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Reflections:
After
the 1999 National Conference on Women and HIV/ AIDS
Briefs
from the 6th Retrovirus Conference Held in Chicago
The
39th ICAAC Conference in San Francisco
Highlights
from the 3rd International Conference on Nutrition and
HIV Infection Cannes, France: April 22-25, 1999
World
AIDS Conference in Switzerland
5th
Conference on Retroviruses and Opportunistic Infections
Reflections
After the 1999 National Conference
on Women and HIV/ AIDS
by Pam
The
1999 National Conference on Women and HIV/ AIDS was
held in Los Angeles, California from October 9-12. The
conference was attended by people who are infected and/or
affected by HIV/AIDS from across the United States and
Canada. There were about 600 scholarships available
and I was of several women from Chicago who received
one. At first, it was difficult to make the choice to
go to Los Angeles. A vacation on the West Coast is one
thing; but, to go and search for answers in dealing
with the virus within is another thing altogether. After
a great deal of soul-searching I chose to go and look
for information and hopefully some new treatments or
breakthroughs.
At
first, it was difficult to make the choice to go to
Los Angeles. A vacation on the West Coast is one thing;
but, to go and search for answers in dealing with the
virus within is another thing altogether. After a great
deal of soul-searching I chose to go and look for information
and hopefully some new treatments or breakthroughs.
I arrived at the convention center and immediately recognized
some familiar faces from past conferences and even some
women from Chicago. I met a woman who was circulating
material concerning a web-site she published dealing
with HIV positive women who are sexually active. Her
internet Г’magazineГ“ is entitled DENTATA. I recognized
the name because my boyfriend had submitted a love poem
about me to the magazine and it had been published in
the premier issue. I knew that Susan was a lesbian and
had initially thought she would be a rough looking Г’dykeГ“.
When I realized this lady was the publisher; I was shocked.
To my surprise Susan was a demure, sweet young lady.
I introduced myself and we laughed and delighted in
the Г’worldГ“ we lived in.
This
Òsmall worldÕÕ atmosphere had begun earlier when I checked
into my hotel and had discovered who my roommate was.
Beri and I had first met over four years ago, in Chicago,
in a support group I was the facilitator of. Beri is
a former IV drug user who had been in denial of being
at risk for several years. She had come to the support
group in an effort to face the truth and accept that
she had the virus. Beri and I had discovered we had
someone in common. I had gotten the virus from having
sex with an old boyfriend who was an IV drug user. Beri
had known him prior to our relationship and had been
the first person to start him on IV drug use. Now over
four years after learning this information we both were
at the National Conference and were roommates. The anger
and hurt one deals with in accepting the virus is eventually
replaced with a determined will to live.
As
you will discover through reading this article; it does
not matter how you acquire the virus. What matters is
how you live with it. I met another old acquaintance
who typifies this will to live. She is positive; her
husband is negative and she is also the mother of twins
who are negative. I first met her at another convention
a few years ago when her twins were just babies. She
writes for a magazine in California and leads what most
people would consider a normal life. The subject of
pregnancy and HIV/AIDS is intense and controversial.
It was the focus of several seminars and I learned a
great deal of facts.
The transmission of HIV from a pregnant woman to her
fetus is known as perinatal transmission. This can occur
prior to delivery, during delivery or from breast feeding.
In 1997 an estimated 7,000 HIV infected women gave birth
in the United States. Without intervention 15-30% of
these infants could become HIV positive. Recent studies
have shown that administering the drug AZT prior to
delivery can reduce this risk to less than 10%. These
findings have given HIV positive women the opportunity
to have healthy babies. The most important factor being
that the pregnant woman knows she is HIV-positive prior
to giving birth. This has created a dilemma amongst
HIV-positive women/families. It goes back to the desire
to lead a normal life. A few years ago I got pregnant
and could not go through with it. Now, women have a
real choice to make. I have a good friend who is pregnant.
Both her and her husband are HIV- positive and they
have chosen to have a baby. The reduction in probability
of having an infected baby and the progress made in
medications have given people with HIV/AIDS the possibility
of living a long, productive and yes, normal life.
Leading a normal life with HIV/AIDS is an extremely
important issue. However, more important than that is
prevention of the virus altogether. Women are one of
the fastest growing groups to be infected with the virus.
The disease is becoming increasingly common amongst
younger women- especially women of color. In 1996 AIDS
became the third leading cause of death in women of
reproductive age and the number one cause of death of
African-American women of that age. The symptoms that
could serve as warning signals of infection may be ignored
because many women do not perceive themselves at risk.
Symptoms include recurrent yeast infections, pelvic
inflammatory disease, abnormal changes in cervical tissue,
genital warts, and severe mucosal herpes infections.
It is possible for a person infected with HIV to not
show signs for extended periods of time. Some people
within a few weeks of becoming infected show flu-like
symptoms. I remember getting sick and having strep throat
but not in a million years did I ever dream I was infected.
I listened to the news and knew of the epidemic, but
never dreamed I was at risk. I was having unprotected
sex with my boyfriend and did not know of his IV drug
use. I found out because I went with a girlfriend who
thought she was possibly positive and we both were tested.
She was negative and I, the one Г’withoutГ“ risk was positive.
Safe sex through condom use and several other methods
is vital. I attended a HIV lesbian seminar to learn
what I could about the virusГ• transmission in this area.
I found out that only 5 cases have been reported to
the Center for Disease Control. I wanted to know about
safe-sex practices during oral sex. Most case workers
and sex educators will advise the use of a barrier during
oral sex. They recommend a dental dam or plastic wrap
to prevent mouth to vaginal contact.
It is very uncommon for these measures to be utilized.
Another recommended preventative is to have sex in the
light to see what your partner looks like. Although,
most people do not like to think about it. It is imperative
that people practice safe-sex methods and regularly
get tested for sexually transmitted diseases or STDs.
A perfect example of how the risk factor comes into
play occurred one night at the hotel I stayed at. I
was enjoying a soak in the hot tub, next to the pool,
with several other women from the conference. All of
us were HIV-positive and there were men getting in the
hot tub and asking us for dates etcetera. They were
unaware that we were attending the conference. One man
brushed against my leg Г’accidentallyГ“ and I jumped out
of the water and left. I am mentioning this because
no one knows who has it. The danger is out there.
There were other people at the conference who I enjoyed
speaking with. One group was called M.A.P. - Mothers
of AIDS Patients. These mothers were a joy to behold.
They each gave me a hug and we discussed my parentsГ•
support and I left their table with tears in my eyes
and a wonderful feeling of support.
I
was told of a story about a very ill woman who attended
the conference against her doctorГ•s wishes. She felt
the need to be there to either add support or receive
it. She passed away during the conference and was an
amazing example of courage.
One
woman proudly told me that this conference was a history
making moment. She had learned that never before had
so many HIV-positive women come together in one event.
Leaving
Los Angeles and the convention I was filled with emotions.
I had overcome my original fear of going and come away
with some useful information and a rejuvenated sense
of hope. I did not find a miracle cure. I do know that
the battle is always with me. But, most of all, I found
that women with HIV/AIDS have a great deal of support,
and the opportunity to live a normal life.
Briefs
from the 6th Retrovirus
Conference Held in Chicago
January
31-February 4, 1999
By
Daniel S. Berger MD
The
first major AIDS conference of 1999, the 6th Conference
on Retroviruses and Opportunistic Infections was held
in Chicago January 31 ГђFebruary 4. Numerous studies
and research was presented. The conference was well
attended by more than 3000 researchers and physicians.
Topics were of a wide spectrum and included new antiretroviral
agents, salvage regimens for patients failing their
current treatments, drug resistance, metabolic complications
of treatment and immune reconstitution. Some highlights
are presented here for our readers.
Monkey
Business
The
first daysГ• reports were focused on the attention of
the chimpanzee subspecies, Pan troglodytes troglodyte
now thought to be the source of HIV in humans and
the cause of the epidemic, as we know it today. It seems
likely that these monkeys may have introduced HIV in
West Africa to hunters via infected blood; DNA sequences
(genes) from the chimps infected with SIV (simian immunodeficiency
virus) confirmed a likeness to HIV-1 in humans. Also,
an HIV-1 subgroup was isolated within SIV from the sequence
of a female chimpanzee brought to the US for research
in the 1950Г•s. This same animal tested positive for
HIV in 1985.
As the chimpanzees do not become ill with HIV, it may
provide researchers with a chance to investigate how
these animals avert disease, and perhaps give rise to
other avenues of research for prevention as well as
treatment.
