DOCTOR FAX
ISSUE 8
Sourced Compiled and Edited by Paul Blanchard
Medical Advisor - Dr Graeme Moyle,
Chelsea & Westminster Hospital.
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Highlights from the 36th ICAAC - Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (New Orleans 15-18 September 1996)
Antiretroviral Combination Therapy and Opportunistic Infection Management
Constance Benson, MD, of Rush Medical College in Chicago, and Mark Jacobson, MD, of
the University of California, San Francisco, warned that the several-hundred-cell increases sometimes achieved with potent anti-HIV
combinations should not make clinicians think their patients have been lifted above the OI danger zone.
Once a person's CD4+ count has fallen to around 50 cells/mm3, Jacobson said, the repertoire
of infection-fighting cells is usually so depleted that merely expanding the number of cells does not necessarily protect
against opportunists. He cited cases in which CD4+ counts climbed from 50 to above 200 cells/mm3 in patients who then succumbed
to CMV end-organ disease.
The two panellists speculated that if memory T-cells for a particular pathogen have
already been lost, the increase in CD4 cells in response to combination therapy is not protective, at least not initially. However,
patients with a less depleted repertoire of cells may fare better. Dr Jacobson commented that if combination therapy can prevent
CD4 cell counts falling below 100 per microliter, patients may be protected indefinitely against the late opportunistic infections.
Both Benson and Jacobson stressed, however, that all patients, no matter how low their
CD4+ count, should be treated with combinations including a protease inhibitor. Such therapy is "imperative," said Jacobson,
unless a person cannot tolerate the drugs or all possible combinations have failed. Benson said she has had patients whom one
might have given a month to live a year or two ago but who now have gone back to work taking protease inhibitor/nucleoside combinations.
Functional improvements in immune function have been reported during protease inhibitor
therapy and are evidenced by improved survival and delay in disease progression reported in 2 studies, including Abbotts 245 study in persons with an average baseline CD4 count of 30/. However, most physicians
now agree that therapy should aim to keep CD4 counts above 200/mm3 for as long as possible to maintain immune integrity. In the future, immune modulators,
such as IL-2, may be used to expand the immune repertoire in persons with low CD4 counts. Most UK physicians encourage patients
to remain on PCP prophylaxis until CD4 rises on therapy to levels consistently above 300/ mm3, however no data are available to support this decision.
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Combination use of Ritonavir and Saquinavir in HIV-Infected Patients Reduces Viral Load by 99.9 %.
Data on safety and efficacy out to 12 weeks were presented at the meeting for this
combination of two protease inhibitors.
HIV viral load was reduced by 99.9 percent (2.97 logs) with a combination of two protease
inhibitors, Abbott Laboratories' ritonavir (NorvirTM) and Hoffmann-La Roche's saquinavir mesylate (InviraseTM), according to new data presented at the 36th ICAAC. This represents an even greater
reduction in the amount of HIV RNA than was seen in this study after six weeks, at which time viral load was reduced by 99.6
percent (2.4 logs).
"These data demonstrate not only the continued antiviral effect of this combination
of two protease inhibitors, but also the enhanced activity of the combination over time," said investigator Calvin J. Cohen, M.D.
of Community Research Initiative, New England.
The 12 week data presented today come from the first-ever study to examine the safety
and efficacy of a combination of two protease inhibitors. The effect on disease progression and survival is unknown. Six week
results from this trial were presented in July at the XI International AIDS Conference.
The multicenter, open-label study randomised approximately 136 patients to one of
four different treatment arms. All patients had baseline CD4 cell counts of 100 - 500 prior to beginning the treatment regimens,
and none had previous exposure to protease inhibitors.
In the first two treatment arms, patients received either 400 mg ritonavir plus 400
mg saquinavir twice daily or 600 mg ritonavir plus 400 mg saquinavir twice daily. After 12 weeks of treatment (n=53), the median
viral RNA level declined 99.9 percent (2.97 logs), and the median CD4 cell count increased by 95 cells. The changes in these
two treatment arms were similar.
In the third and fourth treatment arms, patients received 400 mg of ritonavir plus
400 mg saquinavir three times a day or 600 mg ritonavir plus 600 mg saquinavir twice daily. After six weeks of treatment (n=39),
the median viral RNA level dropped by 99.3 percent (2.14 logs), and the median CD4 cell count increased by 75 cells. Again,
the changes in the two treatment groups were similar.
"The response in both of these dosing regimens demonstrates that saquinavir and ritonavir
appear to work synergistically," said Cohen. "These drugs interact in a way that clearly results in high therapeutic blood
concentrations of both agents and increased antiviral activity."
