center in Boston
discussed preliminary results about an immune therapy which
seeks to use large numbers of the patients own cytotoxic
lymphocytes (CTL) or "killer cells" to fight HIV. The
therapy, known as "autologous ex vivo expanded HIV specific
cytotoxic T-cells," involves taking CTL cells from the
patients own blood and selecting for their ability to kill
HIV-infected cells ("HIV-specific T-lymphocytes"). The cells
are then cultured in the laboratory and added to agents which
stimulate proliferation of these cells. These agents include
PHA, a sugar which activates T-cells by attaching to T-cell
receptors, and IL-2, (see box). The activated cells are then
reinfused into the patients. Dr. Lieberman noted in her
presentation that HIV-specific T-lymphocytes increase in
response to HIV infection and then usually drop as disease
A total of 14 patients, all with 100 to 400 CD4 cells and no
AIDS-related opportunistic infections, were enrolled in the
study. HIV specific cells were expanded over a ten-day period.
Of the fourteen patients, eleven had CTL's that reacted to
parts of the virus (viral proteins, such as gp160, nef 7, nef
17). These patients were given one infusion of their expanded,
HIV-specific CTL's and then evaluated at one, two, four, eight
and 24 weeks. Dr. Lieberman presented data on the first five
patients. Two of these five had "significant and sustained
increases in CD4 cells" and a sustained decrease in viral
load. No patients had significant decreases in CD4 levels or
significant increases in HIV replication. Four of five
patients had an increase in circulating HIV-specific CTL
response that peaked at one week after infusion. It is
important to note that these are preliminary results, based on
a very small number of patients. Dr. Lieberman has told
Treatment Issues that all patients currently in the trial will
be retreated with an additional infusion. In addition, a new
group of five patients will receive a series of three
infusions (one every five to eight weeks).
Researchers from France reported that passive immunotherapy
reduced the number of opportunistic infections in patients
with advanced AIDS (less than 50 CD4 cells). Passive
immunotherapy is a process in which individuals with advanced
disease (who have low levels of HIV antibody production) are
infused with plasma rich in HIV antibodies. Plasma is obtained
from asymptomatic HIV-positive individuals with high levels of
HIV antibodies. In the double-blind, placebo- controlled trial,
a total of 86 patients were randomized to receive either
plasma high in HIV antibodies or placebo (plasma from
HIV-seronegative individuals). Infusions were given every two
weeks and then every four weeks over a one year period.
Participants who received placebo had three times the number
of new AIDS defining infections as those who received passive
immunotherapy. There were seven deaths in the treatment arm
and eleven in the placebo arm. The statistically significant
difference in new opportunistic infections led the
investigators to stop the trial and provide all participants
with treatment. The difference in survival did not, however,
reach statistical significance.
Few Menstrual Irregularities in HIV-Positive Women
Relatively few menstrual irregularities were seen in 207 women
who had been HIV-positive for at least one year, according to
a study by researchers from the Centers for Disease Control
and Prevention (CDC) and Columbia University in New York
City. In the study, the women were compared with 215
HIV-uninfected women who were recruited from STD, methadone
and HIV clinics. Both groups were interviewed about
menstruation patterns. There were no significant differences
in terms of likelihood of monthly menses over one year, length
of menses, likelihood of no menstruation for 90 days, or
difficult or painful bleeding (dysmenorrhea). The only
reported differences were bleeding between periods
(intermenstrual bleeding) and, possibly, in postcoital (after
sexual intercourse) bleeding. Among HIV-infected women, there
were no apparent differences in menstrual patterns based on
levels of CD4 cells.
Saliva May Inhibit HIV
Researchers at the University of Pennsylvania reported that
when human saliva is combined with HIV, a sharp reduction in
the infectivity of HIV occurs. The researchers studied the
saliva of fifteen HIV-negative individuals and found that
ability of the saliva to inhibit HIV varied by individual,
with a range of inhibitory activity from 0 to 95 percent. In
addition, the study suggested that the inhibitory effect of
saliva may be HIV-specific, meaning that it may stop
replication of HIV to a greater extent than other viruses such
as Human Herpes Simplex 1 or Hepatitis B.
HTLV-1 and HIV in Gay Men
Two cases of dual infection with HIV and HTLV-1 among gay men
who did not use injection drugs were reported. One of these
patients developed cutaneous T-cell lymphoma. The researchers
from New York University Medical Center report that the two
viral infections, not previously seen together in patients
without a history of injecting drugs, may act synergistically.
They conclude that dual infections with HIV and HTLV-1/2 are
no longer rare among homosexual and drug abusing populations.
1 D'Aquila RT, et al. Abstract 460.
2 Montaner JSG, et al. Abstract 2.
3 Bryant M, et al. Abstract 261.
4 Chin -Ming Chen, et al. Astract 265.
5 Pachl C, et al. Abstract 312.
6 Mellors J, et al. Abstract 274.
7 Kolberg J, et al. Abstract 294.
8 Schlacker T, et al. Abstract 519.
9 Stein DS, et al. Abstract 527.
10 Thompson C, et al. Abstract 426.
11 Gallo R. Oral Presentation, Session 3.
12 Knox KK, et al. Abstracts 544, 545.
13 Lieberman J. Oral presentation, Session 47.
14 Ellerbrock TV, et al. Abstract 251.
15 Malamud D, et al. Abstract 653.
16 Pluda JM, et al. Abstract 31.
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