T
cell ГђGains and Losses
A familiar observation occurring among HIV-positive
individuals is that after infection, specific T cell
populations get affected. This impacts on the immune
function of the individual. Specifically, a portion
of the CD4+ T cell, known as naive cells (CD45+RO) gets
depressed and takes a longer time to become replenished
after treatment with protease inhibitors. However, a
faster rise in memory CD4+ cells seems to occur. Additionally,
CD8 cells increase with HIV infection and treatment
with antiviral cocktails often reduce the CD8 cell number,
thereby improving the CD4/CD8 cell ratio. With antiviral
treatment, improved responses to opportunistic infections
also are seen, such as to CMV, PCP and Candida.
The thymus gland is the organ where T cells mature.
It was once thought that the thymus becomes a vestigial
organ (shrinks and becomes useless) after adolescence;.
However recent evidence has shown that naive T cells
can continue to be produced by thymus tissue in HIV
infected individuals treated with triple therapy. Various
treatment regimens have been shown to increase the thymic
lymphoproliferative response to T cell mediated antigens
(proteins) as well as to HIV antigens.
During
a late breaker session, researchers from San Francisco
General Hospital presented data examining a comparison
of T cell counts. Patients on therapy and whose viral
loads were undetectable were compared to other patients
on therapy with persistent elevated viral load and compared
again to those patients who were not on treatment. CD4+
T cells were shown to have a higher half life among
the treated patients even if viral loads were detectable.
This study demonstrates further positive benefit of
treatment - T cells can live longer as a result of therapy
even while viral loads are not undetectable. There has
been much discussion regarding changes in viral fitness
resulting from antiviral therapy.
A
Dutch study reported that triple therapy was associated
with T-cell regeneration. Potent regimens of antiviral
agents may help in the conversion of progenitor cells
to more mature T-cells. Several treatment cocktails
including 3 drugs and 5 drug containing regimens were
associated with increased capacity of T-cell development.
Two
studies highlighted the importance of CD8 T cell counts
(T suppressor cells). These studies using the monkey
model have administered a monoclonal anti-CD8 antibody,
which in effect depletes the number of CD8 T cells.
In both studies of the monkeys with depleted levels
of CD8 cells via the monoclonal antibodies, the monkeys
demonstrated increased viral activity and viral load.
In one of the studies, the monkeys showed a rapidly
fatal course when demonstrating high viral loads with
low CD8 T cell counts.
Sparing
the Protease Inhibitors
A variety of protocols studied and compared treatments
for naive patients (patients who have no previous exposure
to antiviral agents), specifically examining the utility
of protease sparing regimens. There has been much interest
in the philosophy of beginning initial treatments without
using protease inhibitors. Moreover, many such possibilities
of protease free cocktails have improved since the approval
and availability of efavirenz (Sustiva) a non-nucleoside
reverse transcriptase inhibitor and abacavir (Ziagen)
a nucleoside reverse transcriptase inhibitor.
Treatment
regimens were studied comparing d4T/ddI/3TC with d4T/ddI/nevirapine
with d4T/ddI/indinavir in a group of 234 patients. Baseline
viral loads were at 4.2 logs (approximately 20,000 copies)
and CD4 T cell count was at 450 cells. On the intent-to-treat
analysis, the protease inhibitor arm demonstrated a
78% rate of undetectable (<400 copies) vs 69% in the
nevirapine arm and 71% in the triple nucleoside arm
(3TC containing regimen).
Another study from the University of Miami examined
the use of abacavir (Ziagen) as the third drug in a
protease sparing regimen. The three drug regimen studied
was unique because all three were from the same drug
class: nucleoside reverse transcriptase inhibitors (NRTIГ•s)
and included AZT, 3TC and abacavir (ABC). The design
of the study compared AZT/3TC/ABC with AZT/3TC. After
16 weeks patients on the AZT/3TC arm were given the
option to add ABC or other agents. After 48 weeks of
treatment, 74% of patients continued to achieve undetectable
viral loads (<400 copies) and that patients of the dual
AZT/3TC arm who at 16 weeks added a third drug, also
showed improved viral loads for the remaining 32 weeks.
However, it should be noted that patients who began
the study with viral loads greater than 100,000 copies
of HIV RNA, did not have as good a response to the triple
RTI regimen.
An additional French study examined substitution of
a non-nucleoside RTI for a protease inhibitor for patients
who were intolerant to their protease inhibitor drugs,
or who developed lipodystrophy or other side effects.
In this small study of only 8 weeks, patients were switched
to either nevirapine (Viramune) or efavirenz (Sustiva).
While at eight weeks the CD4-T cell count remained unchanged,
viral loads were all less than 80 copies. We believe
that although these results are encouraging, 8 weeks
of study is not long enough on which to base clinical
decisions. Further studies are certainly warranted.
More
on Antiviral Therapies
An
update to the original Merck 035 study in which patients
are on treatment of AZT/3TC/indinavir (Crixivan) was
presented. To date 80 patients are still maintained
on study. However and not surprisingly, a drop in the
portion of patients still at undetectable HIV loads
have occurred. Previously reported at 80%, the number
of patients still on study at more than 3 years out
and undetectable was at 67%. Additionally, lipodystrophy
or fat redistribution was reported at a rate of 19%
of patients in the study.
Hydroxyurea,
administered at somewhat higher doses was presented
by researchers at the University of Pennsylvania. At
a dose of 1500 mg per day, hydroxyurea in combination
with ddI resulted in a 1.7 log drop in HIV RNA. At what
many consider the standard dose of 1000 mg per day,
a 1.2 log drop in viral RNA was observed. The higher
dose was associated with more suppression of the bone
marrow with neutropenia being the most common side effect.
Conclusion
Overall,
the 6th Retrovirus Conference added valuable information
regarding a host of topics related to HIV disease. This
conference has become a most important forum to present
research, especially since the international conference
on AIDS is now only held once every two years. While
new complications to long-standing treatment have been
observed during the recent 18 months, efforts to look
for alternatives are being encouraged. Future conferences
to discuss these and other issues will be held later
this year.
The
39th ICAAC Conference in San Francisco
by
Matthew Sirinek, MD
Norvir
increases drug levels of Viagra
Norvir
has been shown to greatly influence the drug levels
of Viagra in the blood. This effect is so great that
major dose adjustments are recommended. The normal dose
of Viagra is 50 mg. This dose should be reduced to 25mg
if taking Norvir. It has also been shown that Norvir
also prolongs the amount of time Viagra stays in the
blood, so one 25 mg dose may last up to 48 hours. Viagra
was shown to have no effects on NorvirГ•s blood levels.
No dose adjustments have been recommended for other
protease inhibitors.
New
data on drug holidays
With
the great success of viral suppression achieved with
HAART, many patients and doctors are wondering about
stopping HAART in patients with long-term undetectable
viral loads. Can our bodies keep HIV at bay if therapies
are stopped? Unfortunately the answer appears to be
a resounding Г’NO!Г“ Dr. Davey from the NIH studied 18
HIV+ patients who had undetectable viral loads (less
than 50 copies/ml ) on HAART for at least 12 months.
He asked them to stop all HAART at once and observed
the results. All 18 patients rebounded to more than
50 copies within 2 months. T-cell counts dropped about
200 points on average over a few weeks in all patients.
15 of the 18 patients restarted HAART after it was clear
they were rebounding. All 15 were able to suppress the
virus to undetectable levels within 2 months.
Leukine in Advanced HIV
Leukine is an injectable drug that has been known to
increase human immune responses. It has also been shown
to decrease HIV replication. A study by Dr. Angel examined
the effect of giving leukine to HIV+ patients with T-cell
counts less than 100 who were on stable HAART regimens.
He found that patients given leukine three times per
week had increased T-cell counts at every point studied.
This trend was not seen in the placebo group. They also
observed that those patients who had viral loads less
than 400 copies and were taking leukine were able to
maintain this low viral load for a much longer period
of time than those patients not taking leukine. While
these results appear promising, further research is
needed using Leukine as an adjunct therapy to HAART.
Using
T-20 in Multi-drug Salvage Therapy
T-20
is an HIV drug that has a novel mechanism of action.
It is a fusion inhibitor that prevents HIV from attaching
to T-cells. This drug may be valuable since HIV has
become increasing resistant to the current classes of
drugs. One study at ICAAC was designed to see how patients
who had developed resistance to all three current classes
of drugs (NRTIs, NNRTIs, and PIs) responded to new regimens
consisting of T-20 and the currently available drugs.
60% of patients achieved at least a one log drop in
viral load at week 16, which appeared to remain stable
over the following weeks. 36% had viral loads less than
400 copies, and 20% achieved a viral load below 50 copies.
Since T-20 was used in various combinations with different
patients, the exact efficacy of T-20 cannot be determined.