The combined regimens were generally well-tolerated, with about seven percent of patients
discontinuing. Most of these patients were in the three times daily 400mg ritonavir/ 400 mg saquinavir regimen. Continuation
of this treatment arm is under review. Tingling around the mouth, diarrhoea, fatigue and nausea, the most commonly reported
adverse events, were generally mild and transient in nature. Since ritonavir interacts with some drugs when taken together, patients
should discuss use of other medications with their doctor.
The Community Research Initiative of New England (CRI/New England)is a non-profit
agency that sponsors community-based research on HIV and AIDS. It was created in 1989 by people with HIV and their physicians,
and researchers, activists and other health care providers.
There are no studies currently running in the UK to examine combinations of protease
inhibitors although the MRC are planning such a study. At present this combination has only been used by a small number of UK
patients, mostly those with intolerance to nucleoside analogues or consistently elevated viral load despite double or triple combination
therapy.
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Further Data on Interleukin-2
Dr H Clifford Lane, Director of the Office of Clinical Research at NIAID, discussed
the latest information on the use of IL-2 to boost CD4 cell production in HIV-infected patients.
Dr Lane said that IL-2 therapy results in an expansion of the T-cell population that
exists at the point of initiation of therapy, but with a slight preferential increase in naive over memory T-cells. Over time,
he commented, ...you see more diversity in the repertoire.
From 1991 to 1993, Dr. Lane studied intermittent IL-2 stimulation in 10 patients.
They showed at least a 50% increase in T-cell count. The patients are now out more than 4 years and are still showing an elevated
count from the baseline level. Some are above 1,000 cells per microliter, and one patient has discontinued antiretroviral therapy
of his own choosing.
Two-year data from a randomised trial show that the median count continues to rise
in about 30 patients treated with IL-2. Dr. Lane said that in the study thus far there have been a total of seven opportunistic
infections -- five in the control group, two in the IL-2 group. Although the data are limited, opportunistic infections have been
occurring at the expected CD4 count.
In a separate study it was shown that CD4 levels can be maintained with an IL-2/Indinavir
combination in HIV-infected patients.
Combination treatment with interleukin-2 and indinavir can help sustain CD4+ T-cell
counts in HIV-positive patients, according to Dr. Judith Falloon of the NIAID and colleagues.
Dr. Falloon examined the combined effects of treatment with indinavir, a HIV protease
inhibitor associated with substantial decreases in viral burden and stabilisation of CD4 counts, and IL-2 therapy, which is
associated with sustained increases in CD4 counts. The subjects under study had CD4 counts of less than 300 or had been in other
IL-2 trials.
Dr. Falloon randomly assigned the patients to one of three regimens -- two regimens
containing combination IL-2 and indinavir -- and one regimen containing indinavir alone. At follow-up, she found that HIV RNA
levels were comparable for all subjects. However, CD4 levels declined in the patients receiving indinavir alone compared with the
patients receiving a combination regimen.
Mean CD4 counts increased with combination IL-2 and indinavir treatment over a 1-year
period compared with baseline measurements, while viral burden was suppressed. "This combination permits the extension of IL-2
therapy to a lower CD4 count group and should prove to be useful in the design of an efficacy trial for IL-2," Dr. Falloon concluded.
Comment - previously patients with CD4 less than 200 had been shown to respond poorly
to IL-2 therapy with non-responsiveness in CD4 count and increases in viral load. This study suggests that adequate suppression
of viral replication will allow patients with CD4 counts below 200.to consider IL-2 therapy. A small access supply of IL-2 is
available via Chiron (UK) at around 350 per infusion. In general it is advised that patients with low CD4 counts should
achieve below detectable viral loads before considering IL-2
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KS herpesvirus in saliva.
Kaposi's sarcoma-associated herpesvirus (KSHV) was found in the saliva of 17 of 23
HIV-positive KS-positive persons, reported David Koelle, MD, of the University of Washington in Seattle. The herpesvirus also turned
up in the saliva of one HIV-negative KS-positive individual, in two of 17 HIV-positive KS-negative persons, and in no HIV-negative
KS-negative volunteers. Salivary viral shedding persisted over a five-day sampling period. The findings suggest that the
oropharynx could be a route of KSHV transmission and site of replication, according Koelle, but so far it is not clear whether
the isolated virus is infectious. Confirmation of an oropharyngeal route would undermine the epidemiologically based assumption
that anal intercourse is the principal path of KS transmission.
HIV is also detectable in saliva but not in amounts sufficient for cross infection.