Still, these results appear to be better than what is
generally seen when highly resistant HIV patients are
put on a salvage regimen using only combinations of
the three available classes of drugs. As a component
of a new cocktail, T-20 may be a key agent for those
with resistance to the current medications.
ABT 378 data looks promising in naive
and PI-experienced patients
In two studies presented at ICAAC, the protease inhibitor
ABT-378 showed encouraging results. One study examined
d4T, 3TC, and ABT-378 given to naive patients. 95% of
these patients achieved a viral load less than 400 copies
at week 36. The other study examined ABT-378 in PI-experienced
patients. These patients had failed one PI-containing
regimen and had never been on an NNRTI. All patients
were given ABT-378 in combination with nevirapine and
2 nukes. 78% of these patients achieved a viral load
below 400 copies at week 36. Additionally, the ABT-378
combinations were very well tolerated. The major side
effect was loose stools, but this led to only 1% of
patients stopping the drug.
Once-a-day
Dose Protease Inhibitor Combo?
Several
studies have shown that Norvir greatly increases the
levels of Fortovase and Crixivan in the blood. This
has already allowed us to combine Norvir with either
Fortovase or Crixivan in convenient twice a day dosages.
One study by Dr. Saag, et al. at UAB studied the possibility
of using the combination of Norvir and Fortovase in
a once-a-day dose. The study suggested when a small
amount of Norvir is combined with regular amounts of
Fortovase, it is possible to achieve appropriate blood
levels in a once-a-day dose. The combination was also
shown to be reasonably well tolerated with diarrhea
and bloating to be the major side effects.
New treatment for Hepatitis C
Although
not presented at ICAAC, it is worth mentioning that
a new drug developed by Roche called Pegasys may be
much more effective in treating Chronic Hepatitis C
than conventional treatments. In one study, this drug
was combined with ribavirin, another common Hep C drug,
and 70% of patients with Chronic Hepatitis C achieved
an undetectable HCV viral load by week 48. In comparison,
current therapy results in a success rate of less than
33%. The combination in the study had mild to moderate
adverse events including fatigue, fevers, chills, nausea/vomiting,
and anorexia, similar to side-effects of current therapies.
Highlights
from the 3rd International Conference on Nutrition and
HIV Infection Cannes, France: April 22-25, 1999
The
latest FAT Facts & Abnormal Changes in Body Composition
By
Daniel S. Berger MD, FACN
Attending
the 3rd International Conference on Nutrition and HIV
Infection in Cannes, France was quite an experience.
One doesnГ•t routinely expect to be at an AIDS conference
on the French Riviera. But the meeting was an excellent
display of 300 international specialists uniquely involved
in helping to develop our understanding of new metabolic
complications of HIV treatment and itsГ• clinical concerns.
Additionally a satellite symposium was held to discuss
immune reconstitution in HIV.
Looking back, it has been quite a journey participating
in the research for the development of HIV treatments;
the field of nutritional intervention has evolved alongside.
In many ways we have developed a greater understanding
of body composition and nutritional management. Five
to 15 years ago we were involved in better defining
wasting syndrome and treatment. Only three years ago,
and after the widespread use of protease inhibitors,
one thought that nutritional problems and wasting was
nearly conquered. Now, however, we are left with a completely
different picture of unanswered questions. HIV specialists
and scientists are actively engaged in researching the
various factors that influence the metabolic and fat
redistribution changes that seemingly have become complicatedly
prevalent and upsetting amongst our patients. This third
international conference in Cannes was organized to
encompass new data on the impact that protease inhibitor
containing regimens have on body composition changes,
alterations in lipid and glucose metabolism as well
as hormonal aberrations.
What's
in a name?
There
have been many different names to describe the body
compositional changes among HIV positive patients. They
include Lipodystrophy Syndromes (LS), fat accumulation,
protease paunch, Crix-belly, fat redistribution, buffalo
hump, HIV-Associated Lipodystrophy or HALS as well as
fat depletion. Some patients are developing various
manifestations but in mixed and variable degrees. (Please
see the previous issue of AIDS INFOSOURCE for a more
detailed description).
Are
Antivirals the Cause?
Some
studies have retrospectively looked at antiviral drug
regimens to elicit any associated or contributing factors.
While an Australian group has ascribed the changes occurring
from protease inhibitor use, there have now been many
reported cases of patients never treated with these
agents who also manifest these abnormalities. Additionally
at this conference, Dr Thierry Saint Marc from Lyon,
France presented data that attempts to associate d4T
use to programmed cell death of adipose tissue (fat
cells). An investigator from Westminster Hospital of
London, Dr. Bria Gazzard, looked at patients on non-nucleoside
(NNRTIГ•s) drugs and presented data showing no associated
relationship to the NNRTI, delavirdine.
Dr Esteban Martinez from Barcelona Spain had examined
a group of patients who developed fat accumulation and
subsequently taken off their protease inhibitors in
exchange for a non-nuc, nevirapine. The early data showed
a trend towards improved body composition changes, while
maintaining their viral loads below the level of detection.
Moreover, we (NorthStar Medical Center) are currently
enrolling patients for a new study (DMP-049) that looks
at body composition changes and the safety and effect
of exchanging therapy of protease inhibitors for Sustiva.
More studies should be done with this approach.
A
large study was presented involving more than 200 patients,
who filled out a 19 page questionnaire with their companion
physicians completing another 16 pages of questions.
This SALSA study (Self-Ascertained Lipodystrophy Syndrome
Assessment) attempted to define lipodystrophy syndromes
and itsГ• prevalence. Dr. Norma Muurahainen presented
their findings that described 85% of patients with fat
accumulation and 73% with fat depletion. Additionally,
the majority of patients also described a mixed picture,
whereby they had areas of their body showing accumulation
and other body parts with depletion. There was a strong
correlation to patientsГ• and their physiciansГ• assessment
of their body composition changes.
Male
vs. Female
Several
studies presented attempted to discern specific gender
differences to the lipodystrophy syndromes. Dr. Julian
Falutz from Montreal discussed gender associated differences
among his cohort of patients, whom the overwhelming
majority were at undetectable viral loads and had moderate
CD4-T cell changes. Falutz observed that men showed
more fat depletion while the women were more apt to
demonstrate accumulation. Blood lipid abnormalities
were also common among all patients but were more frequent
among patients with fat lipodystrophy syndromes. Dr.
Kathleen Mulligan from the University of California
at San Francisco studied women with fat redistribution,
demonstrating breast enlargement and truncal obesity
being the most common manifestation. However, it was
also observed that many also had fat loss in the buttocks,
calves and thighs.
Treatment?
Dr
Christine Wanke from Boston reported 10 patients on
protease inhibitors with fat redistribution who were
then treated with growth hormone for 12 weeks. These
patients demonstrated decreases in abdominal or waist-to-hip
ratios while increasing thigh measurements. Other researchers
at the Cannes meeting described anecdotal reports of
patients with fat accumulation who were treated with
growth hormone because of buffalo humps or abdominal
fat increases and one report was of a man with a large
accumulation of fat on his head. These patients were
treated with recombinant human growth hormone and showed
improvement in their fat accumulation condition.
Other
Complications
Among some of the various metabolic complications of
HIV therapies lipid disorders appear to be highly prevalent.
Elevations in triglycerides, cholesterol and decreased
HDL cholesterol have been reported. While the true clinical
significance of these are controversial, case reports
of coronary artery disease in HIV positive individuals
have been surfacing. This Chicago author reported on
a cohort of 19 patients, most of whom also had some
component of lipodystrophy, and 50% had elevations in
cholesterol or triglycerides. 17 of 19 patients had
to be treated for new onset hypertension (high blood
pressure) and 4 patients developed coronary artery disease
(3 of whom subsequently underwent angioplasty. Interestingly,
many of the patients had a history of anabolic steroid
use and therefore questioned whether anabolic steroid
use contribute to new onset hypertension in patients
with added risk factors.
Dr.
Mary Romeyn from San Francisco reported on a small group
of 17 subjects. 13 of 17 demonstrated a loss of bone
density and 6 of the 17 had osteoporosis. This patient
group was largely very immune compromised, with CD4
+ T cell counts below 100 cells but without any history
of immobilization or corticosteroid use.
Another
metabolic abnormality has been the development of insulin
resistance and can often lead to elevated sugar levels
(hyperglycemia) and diabetes. Diet and exercise is the
mainstay of treatment but drug therapy may sometimes
be indicated. Drugs such as troglitazone (rezulin) and
metformin (glucophage) as well as insulin have been
used. Saint Marc from France reported a small group
of patients who were treated with metformin with resultant
decreased body fat, visceral adipose tissue and reduced
waist-to-hip ratios. Further studies with metformin
should be done.
Summary
In
summary, progress in this relatively new field of body
composition problems and associated metabolic abnormalities
is underway. However, the etiology of fat redistribution
still remains elusive while the research is barely scratching
the surface. Hopefully, further studies to expand our
knowledge in this area will result in new interventions
and treatment for the not-too-distant future.
The
World AIDS Conference in Switzerland
by Daniel S. Berger MD
"Bridging
the GapГ“ was the theme of this summer's International
Conference on AIDS which was held in Geneva, Switzerland.
The conference attempted to close the gap between the
scientific and world communities. While thousands of
abstracts were presented most in poster format only
300 were presented orally. The topics ranged from technical
scientific research to broader social issues such as
epidemiology, prevention, and public health. Attending
all the scientific sessions as well as the evening satellite
sessions and other amusements was nearly impossible.
Bradley Baker, MD, and myself were more prudent in our
activities, conserving strength for the days rigorous
scientific presentations.
Overall,
the conference was filled with relevant and high quality
research. While there was hopeful news from many of
the scientific studies, there were also many questions
still to be answered about the future.
DonГ•t
believe the hype
Many
of the presentations focused on drugs that are likely
to become available in the marketplace soon. Other studies
elaborated on medications that have been used for several
years. It was interesting to observe the intense competition
of pharmaceutical companies as they promoted regimens
that included their drugs. Physicians and patients,
however, should be leery of pharmaceutical marketing
tactics. ItГ•s never wise to choose drugs based on slick
advertising or company propaganda. Often drug manufacturers
claim their particular drug has less side effects and
is better tolerated than others. However, individual
patients may experience other side effects (not to mention
the frustrations of food restrictions and lifestyle
changes that may come with a certain drug). Companies
often claim that their drug should be used as "salvage,"
that is, when other drugs have failed. However, in choosing
drugs for salvage, a physician must consider cross resistance,
scientific data, clinical experience, and a patients
treatment history.
Protease
predicaments
It
was no surprise to clinicians and virologists that resistance
to protease inhibitors is much more common than first
suspected. The more protease inhibitors already taken
by a patient, the greater the likelyhood of drug resistance.
Thus, an important take home message to patients: if
you know that you’re doing well on a particular
drug cocktail, don’t become lax about taking these
medications. Take them as prescribed and on time. While
newer drugs are being developed, its not clear if they
will be as effective as an initial treatment regimen.
Many new drugs have similar resistance profiles and
probably won’t be as effective for people who have
taken numerous drug before.
One
up and coming new protease inhibitor, developed by Glaxo,
is called amprenavir. Early reports show this drug is
likely to have similar resistance profiles to other
approved medications. Therefore, if ritonavir or indinavir
has failed for a patient, amprenavir may be of little
help. A non-nucleoside reverse transcriptase inhibitor
(NNRTI) very close to being available by prescription
is called efavirenz (its brand name is Sustiva). Because
of a common mutation called K103, efavirenz may have
cross resistance to other drugs in the NNRTI class.
This finding has important implications for doctors
and patients.
Backing
off from bare backing
Alarming
is new evidence that drug resistant virus can be spread
from person to person. Two studies were presented at
the conference that described this unfortunate reality.
It was reported that drug resistant virus was discovered
in patients who have never taken HIV medications. An
additional study, recently published in the New England
journal of Medicine, described a patient who was recently
infected and was started on a triple drug regimen with
a protease inhibitor. The patient did not respond to
treatment and all subsequent attempts at salvage regimens
failed as well. After investigation, genotypic analysis
showed broad resistance to most available anti-HIV drugs.
It turns out that he had unsafe sex with an individual
who had been on extensive HIV treatment. Person-to-person
spread of resistant virus appears to be very much in
existence. This should serve as a warning to those who
feel that "bare-backing” and unsafe sex poses
little risk.
The
good news
On
the brighter side, there was good news presented at
the conference and much of it not receiving media attention.
Most important, many patients on triple drug therapy
that included protease inhibitors or NNRTls have remained
"undetectable" for more than three years.
Also, of the many patients who had not achieved undetectable
viral levels continued to maintain T cell (CD4) counts
above their base lines. Equally heartening is that these
patients did not develop opportunistic complications.
Finally, the prevalence of AIDS related complications
including MAC, CMV, or Wasting Syndrome are remarkably
less than several years ago. Overall, patients are much
better off than in years past.
More
good news stems from the work to develop less complicated
drug regimens for patients. Simplifying drug cocktails
to twice daily and less pills are critical to improving
patient adherence. There was data presented about modified
dosing to allow for twice daily regimens. This, along
with new drug development, significantly reduces the
burden of drug regimens. One example is indinavir (Crixivan)
when taken in combination with ritonavir (Norvir): both
be taken together, twice daily and with food (indinavir
is otherwise required at three times daily on an empty
stomach). Nelfinavir (Viracept) has also been shown
to be effective at 1,250 mg (five tablets) twice daily
and ddlВ (Videx) can be taken once daily at four tablets.
Finally, newer drugs such as efavirenz and adefovir
(Preveon) allow for once daily dosing (see "TKTKT"
in this issue). A new drug called abacavir, (formerly
known as 1592 and now being marketed as Ziagen), will
be dosed at twice daily. These new developments should
help patients to better adhere to their regimens, which
is crucial for the drugs to work. Lack of adherence
is thought to be one of the primary causes of treatment
failure.
Spare
me the protease
There
has been increased interest in regimens that do not
include protease inhibitors. This is especially true
because of emerging complications that may be associated
with the use of protease inhibitors. These complications
are being referred to as "lipodystrophy" a
syndrome that alters fat distribution within the body.
These body composition changes have been described and
sometimes are associated with hormonal abnormalities
and elevated blood cholesterol and triglycerides levels
(see "TKTKT" in this issue). These elevations
in blood lipid levels can potentially lead to premature
development of cardiovascular abnormalities. In fact,
a recent report published in the Lancet describes two
young patients on protease inhibitors who developed
premature heart problems. The hormonal abnormalities
observed can result in impaired glucose tolerance and
diabetes.
These
new perplexing complications have sparked interest in
drug regimens that do not contain, or, spare protease
inhibitors. Nonprotease inhibitor drugs being used in
cocktails (combined with two nucleoside reverse transcriptase
inhibitors) include the nevirapine (Viramune), efavirenz
(Sustiva), hydroxyurea, and abacavir (Ziagen).
New
drug watch: PMPA and T20
New
drugs being developed include Gileads second-generation
nucleotide reverse transcriptase inhibitor called PMPA.
This drug, chemically similar to adefovir, appears to
hold significant promise because of several unique properties.
Firstly, PMPA has a broad spectrum of activity that
includes HIV and hepatitis B. Secondly, early reports
seem to demonstrate activity against resistant virus.
Thirdly, synergy has been observed with many other agents,
including ddl, nelfinalvir, amprenavir, nevirapine,
and others. Anecdotal reports suggest the possible synergy
with hydroxyurea.
An
unprecedented finding, however, was a PMPA study using
monkeys. The animals were administered one dose of PMPA
and it appeared to be effective in preventing a virus
very similar to HIV (simian immune deficiency virus).
These results were found in 100 percent of the monkeys
for up to four weeks. These animal studies may have
promising implications for humans. NorthStar Medical
Center is currently participating in phase II clinical
trials with PMPA
Another
unique approach to HIV treatment involves the agent
T 20. Its manufacturer, Trimeris, is developing this
compound which is quite different from current HIV drugs.
T 20 is a "fusion inhibitor," it appears to
block HIV from entering human cells. With its unique
mechanism of action, resistance to other HIV drug are
believed to be unlikely. But the drug will not be taken
by mouth. Instead, administration requires individuals
to wear a detachable portable pump, similar to those
worn by some diabetics. Preliminary studies have indicated
a quick and potent reduction in HIV levels. Phase I
trials are underway, larger scale studies are planned
for later this year.
Immune
boosting
Immune
based therapies for HIV are also receiving increased
attention these days. This author gave an oral presentation
at the conference about a small study of patients with
late stage HIV infection who were treated with an immune
stimulator called interleukin 2. The Chicago study was
important in several respects. Previous thinking held
that interleukin 2 (IL 2) was only effective in patients
with at least 200 300 CD4 cells. This study refuted
this previously held belief and demonstrated a broader
range of immune system restoration. In this advanced
patient population. (with histories of multiple AIDS
related complications), IL 2 significantly increased
certain subset of immune cells including critical naive
cells. Authors of the study at NorthStar Medical Center
concluded that treatment with protease inhibitors can
be combined with IL-2 to maximize HIV control and immune
reconstitution.