Detectability of KSHV in saliva does not mean it is transmissable via the oral route. Epidemiological studies of KS suggest the
major route of transmission to be sexual.
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Studies on Cytomegalovirus (CMV) Disease
Cytomegalovirus resistance to ganciclovir may be more common than previously thought,
according to Dr. I. L. Smith of the University of California at San Diego. In addition, the "....clinical failure of CMV retinitis
treatment is frequently associated with the development of ganciclovir resistance."
Dr. Smith's group evaluated 40 AIDS patients who were treated with intravenous ganciclovir
for CMV retinitis. The UCSD clinicians examined susceptibilities of CMV isolates from 17 patients and found ganciclovir
resistance in 53% of the patients with positive CMV cultures. And Dr. Smith observed an overall resistance of "..at least 40%..."
in these patients. "Cross-resistance to cidofovir was identified in 2 of 9 ganciclovir resistant CMV isolates...[but]...foscarnet
resistance during ganciclovir treatment was not observed," Dr. Smith added.
Another California team reported that CMV does not play an in vivo cofactor role in
HIV replication. Dr. W. L. Drew of UCSF and colleagues monitored AIDS patients enrolled in a study of prophylactic ganciclovir
for CMV infection. Dr. Drew's group compared the viral load in 12 subjects receiving oral ganciclovir and 7 subjects receiving
a placebo. Oral ganciclovir was effective in suppressing CMV viral load, but this had no "...significant impact upon HIV load."
Meanwhile, Spanish investigators shared results of a CMV study that showed that "...CMV
quantitative antigenaemia is a useful tool for the diagnosis of CMV disease in AIDS patients." According to Dr. J. A. Carton
of Universidad de Oviedo in Spain, risk factors associated with CMV disease in AIDS patients included sexual transmission of
HIV, low mean CD4+ counts and a long course of AIDS. All patients with a positive CMV blood culture had antigenaemia but "...viraemia
was present in only 42% of the patients with antigenaemia," Dr. Carton reported. In addition, patients with CMV disease and
extraretinal infection tended to have a worse prognosis compared with those without extraretinal infection.
Source: Reuters Health Information Services, Inc.
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Reproduced from Project Inform Perspective #19 (September 1996) as part of AIDS Treatment
Projects endeavour to stimulate debate on standards of care and treatment strategies. Project Inform are one of the leading
treatment advocate agencies in the U.S.
Developing Long-Term Treatment Strategies
Studies of protease inhibitors and non-nucleoside reverse transcriptase inhibitors
(NNRTIs) have begun to answer key questions about the treatment of HIV infection. It is tempting to wish for precise, cook-book
style instructions, such as exactly when to start therapy, which are the best drugs to combine, and when therapy should be changed
or stopped. The history of medicine suggests that there will never be universal answers to these questions. There will always
be individual differences in how people respond to specific therapies and how aggressively people choose to fight illnesses. The
right answer for one person will not always be right for another, however similar their conditions may seem. Medicine is both
an art and a science. Physicians and patients need guidelines and general strategies, not rigid rules.
Earlier in the epidemic, loose strategies dictated by study designs were seen as "rules"
of medicine or standards of care. This led many physicians to insist that everyone with CD4+ counts below 500 be treated,
while others just as rigidly chose to wait for counts to fall below 200. We now know that both approaches are sometimes right,
sometimes wrong. People with similar CD4+ counts do not always have similar rates of disease progression or life expectancy. Studies
of viral load have given us a clearer picture of disease progression and have shown that viral markers can be more predictive
than CD4+ counts alone. Even these do not tell the whole story for every individual. With this in mind, the new International
AIDS Society guidelines for using viral load tests suggest that physicians assess multiple factors in treatment recommendations.
They do not imply a rigid formula, recognising that two physicians might easily interpret the same situation and lab markers quite
differently. There is always a need for judgement and weighing of personal factors.
A few principles are becoming clearer from the protease inhibitor studies. Factors
influencing medical strategies include what we know about managing other infectious diseases, like tuberculosis, as well as our
growing understanding of viral resistance and HIV pathogenesis. Any discussion of strategy is, and is likely to remain, a mix of
hard facts, judgement and opinion.
Several factors and beliefs underlie the general strategies proposed here. They are
an attempt to combine what has been learned in clinical trials with a core logic from the general treatment of diseases. Critics
may argue that not all of these points are the subject of hard proof, but that is not a useful criterion for evaluation. Insisting
that we know only what is considered absolutely proven is as short-sighted as pretending that we already know everything about
HIV. It is important to take what is known from clinical trials and disease pathogenesis, combine it with the beliefs and expectations
of experts and generate reasonable strategies for making treatment decisions. Some key factors and beliefs which drive
the strategies suggested here include:
Achieving long-term successful use of therapies is more important than short-term
gains
. It is possible to get short-term benefits while ignoring or wasting potential long-term
benefits.