IL-2
was also discussed by Anthony Fauci, MD, director of
the National Institute of Allergy and Infectious Diseases.
He presented information on HIV pathogenesis as well
as current theories about eradicating the virus. Fauci
described patients who were taking highly effective
HIV medications and who had achieved undetectable viral
loads. In these patients, however, it was demonstrated
that a latent pool of HIV continued to survive and was
capable of becoming active. Current HIV therapy has
unable to eradicate this pool of virus. But at a separate
meeting at the Institute of Virology, Fauci revealed
the results of using IL-2 in 13 patients in who already
had undetectable viral loads. In 3 of the 13 patients,
this latent virus Pool was not observed (see Whispers
in this issue). IL-2 may have activated this latent
virus, making it susceptibility to antiviral therapy.
While this finding is preliminary, more research is
urgently needed.
Competition
among manufacturers
During
the conference, a colossal meeting hall was devoted
to pharmaceutical company displays, most of which were
flashy and excessive. Meaningful networking and other
meetings, and discussions took place in the pharmaceutical
display room: it was obvious how competitive and commercialized
the HIV industry has become. It is believed that competition
among the industry is important and necessary This encourages
drug manufacturers to improve on existing products;
better antivirals that are easier for patients to take
with less side effects should be developed. Additionally,
Pharmaceutical companies will have to research and develop
antivirals that are effective against resistant or mutated
virus.
5th
Conference on Retroviruses and Opportunistic Infection
5th
ANNUAL CONFERENCE
Wednesday, February
4, 1998
Daniel
S. Berger MD.
Tuesday's sessions at the 5th Conference
on Retroviruses and Opportunistic Infections covered
a wide spectrum of topics and included pathogenesis
and prophylaxis of opportunistic infections, dual protease
therapy, resistance to Antiretroviral protease inhibitors,
salvage regimens, neurologic complications of AIDS and
new and unique adverse effects to protease inhibitors.
During the opportunistic infection session, the incidence
rates (prior to HAART - protease inhibitor therapy use)
of different infections were discussed. Most common
opportunistic infections were PCP, CMV and MAC. For
patients with HIV RNA increases, there was an associated
increased risk for developing these infections.Additionally,
patients that demonstrated only poor response to antiviral
therapy, namely less than 10 cell increases, were at
an added risk for CMV.
A study conducted in South Africa investigating the
changes in HIV viral load during therapy for TB was
presented. However, although therapy stabilized immunologic
status in these individuals, no antiviral therapy for
HIV was used. The presenter commented that Antiretroviral
therapy is not the standard of care in South Africa.
Herpes Simplex reactivation may be associated with increases
in HIV RNA. This study examines the possibility of sub-clinical
shedding of herpes and its relation to HIV RNA levels.
The results demonstrated that no significant changes
occurred with shedding but that suppression of herpes
with antiherpetic medications was associated with decreases
in HIV viral loads. Whether herpes suppression will
lead to reductions in HIV RNA and survival benefit in
the era of protease inhibitors still needs further study.
Various "salvage regimens" for patients failing
triple therapy with protease inhibitors were presented.
A striking study of a small group of patients who were
placed on 6 antivirals for salvage and included three
RTI's including d4T,ddI and 3TC with two protease inhibitors-
nelfinavir and saquinavir (hard gel capsule) with nevirapine.
Most patients remained undetectable below 400 copies/ml
at 20 weeks of therapy.
A unique complication to protease inhibitors, changes
in peripheral fat distribution- a syndrome of peripheral
lipodystrophy was described. Patients observations that
they are losing fat mass as a consequence of metabolic
changes that occur with protease inhibitors was demonstrated
in this Australian study. This will be discussed in
further detail on the next posting of the conference
Tuesday,
February 3, 1998
Daniel S. Berger MD.
The
5th Conference on Retroviruses and Opportunistic infections
met today for its' first full day of meetings. Some
Topics and points covered included: Incidence of AIDS
DEATHS for the first half of '97 decreased by 44% This
decline is due to the widespread use of newer therapies.
New
Drugs Are About to be Coming Down the Pipeline
Studies presented included a small trial with ABACAVIR,
otherwise known as 1592 in used in five different treatment
arms each with 5 different protease inhibitors. Results
demonstrated goood safety and efficacy over the first
16 weeks of study.
However, side effects to abacavir, include a potentially
severe systemic allergic reaction: if symptoms occur,
the drug needs to be stopped and can not be restarted.
Additional study of a new protease inhibitor, called
AMPRENAVIR (also known as 141W94). Also a small study,
but early indications show good safety profile combined
with other protease inhibitors. These dual protease
combinations may eventually show good promise, but resistance
patterns were not discussed during this session.
Preliminary findings of the potential use of the Zinc
Fingers-site for attack of HIV. Zinc fingers are required
for infectivity and packaging of HIV. Certain drugs
can be engineered to attack this site, to prevent infectivity
of HIV.
AIDS Malignancies were discussed in an afternoon session.
A variety of clinical trials utilizing new and thoughtful
combinations for lymphoma, kaposi's sarcoma and cervical
cancers were reviewed..
The impact of triple combination therapies, which use
protease inhibitor combination have had a marked reduction
on the incidence of many opportunistic infections was
discussed during the late afternoon poster session.
Declines in PCP, CMV, neurologic disease and other opportunistic
infections were demonstrated.
Highlights
from the 5th Conference on Retroviruses and
Opportunistic Infections. Tuesday February 3, 1998
Project
Inform; Tuesday, February 3, 1998
The
following material does not live up to our typical rigorous
editorial standards. This is Project Inform’s method
of providing the timeliest important new treatment information
from this important conference. The fully edited report
from this conference will be available in the March
edition of "What’s New" which is available
through the Project Inform website or by calling the
Project Inform HIV/AIDS Treatment Information Hotline
at 800-822-7422.
Reflections
on the Conference - Day Three
One
aspect of the Vth Conference on Retroviruses and Opportunistic
Infections which seems little changed from last year
is the perception by many of those attending that the
conference management gave preferential treatment to
a select group of closely associated researchers. Many
people perceive that a certain "cronyism"
has an undue influence on who is invited to make special
lectures and prominent oral presentations, while rendering
secondary roles such as poster presentations to those
less well connected. Still worse is the perception that
a number of well regarded scientists who are making
otherwise notable contributions to the field are conspicuously
absent from the conference altogether, often for several
years running. Although Project Inform raised these
concerns last year, what is different this year is how
widely these issues are being voiced by scientists on
the floor of the conference.
Certainly,
some of this can be attributed to jealousy or hard feelings
on the part of those whose work was rejected or given
secondary status. But even some scrupulously fair observers
were voicing concerns that many posters relegated to
the basement appeared more important and better done
than some of the presentations made in the main auditorium.
As one well-known conference attendee whispered during
a top level presentation "Why is this four year
old dreck being presented on the main stage when far
better studies are languishing on the poster boards
downstairs?" Indeed, a cursory glance at the lists
of presentations selected for prominent presentation
suggests that, at least in some subject areas, a disproportionate
number of oral presentations were made by members of
the conferences Scientific Program Committee or their
close friends.
To
be fair, it should be noted that the Scientific Program
Committee includes some of the most respected names
in AIDS research, so it not unusual that their work
and that of their immediate colleagues should score
well in the evaluation process. That is as it should
be. But in contrast, many other respected names in AIDS
research are not on or connected to the Program Committee
and it seems more than a coincidence that their work
was so poorly represented in the program.
The
danger of all this is that the Conference has begun
to overemphasize a narrow scientific point of view,
making it less valuable overall. For example, last year’s
conference led to an enormous public and scientific
fascination with the prospects of HIV eradication. For
months, it was all that many could talk about, while
voices that questioned such prospects were pushed aside.
Scientific diversity, even scientific competition, must
be encouraged rather than censored.
A
few years ago, Science Magazine editorialized about
the benefits expected as a surge of "Young Turks"
came to prominence in AIDS research. The Young Turks
were expected to demonstrate a new collegiality and
open doors that had been supposedly held shut by older,
dogmatic scientists. A new era of cooperation and creativity
was promised. A few years later, it seems that a subset
of the Young Turks are now themselves the ones closing
doors and crudely enforcing dogma.
Perhaps
the lure of power is always intoxicating.
What
to do about it? First, we believe that the National
Institute of Allergy and Infectious Diseases (NIAID),
the sole government co-sponsor, should reconsider its
sponsorship or use its powerful influence to improve
matters.
Many
voices within government share with us their concerns
about favoritism in the conference. NIAID needs to consider
its role in letting this happen. Second, changes should
be made in how the conference is organized and led.