Reducing viral load as low as possible, preferably below the level of detection with
the current tests, is the appropriate goal of anti-HIV therapy
.
Partially effective treatment is an engine which drives the development of viral resistance
. Whenever possible, treatment which reduces viral load but still permits a continuing
measurable level of viral activity should be avoided. Such treatment is bound to fail over time while leaving viral resistance
in its wake. It makes sense to try to fully suppress viral replication if this can be done with a reasonable quality of life.
When this goal cannot be achieved, people should realise they can still benefit from therapy and that longer-term solutions may
open up for them when additional therapies are available.
People who are being treated for the first time have the greatest number of options
. It is critical to think of the long-term picture when choosing from among those
options. Failure to take a long-term view can result in rapid loss of options. A strategy should provide long-term benefits from
the chosen therapies while preserving options for future use. An example of an ineffective strategy would be one which began therapy
using single drugs or modest combinations which merely reduce, but do not fully suppress viral replication.
The question of whether everyone should be treated immediately is not yet fully answered
. Many researchers argue that it is best to "hit it hard and hit it early" - an aggressive
strategy of early intervention. They believe this preserves immune function, suppresses the development of drug-resistant
viral mutations, and has the best chance of giving long-term benefits. This belief is reasonable based on knowledge of HIV biology.
Yet, others argue that the potential benefit must be balanced against unknown side effects of long-term therapy, long-term
interference with quality of life, and the risk of using up options prematurely. This last concern has diminished with recent
discoveries about slowing viral resistance and the rapid development of new therapies. An individual's ability to take the medications
correctly also impacts on this strategy. Both the "very aggressive" approach and the "less aggressive" approach can be determined
and supported as matters of reasonable personal choice. For now, neither has been proven "right" for all situations.
Lessons from treating tuberculosis tell us that it is important to change or add two
new therapies at the same time
. The rule of "change by twos" is designed to best combat the development of viral
resistance.
Just adding a protease inhibitor on top of a therapy regimen which has been used for
a few months or longer is unlikely to produce the highly potent benefits seen in clinical trials
. The best results reported in clinical studies have always come when two or more
new drugs are started together at the same time. It may be possible to achieve the necessary degree of viral suppression simply
by adding a protease inhibitor in some situations, but this produces far less consistent results than changing at least two drugs
simultaneously. It is unknown whether it is feasible to combine protease inhibitors with NNRTIs such as nevirapine and delavirdine.
Drugs and combinations of drugs which have a larger, more consistent, and longer-lasting
effect in reducing viral loads and increasing CD4+ counts are likely to produce larger and longer-lasting clinical and survival
benefits
. This has been repeatedly demonstrated in clinical studies.
Considerations When Selecting a Protease Inhibitor
The three available protease inhibitors are radically different drugs. Each has a
unique blend of activity, side effects, and drug interactions and must be selected carefully.
Only ritonavir and indinavir should be considered as first-line protease inhibitors
. Due to a formulation problem, the current version of saquinavir (InviraseÆ) is not in the same class as these two drugs. Because it is very poorly maintained
in the bloodstream, using the drug is equivalent to using a protease inhibitor at one fourth to one fifth the desired dosage.
This is likely to produce significant and negative consequences in any long-term strategy.
Indinavir has relatively few and infrequent side effects but can be complex to use
. It must be taken three times daily, one hour before or two hours after eating. This
requires people to plan their day and meals schedules around the drug. For some, this is quite intrusive. Taking indinavir with
ddI is particularly demanding because of complicating fasting schedules of both drugs.
Ritonavir is easier to use for many people but creates difficult problems of side
effects and drug interactions
. It is an easier choice for people with busy schedules because is used only twice
a day and can be taken with food. This is offset by a very high rate of initial side effects (nausea, vomiting, diarrhoea, numbness,
etc.), which can also complicate life for people, whether busy or not. Many people who chose this drug abandon it within 60
days. Ritonavir and indinavir are highly cross-resistant (resistance to one causes resistance to the other) and partially cross-resistant
to saquinavir.