The same closely related group seems to have held the
reigns for several years in a row. Moreover, there has
only been slight and slow turnover in the membership
of the Scientific Program Committee. Both factors must
change. Nobody appointed anyone to "own" this
important meeting. Membership on the Scientific Program
Committee can easily be widened or made to turn over
more quickly. Shorter terms and a more open nomination
process for membership would make an immediate difference.
For now, the nomination and membership processes seem
to be a black box. A little light could go a long way.
As
for overall leadership of the conference and Scientific
Program Committee, it is almost certain that the work
is difficult and unappreciated. Those who have contributed
in this way for years should be genuinely thanked, but
they should also move aside and let others take the
helm, and allow new leadership to be appointed in a
much more democratic manner. Unfortunately, today the
same few people not only dominate this conference, but
several other conferences throughout the year. We encourage
them to take a healthy vacation, or at least to begin
mentoring others to take their places as soon as possible.
The
bottom line is that all of AIDS research - and more
importantly, people living with AIDS - will benefit
if this conference is as open and above reproach as
possible. Without a free exchange of ideas, the path
to better drugs and a vaccine will almost certainly
be longer and more painful. The voices of all scientists
doing good work should have an equal chance to participate,
not just those of a self-selected inner circle. This
year, the number of people openly raising concerns about
bias and favoritism is too large to simply write off
as jealousy. Let’s get some fresh air in this room.
The third day of the conference had several different
foci for anti-HIV therapies including: studies looking
at the potential of combining protease inhibitors both
as initial therapy as well as for people who have failed
their existing treatment regimen; some insight in to
the development of side effects from long-term protease
inhibitor use; and simplified dosing regimens for protease
inhibitors.
A
small study looked at the safety and antiviral effects
of nelfinavir (Viracept) in combination with indinavir
(Crixivan).Twenty-one people with a median CD4+ cell
count of 259 and a viral load of about 50,000 copies
of HIV RNA participated in this study. Approximately
half of the participants had been on previous nucleoside
analogue therapy and none have taken a protease inhibitor.
The
doses studied were 1000 mg every 12 hours of indinavir
and either 750 mg every twelve hours or 1000 mg every
twelve hours of nelfinavir. After 32 weeks of the study,
10 people had less than 400 copies of HIV RNA and of
those 10, 6 had less than 50 copies of HIV RNA. Three
people had to add reverse transcriptase inhibitors because
they either had an increase in viral load levels or
they did not have a sufficient antiviral response. There
was a median increase of 133 CD4+ cells after 32 weeks
of the study.
Long-term
results from the ritonavir (Norvir) + saquinavir (Invirase)
study which we have previously reported continues to
have potent anti-HIV activity.
One
hundred and forty-one people received four different
doses of ritonavir and saquinavir. After 48 weeks of
the study everybody remaining in the study were switched
to receive 400 mg saquinavir and 400 mg ritonavir both
taken twice a day. This was found to be the most well
tolerated dose of the combination. After 60 weeks of
the study, 89% (89 of 100 people) who has remained on
the study have less than 200 copies of HIV RNA. There
was also a median increase of 176 CD4+ cells. Eleven
percent of the participants developed moderate to severe
increases in triglyceride levels, however antihyperlipidemic
drugs such as Lopid and Atromid generally decreased
triglyceride levels. Twenty-seven people added up to
2 nucleoside analogue drugs because of increasing viral
load levels. Most people added d4T + 3TC. Twenty-three
of the twenty-seven people then had viral load levels
below 200 copies of HIV RNA and has remained there after
60 weeks of the study. These results are somewhat surprising
as most people believed that dose intensification with
two nucleoside analogues would not be sufficient to
get viral replication under control and would result
in only a transient viral load drop.
A
study conducted in Europe compared ritonavir + saquinavir
to ritonavir + saquinavir + d4T. The doses used were
400 mg twice daily of ritonavir, 400 mg twice daily
of saquinavir and 40 mg twice daily of d4T. Two hundred
and eight people with an average CD4+ cell count of
about 260 and a viral load of about 20,000 copies HIV
RNA participated in this study. Approximately half of
the participants had been on prior nucleoside analogue
therapy before participating in this study. After 24
weeks of the study, about 90% of the participants still
remaining on the triple combination had viral loads
below 400 copies HIV RNA
compared
to about 65% of people receiving the two drug regimen.
Both groups had about 150 CD4+ cell increases after
24 weeks of the study. Six of the participants receiving
the two drug combination added d4T + 3TC after 18 weeks
of the study because of increasing viral loads. All
six participants subsequently had viral loads below
200 copies of HIV RNA. Mild to moderate diarrhea and
tingling around the mouth were the most commonly reported
side effects.
Preliminary
results from a study conducted in Europe of combination
protease inhibitors (known as the SPICE study) show
that a dual protease combination may have about the
same antiviral effects as a protease inhibitor in combination
with nucleoside analogues. One hundred and fifty-seven
people with an average CD4+ cell count of 301 and a
viral load of 63,000 copies of HIV RNA received either
soft gel saquinavir (Fortovase) + 2 nucleoside analogue
reverse transcriptase inhibitor (NARTIs), nelfinavir
+ 2 NARTIs, nelfinavir + saquinavir or nelfinavir +
saquinavir + 2 NARTIs. The results after 32 weeks of
the study were as follows: Viral load dropCD4+ cell
increase % below 400 copies HIV RNA
SQV
+ 2 NARTIs1.96 logs9270%
NFV
+ 2 NARTIs1.77 logs7355%
SQV
+ NFV + 2 NARTIs1.75 logs 13483%
SQV
+ NFV1.86 logs161 69%
Another
small study looked at the anti-HIV activity of soft
gel saquinavir (Fortovase) in combination with nelfinavir.
Fourteen people with a median CD4+ cell count of 327
and a viral load of about 40,000 copies of HIV RNA received
1200 mg three times daily of saquinavir and 750 mg three
times daily of nelfinavir. After 11 months of the study,
there was a median increase of 172 CD4+ cells and a
viral load drop of 2.23 logs. About 90% of the participants
had viral loads below 500 copies of HIV RNA. Preliminary
results from a small study shows that the combination
of nelfinavir + ritonavir has potent anti-HIV activity.
Twenty people with a median CD4+ cell count of about
330 and a viral load of 33,000 copies of HIV RNA received
400 mg twice a day of ritonavir and either 500 mg or
750 mg twice a day of nelfinavir.
There
were no differences between the two nelfinavir doses
in antiviral response. After 12 weeks of the study,
there was a 2 log reduction in viral load and over a
hundred CD4+ cell increase. About 70% of the participants
had viral loads below 400 copies of HIV RNA. Almost
half of the participants had mild to moderate diarrhea.
Some
preliminary results suggest that it may be possible
to recycle drugs in order to put together a combination
regimen. Twelve people who had failed regimens containing
all the NARTIs and three protease inhibitors (saquinavir,
indinavir and ritonavir) went on a 6 drug regimen consisting
of d4T + 3TC + ddI + nevirapine (Viramune) + nelfinavir
+ hard gel saquinavir (Invirase). Only nelfinavir and
nevirapine were drugs new to the participants and all
the others were ‘recycled’. After 12 weeks
of the 6-drug regimen, 9 of the 12 participants had
viral loads below 400 copies of HIV RNA and most had
an increase in CD4+ cells (between 30 and 220 cells).
Preliminary
results show that the antiviral activity of nelfinavir
taken either twice daily or three times daily is similar.
Two hundred and forty-one people with an average of
about 100,000 copies of HIV RNA received d4T + 3TC and
either the approved dose of nelfinavir (750 mg three
times a day) or750 mg, 1000 mg or 1250 mg of nelfinavir
all taken twice a day. All of the participants who received
either 750 mg or 1000 mg twice daily were subsequently
dose escalated to receive the 1250 mg twice daily dose.
The results after 32 weeks of the study were as follows:
Viral
load dropCD4+ cell increases % below 400 copies HIV
RNA
NFV
three times daily2.3 logs 15075
NFV
twice daily2.2 logs17075
Diarrhea
and nausea were the most commonly reported side effects
although they were not different between the two groups.
Similarly,
preliminary results show the antiviral activity of indinavir
taken either twice daily or three times daily are similar.
Eighty-seven people with a average CD4+ cell count of
about 275, a viral load of about 50,000 copies of HIV
RNA and
who
had not previously taken 3TC or a protease inhibitor
received
AZT + 3TC + indinavir (800 mg three times daily, 1000
mg
twice daily or 1200 mg twice daily). The results after
32
weeks
of the study were as follows:
Viral
load dropCD4+ cell increases % below 500 copies HIV
RNA%
below
50 copies HIV RNA
800
mg IDV1 log150 50%40%
1000
mg IDV2 logs50 70%60%
1200
mg IDV2 logs50 70%60%
The
side effects were similar between the three groups.
The most commonly reported side effect was nausea/vomiting.
A study comparing the old formulation of hard gel saquinavir
(Invirase) to the new soft gel formulation (Fortovase)
shows that the new formulation has significantly better
antiviral activity compared to the old version. One
hundred and seventy-one people with an average CD4+
cell count of about 420 and a viral load of 63,000 copies
HIV RNA received either hard gel saquinavir (600 mg
three times daily) or soft gel saquinavir (1200 mg three
times daily) in combination with 2 NARTIs. After 16
weeks of the study everybody received soft gel saquinavir.
The results after 16 weeks of the study were as follows:
Viral
load dropCD4+ cell change % below 400 copies HIV RNA%
below
50copies HIV RNA
Hard
gel SQV1.8 logs11543%47%
Soft
gel SQV2.5 logs9780%28%
There
was a higher incidence of gastrointestinal; side effects
among people receiving soft gel saquinavir compared
to hard gel saquinavir.
Preliminary
results from a small study a show that there is no difference
in antiviral activity between two triple drug regimens.
One hundred people with a mean viral load of about 35,000
copies of HIV RNA and a CD4+ cell count of 400 received
either AZT + 3TC + indinavir or d4T + 3TC + indinavir.
After 24 weeks of the study, the results were as follows:
Viral
load dropCD4+ cell change % below 500 copies HIV RNA
AZT
+ 3TC + IDV1.6 logs14580%
d4T
+ 3TC + IDV1.9 logs17085%
There
were no differences in side effects between the two
groups. The most commonly reported side effects included
increases in bilirubin levels and elevated liver enzymes.
Another
small study also shows no difference in antiviral activity
between two triple drug regimens. One hundred people
with a mean viral load of about 30,000 copies of HIV
RNA and a CD4+ cell count of about 450 received either
AZT + 3TC + IDV or d4T + ddI + IDV. After 24 weeks of
the study, the results were as follows:
Viral
load dropCD4+ cell change % below 500 copies HIV RNA
AZT
+ 3TC + IDV1.6 logs14575%
d4T
+ ddI + IDV1.6 logs21070%
There
were no differences in side effects between the two
groups. The most commonly reported side effects were
nausea and vomiting.
There
were several reports of lipodystrophy (changes in fat
distribution) after long-term protease inhibitor therapy.
Although there were reports of this phenomenon, there
were no answers as to the cause. One study found that
11% of people developed protease paunch and that it
was more common in older people and those who were on
prolonged antiviral medications. Another study found
that lipodystrophy affected 64% of people on protease
inhibitors. All areas (face arms, legs) except the abdomen
were affected. This study also noted that the median
time to onset of lipodystrophy was about 10 months.
The
overall U.S.-based decline in the rate of disease progression
and mortality over the past year has been one of the
more encouraging themes of this meeting. Data have been
presented in several formats including lectures, slide
presentations, and posters heralding the dramatic decreases
in the rates of AIDS defining illnesses and death. However,
in many of these presentations, the disparity in benefit
based on race/ethnicity, risk behaviors, and sometimes
gender is alarming. This disparity has been consistently
linked to lack
of
access to therapies, appropriate health care and a physician
experienced in treating HIV. Studies conducted in New
York and British Columbia both reported on lack of survival
benefit seen in the injecting drug user (IDU) population
probably attributable to these issues and possible physician
bias perhaps driven by adherence concerns. The Women’s
Interagency HIV Study (WIHS) reported on viral load
and other factors associated with survival in women
enrolled in this study between 10/94 and 10/95. Based
on the 249 deaths, WIHS found that CD4+ cell count and
viral load were the strongest predictors of survival.
There was a trend toward CD4+cells being better predictors
of survival than viral load when CD4+ cell counts were
less than 50 (this has been seen in other studies as
well). This study did show that the risk of death increased
considerably when viral load was greater than 100,000
and even more when over 500,000.
Although
a few posters demonstrated improvement in survival pre-HAART
(highly active antiretroviral therapy), the most dramatic
and universal increase in survival benefit has been
shown since the approval of protease inhibitors and
initiation of triple combination therapy recommendations.
Epidemiological studies asked the question of whether
this change is due to previously foreseen reductions
in the infection rate from several years ago or whether
it is a true reflection of therapy. Without exception,
these studies concluded that the improvement in survival
was above and beyond anything that could have been attributed
to earlier changes in the infection rate. One presentation
reported data from the Adult Spectrum of Disease Project
which found an 86% decrease in the risk of death for
persons on triple combination therapy as compared to
those on no anti-HIV therapy at all. The design of this
study automatically accounted for any changes due to
changes in the infection rate, and thus showed a true
picture of the benefit of therapy. The same study found
that for individuals on antiretroviral therapy, there
was a 20% decreased risk of death
for
those using PCP preventative therapy and a 27% decreased
risk of death for those using MAC prevention as compared
to individuals who did not use these preventative treatments.
Several
posters reported studies showing significant decreases
in the rates of opportunistic infections (OIs) and other
AIDS defining illnesses since HAART. A study from British
Columbia looked at 2533 AIDS-free, HIV-positive participants
from 1/1/94 to 12/31/96 to assess the incidence of primary
AIDS defining illnesses. In this 3 year period, 344
participants developed their first AIDS defining illness.
The most common primary illnesses were PCP and KS. In
this study, the incidence of first AIDS defining illness
peaked in 1994 at .80 cases per 1000 participants, and
declined to .22 cases per 1000 participants in 1996.
Overall, the number of primary AIDS cases declined at
a rate of 18 per 1000 every 6 months from 1/94 to 12/96.
It should be noted in this study that the various AIDS
defining illnesses and the level of immunosuppression
at which they occur did not change substantially despite
overall decline in incidence.
Another
study, conducted at San Francisco General Hospital,
also found a dramatic decrease in the incidence of specific
OI’s between 1994 and 1997. This study reported
a reduction of the incidence of PCP from 224 cases in
1994 to 64 cases in 1997, a 71.4% decrease. CMV retinitis:
48 cases in 1994, 3 cases in 1997, 93.8% decrease; Culture
positive MAC: 165 cases in 1994, 27 cases in 1997, 83.6%
decrease; and Culture positive Cryptococcal meningitis:
27 cases in 1994, 10 cases in 1997,63% decrease.
A
similar study from the Tulane School of Public Health
at Louisiana State University tracked the experiences
of 1181 people with advanced disease in an 18 month
period just before the availability of protease inhibitors
and for 1284 people for 18 months after the new drug
combinations became available. All participants in the
retrospective study had fewer than 200 CD4+ cells at
the time of their entry. The statistically significant
differences in rates of specific opportunistic infections
were as follows:
Event18
months prior to Protease combinations18 months post
protease combinations
PCP
18.0%11.7%
Wasting9.5%4.8%
KS4.3%2.5%
MAC8.5%6.0%
CMV4.6%3.0
Treatment
in the 18 month "prior" consisted primarily
of nucleoside monotherapy and nucleoside dual combination
therapy, plus typical prophylactic regimens. This period,
therefore, is likely to reflect a considerable initial
improvement over untreated disease progression. Additional
improvements were seen in "post protease"
period for other opportunistic conditions, including
toxoplasmosis, dementia, candida, cryptoccocal meningitis
and crptosporidium, but these effects were not statistically
significant due to the small number of incidences overall
in both groups.
Although
these improvements overall were impressive, they may
not yet reflect the best possible outcomes of protease
combination therapy since they were collated during
the first 18 months of the use of the new drugs. This
period often did not reflect optimal therapy do to a
lack of initial information about the most potent combinations
and the delayed availability of some compounds.
HPV
and AIDS-Related Cancers
Human
Papillomavirus (HPV) is a sexually transmitted virus
that causes genital warts and has long been associated
with both anal and cervical cancer.
Apparently
93% of anogenital tumors in women, and 65% in men, are
positive for HPV DNA. 60-90% of sexually active women
less than 20 years old test positive for HPV DNA. The
importance of regular monitoring and preventative measures
can not be overstated. Fortunately, these cancers can
be prevented in most cases with early detection via
anal and vaginal Pap smears. For men who have sex with
men, anal Pap smears should be considered. Although
the risk of progression to cancer in both men and women
does not appear to be greater in HIV-infected persons,
this may change as people live longer.