Claims that there is no risk of cross-resistance between saquinavir and other protease
inhibitors are inaccurate
. Data from the manufacturers indicate that at least 15% of the people who become
resistant to saquinavir will have immediate high level resistance to indinavir and ritonavir. Anecdotal experience in the community
suggests the risk may be higher. Even when it does not result in immediate cross-resistance, saquinavir use may, in theory,
result in more rapid development of resistance to the other protease inhibitors once they are used. Of even greater concern are
data from recent studies of high doses of saquinavir which have begun to show patterns of resistance similar to those of indinavir
and ritonavir. Earlier studies suggested that saquinavir had a different pattern of resistance than other protease inhibitors.
Considerations When Selecting Nucleoside Analogues:
There are no mutations proven to cause resistance to d4T
. This does not mean, however, that the drug will not fail. But it does suggest it
is unlikely to have problems of cross-resistance.
Resistance to 3TC occurs almost universally in people who use it for 2 months or longer
(except when it is initiated along with a potent protease inhibitor). Once resistance
sets in, the drug remains useful only because the mutation which causes the resistance conversely increases the effectiveness
AZT and perhaps other nucleoside analogue drugs. Once resistance is present, 3TC loses its ability to directly produce large
reductions in viral load.
The best results from combinations using AZT, protease inhibitors and 3TC only occur
in people who initiate 3TC for the first time when they start the protease inhibitor
. In this context, suppressing viral load below the limit of detection appears to
prevent the development of resistance to 3TC. People in such studies have usually been AZT-resistant from the start. Thus, we are
seeing the activity of 3TC combining with the activity of indinavir or ritonavir. 3TC's impact on AZT is probably lost in this
context as it is based on the development of a specific 3TC mutation which no longer occurs or is greatly depressed in the presence
of indinavir or ritonavir. Such a therapy may only be acting as a 2-drug combination (protease plus 3TC). However, if indinavir
or ritonavir is simply added to an existing regimen of AZT and 3TC (where 3TC resistance is already likely), the direct antiviral
activity of 3TC may be lost due to 3TC resistance. Thus, such a combination is unlikely to give the suppression seen in the
best studies.
Quality of Life Issues
Tolerance is at least as important as the potency of a drug. If you can't take a drug
consistently as prescribed, it is irrelevant how potent it is. Whatever the cause, lack of adherence to the protocol will quickly
contribute to the development of drug-resistant mutations of HIV. When choosing a combination, consider how many total pills
must be taken each day (antivirals and everything else), when they will be taken, whether they can be taken with other medications
and whether they can or cannot be taken with food.
It is easiest to combine drugs which require similar conditions for their use (with
food, without food, etc.) Otherwise, one's life becomes quickly dominated by drug schedules. Also, it is generally best to avoid
mixing drugs with similar side effects, though sometimes this is impossible. And it is critical to learn about possible drug
interactions before mixing any of these drugs.
Quality of life might benefit if the gains from new combination therapies improve
the immune system enough to make it possible for people with advanced disease to eliminate their use of prophylactic medicines,
such as septrin or dapsone for PCP, etc. But current clinical experience suggests this represents an unwarranted risk-for now, prophylaxis
must be maintained.
Commentary
Ideal combination strategies call for the use of fresh new drugs started at the same
time. This is readily achievable for people beginning therapy for the first time. It is far more difficult for those who have
used many therapies. Existing therapies can sometimes be juggled to achieve the desired effect. At other times, this is impossible.
For some people, the best choice might be to delay using protease inhibitors or other new therapies until there are enough
new drugs available to initiate an ideal combination. For most people, such a moment is seldom more than a year away. Several new
therapies are on the near horizon which should make this possible. But getting there will require some people to resist the instinct
to jump to each new drug as soon as it is available. Those who have fresh combinations at hand needn't hesitate to use them.
Those who don't must consider the long-term implications of choices they make today. This shift toward long-term thinking is
the true hallmark of this second decade of anti-HIV therapy. It must become a part of everyone's thinking. The alternative is the
perpetuation of the short-term benefits and long-term failures characteristic of the last decade's approach to therapy.
All of this emphasises the importance of a recent study which showed that people who
received their medical care from physicians with a great deal of experience treating HIV infection actually lived longer than
those who saw less experienced physicians. The complexity of treating AIDS has changed dramatically in the last year and the demands
on the knowledge of physicians have increased proportionally. Whatever medical strategy a person chooses, it should begin
with finding a physician who is experienced in treating HIV and who is wise enough to continue studying and learning from new developments
in AIDS research.
From Project Inform, for more information contact the Project Inform Hotline, 800-822-7422.
(Toll free USA only) Project Inform, established in 1985 as a national, non-profit, community-based HIV/AIDS treatment
information and advocacy organisation, serves HIV-infected individuals, their caregivers, and their healthcare and service providers.
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