Perinatal
Transmission
Perinatal
transmission of HIV from mother to infant has decreased
dramatically, although the precise time of infection,
vehicle for transmission, and predictors of risk are
not fully understood. A seminar on the advances in perinatal
transmission reviewed data from Pediatric AIDS Clinical
Trials Group (PACTG) 076 and 185, in addition to data
from other sources, to provide a comprehensive overview
of this issue. In recent studies, the transmission rate
for women who use no antiretroviral treatment is 20-32%
as compared to 3-5% for those who use AZT. Use of triple
combination regimens during pregnancy were discussed
on two posters, both suggesting that combination therapy
is generally well-tolerated (in this case AZT/3TC/nevirapine
and d4T/3TC/nevirapine) in pregnant women. The most
common side effect seen in the newborns was transient
anemia.
Risk
of transmission does appear to be linked to viral load
levels, however there has not been a threshold level
identified below which transmission does not occur.
Lower is still better. One study showed that maternal
viral load is a poor predictor of risk of transmission
in the presence of antiretroviral treatment. This same
study maintains that the rate of transmission for women
with a viral load less than 2,000 is about 5% in both
treated and untreated women.
In
PACTG 185, risk factors not associated with transmission
were: mode of delivery (vaginal or cesarean), duration
of membrane rupture, gestational age, birth weight,
or duration of prior use of AZT. In addition, risk of
transmission does not appear to be affected by mode
of delivery (13% for vaginal delivery, 17% for cesarean
in untreated women) but rather by treatment (5% transmission
in treated women regardless of mode of delivery).
Pediatric
Studies
The
use of double and triple combination regimens in children
showed a variety of results. PACTG 300 demonstrated
that AZT + 3TC was significantly better than ddI monotherpay
in both disease progression and survival. The combination
produced rapid decreases in viral load, increases in
CD4+ cell counts,
and
more rapid increases in weight and height for age than
ddI alone. Several studies using protease inhibitors
in children also showed a variety of results. One poster
reported about an 18% rate in kidney stones in children
using both 350mg and 500mg doses of indinavir. Another
poster stated that long-term combination treatment with
indinavir is limited by difficulty adhering to the regimen,
intolerance to the drug, and toxicities. However, even
children who are antiretroviral experienced may derive
beneficial effects on surrogate markers which persist
for one year or longer. Nelfinavir combinations seem
to be well-tolerated, but also limited in their duration
of effect, as were ritonavir combos.
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Project
Inform (New Address) 205 13th Street, #2001
San Francisco, CA 94103 Treatment Hotline: 800-822-7422
(toll-free) or 415-558-9051 (in the San Francisco Bay
Area and internationally) Hotline hours: Monday—Friday,
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web@projinf.org
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Update
February
1st Summary
DT
980202
SO Project Inform; Monday, February 2, 1998
TX
Researchers from around the world have converged in
Chicago, Illinois, for the 5th Conference on Retroviruses
and Opportunistic Infections, being held February 1st
through 5th at the Sheraton Hotel. Unlike last year's
conference, which began with a flurry of activist activity
as clinicians, researchers and activists alike arrived
at the conference only to be turned away and barred
entry due to space limitation, this year's event welcomed
all who applied for registration and thus far no one
has been turned away. Presentations by two distinguished
professors opened the five day conference, which has
come to be known as one of the most important AIDS conferences
of the year. This year's honored speakers included Dr.
Ashley Haase, from the University of Minnesota, Minneapolis/St.
Paul campus and Nobel Laureate Dr. David Baltimore,
from CalTech in Pasadena, California. Dr. Haase's presentation
was titled The Measure of Reality, and overviewed what
we know about tissue reservoirs of HIV and the impact
of anti-HIV therapy on these hiding places of the virus.
Dr.
Baltimore spoke on the issues of preventative vaccine
development, the urgent public health need for an HIV
vaccine and the challenges facing the scientific community
in this regard. To the average person living with HIV,
a discussion of tissue reservoirs of the virus may seem
like an esoteric discussion, academic in nature and
not understandably relevant to decision-making with
regard to HIV treatment. Over the past year, however,
with the broader availability and use of potent triple-drug
antiviral regimens, increasingly there have been reports
of individual's that have achieved levels of viral suppression
to below the limit of detection of currently available
tests. Despite this suppression in HIV activity, the
virus does not appear to be eradicated from their body,
and for many people, over time, there is a re-emergence
of detectable HIV. When the virus is being suppressed
so dramatically by anti-HIV regimens, how is the infection
persisting? Where is the virus hiding? Do anti-HIV regimens
get in to and impact HIV in these hiding places? Is
the virus causing damage to immune system in these hidden
reservoirs, and can that immune damage be restored?
It has long been hoped that the blood and plasma that
is drawn from a vein in the arm represent some window
through which to evaluate the status of the immune system
and the virus. Unfortunately, at any given time it's
unlikely that anymore than 10% of cells, particularly
CD4+ cells, which are commonly measured to assess status
of immune health, are circulating in the periphery.
Similarly, the virus is drawn to deeper immune compartments
and what circulates only represents a small part of
the picture when it comes to the actual amount of virus
in a person's body. A great deal of immune system processes,
as well as the vast majority of CD4+ cells, centralize
in the lymph system. While measurements of CD4+ cell
counts, other immune parameters, and viral load, gathered
from standard blood samples are useful in understanding
general health status, levels of viral activity and
the impact of intervening with therapy, these measurements
represent an incomplete picture. Getting the snap shot
in clearer focus requires getting closer to the action,
the tissues of the lymph system and inside of individual
cells.
Dr. Haase's presentation was thus aptly titled, Measures
of Reality. How clearly we see a problem informs how
capable we are of understanding it. Moreover, if we
better understand a problem, we're better capable of
coming up with strategies for dealing with it. Rather
than simply measuring the immunologic and virology reality
of what's happening in the periphery, Dr. Haase and
others have developed and studied techniques to look
not only at lymph tissue, but what's happening on a
single-cell level. His and other's work have shown that
the amount of virus in the lymph nodes is significantly
higher than what is measured in the blood. In looking
at the lymph nodes, the vast majority of virus is not
inside of cells, nor is it being actively produced.
Instead, the majority of HIV is lodged in a network
of immune cells, called follicular dendritic cells (FDC),
which center in the lymph node and act as a clearing
house to capture infectious agents circulating through
the blood stream. Dr Haase notes that, without treatment,
the amount of virus caught in this FDC network is 10
to 40 fold higher than the amount of virus lurking inside
of individual immune cells, and 100 to 1000 fold higher
than the amount of virus measured in the blood/plasma.
Dr.
Fauci, who is the Director of the National Institute's
of Allergy and Infectious Diseases, and others have
previously shown that the FDC network, important in
immune processes which allow the immune system to fight
diseases, becomes damaged and destroyed throughout the
course of HIV infection. This damage is likely due to
the centralization of virus in the FDC network and the
chemicals released when the immune system battles the
virus that is harbored there. Dr. Haase presented data
from a study of HIV+ individuals receiving AZT (zidovudine,
Retrovir) + 3TC (lamivudine, Epivir) + ritonavir (Norvir).
Serial lymph node biopsies were conducted and the tissue,
structure and cells in the lymph nodes were examined.
Use of potent anti-HIV therapy resulted in a dramatic
and rapid decrease in the amount of HIV caught in the
FDC network. After 3 weeks of therapy, viral levels
in the blood had dropped to below the limit of detection,
yet in the lymphnodes there was a group of cells that
still contained HIV RNA. In other words, even though
HIV RNA outside of cells had fallen to undetectable
levels, the virus persisted, hidden inside of individual
cells.
However,
separate studies have shown that within two to six months
of initiating a potent anti-HIV therapy regimen, damage
to the FDC network appears to be reversing itself and
the network shows visible signs of repair. In Dr. Haase's
study, at 6 months after therapy, the pool of virus
trapped in the FDC network had decreased farther and
was typically undetectable. In some cases, the cells
previously containing HIV RNA were now free of detectable
virus. In some, these cells remained free of detectable
virus at 1 year. If the virus is at near undetectable
levels in the periphery and signs of viral control and
immune recovery are noted both in the periphery and
the lymph nodes, where is the virus hiding? How is it
that HIV has not been eradicated entirely and how is
it that many people see a re-emergence of HIV levels?
Where is the virus coming from? Like others who have
published on this matter, Dr. Haase supposes that inactivated
or latent T cells, or possibly other cells, might harbor
very very low levels of HIV and that these cells may
be enough to rekindle the fires of HIV infection. Project
Inform (New Address) 205 13th Street, #2001 San Francisco,
CA 94103 Treatment Hotline: 800-822-7422 (toll-free)
or 415-558-9051 (in the San Francisco Bay Area and internationally)
Hotline hours: Monday-Friday, 9am-5pm and Saturday,
10am-4pm (Pacific Time) Office Telephone: Fax: E-mail:
WWW: 415-558-8669 415-558-0684 web@projinf.org http://www.projinf.org
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