Vitamin B12 and Cognitive Impairment
Return to Contents
|
TREATMENT STRATEGIES
|
New Realism over Treatment Effects Hits U.S.
Recent conference presentations including those at Hamburg and ICAAC, as well as new
data on elimination of HIV to be published in Science, has led to a reassessment of previously overly optimistic
views on the limitations of currently available antiretroviral drugs.
Reports of treatment failure in the real-world (see DocFax 32, Deeks data from ICAAC), and new data extending the theoretical estimated
time to elimination (see this issue) has led to a wave of articles expressing a new realism of adjusted
expectations of treatment effects. This issue of AIDS Treatment Projects Doctor Fax includes further reports from ICAAC and the
Sixth European Conference on Clinical Aspects of HIV-Infection held in Hamburg, as well as reflections on the new data from leading
treatment activists in the U.S.
Return to Contents
Treatment Failure in the "Real World"
Media reports from the recent ICAAC conference in Toronto are beginning to focus on
the evidence of "drug failure" being reported at San Francisco General and a few other sites. Just as earlier media reports made
the protease inhibitors sound like a cure and invited excess optimism, the new reports tend to make the drugs sound like a complete
failure and invite undue pessimism. The truth, as always, is not to be found in either extreme.
Steven Deeks at San Francisco General Hospital (SFGH) is reporting that some 53% of
his patients (in a group of 136) have now "failed" on protease inhibitors. This number apparently includes some that never responded
in the first place, as well as a majority who responded initially but has now seen a return of detectable virus. In contrast,
some other researchers at the same meeting in Toronto reported that they were seeing surprisingly high rates of continued success,
often beyond their expectations.
Even at its worst, this data is not unexpected. Those who have paid attention have
known all along that the current drugs are not a cure, even in the best of circumstances. Weve known all along that they work much better in people who are just beginning treatment
as compared to those who have been using therapy for years. It is obvious that this should be the case since people who have
extensive prior treatment experience are almost certainly resistant to at least some of the medications they are using. Weve also known that the drugs presented difficult challenges of adherence and any significant
deviation from the prescribed program could contribute to hastened drug resistance. And it has been clear from the beginning
that toxicity could interfere with peoples ability to use the drugs properly.
Considering all these things, its actually surprising that the drugs have held up as well as they have in so many
people. It remains an undisputed fact that they have reduced the death and disease rates dramatically, as virtually any HIV treatment
centre can confirm. By any standard, they remain far superior to anything that has come before.
What is Meant by "Treatment Failure?"
Before everyone gets unduly depressed about imminent drug "failure," its important to take a careful look at how "failure" is defined in these studies. In
the Deeks/SFGH study, "failure" simply means that a person using the drugs has either continuing or reappearing measurable viral
replication. In other words, 53% either failed to become "undetectable" in the first place, or they initially became "undetectable"
but have since seen some return of measurable viral load. This is a very narrow and perhaps misleading definition of "failure,"
especially when it is accompanied by record low rates of new opportunistic infections and death. "Failure" here makes no
distinction between someone whose viral reached 800 and another whose viral load soared to 8 million. It also doesnt tell us whether the patient was later able to go on to some different or more aggressive
therapy that brought viral replication back under control. And it tells us nothing about the patients actual clinical condition.
Its very unclear just what the clinical consequence is of seeing a return to measurable
viral load. A good deal of evidence already suggests that it is unlikely to be accompanied by an immediate return of clinical
symptoms or a loss of the improvement experienced in measures of immunity. It just means that the viral load has moved above a
certain arbitrary threshold.
One might also ask whether there is anything different or unique about the SFGH cohort.
For example, it would be important to know what percentage of the people in the study began their first use of a protease
inhibitor with saquinavir back in 1995. A separate study presented at ICAAC reports that prior use of saquinavir is the clearest
predictor of failure for people using indinavir. We also know that most patients in most of the SFGH clinics were at least briefly
put on full dose ritonavir back in March of 1996. Almost all switched to something else within the next two months because of
toxicity, which was also contributing to serious levels of non-adherence. Also unclear is whether the population at SFGH is different
from the average HIV positive population were those in Dr. Deeks cohort more or less likely to be treatment na ve? Is there any reason to believe they were more or less likely to adhere to treatment
requirements? Were they more or less likely to get all the care they need and able to see their medical support team often
enough to support full adherence? We dont know the answers to these questions, but they could all affect the "failure" rate.
We do know, however, that Dr. Deeks has acknowledged that many of the people experiencing drug "failure" had had difficulties
with adherence.
We also know the answer to some general questions about treatment failure and resistance
from data reported at the Resistance meeting in the summer of 97 in Florida. Essentially, it showed that if people achieved "undetectable" levels
of virus on the new super-sensitive assays (measuring down to 50 or 20 copies), then they would be very likely to have a long
and successful run on their treatment regimen, probably measured in years. In contrast, those who never reached "undetectable" in
the first place or, surprisingly, even those who only reached it on the standard viral load tests at the limit of 500 copies,
were very likely to experience rising viral load on their regimen with 6 to 12 months. The ability to reach "undetectable" status
on either version of the test was greatly affected by the patients baseline viral load. If it was low to begin with, it was easy to keep it undetectable
for long periods. The higher it was at the start, the tougher it was to reach "undetectable" status.
What does all this mean to people who are counting on these drugs to give them hope
of a future? A few questions many people find themselves facing, and a few possible answers:
Im doing OK for now, but does this mean that I am doomed to see my drugs fail? How
soon?
No treatment yet known for HIV disease is likely to last for a normal lifetime. Until
we can completely suppress viral replication, drug resistance is still likely to contribute to treatment failure over time.
How long it can be suppressed is anybodys guess. When people achieve undetectable levels on the new super-sensitive assays,
the durability of treatment is greatly enhanced. People concerned about their own situations might check around to see if they
can get access to the super-sensitive test. But for some, this may not be necessary. Recent research suggests that if people go
for a year or longer at the "undetectable" level on the standard test, its very likely they are also "undetectable" on the super-sensitive test. Otherwise,
they are likely to have failed within the first year.
Whats going to happen when the drugs fail?
We really dont know. We dont know what it means when measurable viral load returns or how quickly the immune
system might be compromised again. Even if we assume that all possible options have been tried without success, and no new drugs
bring viral load under control, its not at all clear that people will simply slide downhill clinically. As a general
rule, we already know that this is not happening, since the levels of return of clinical illness and new OIs are nowhere near as high as the reported incidence of "treatment failure." There
is plenty of evidence that even temporary success in suppressing viral load can lead to useful levels of immune restoration. In
fact, many researchers report being pleasantly surprised by the degree of renewed immune response being seen. The longer suppression
is maintained, the larger this response seems to be. Whatever the gains, they seem unlikely to disappear overnight, perhaps
thus providing a cushion of time while awaiting new and better therapies.
Some virologists also believe that the highly mutated form of virus that evolves to
escape the drugs is in many ways not as "fit" or destructive as the original, "wild type" virus that most people started off with.
In other words, the virus has to pay a price, perhaps a high price, for accumulating all those mutations along the way. It
may still be capable of replicating, but it may be diminished in other ways, such as its ability to damage the immune system. At
worst, things would only be back to where they were before the advent of the protease inhibitors, with new treatments on the way.
When these drugs fail, will anything else help?
Yes, there is reasonable hope that other things may help. First, we neednt always think of resistance as a simple, on-off thing. It comes in degrees ranging
from high level, which will completely cripple a drug, to low level, which might only require changes in dosage or companion drugs.
Some degrees of resistance might be modest enough to be overcome by a quick change to more aggressive therapy, such as dual
protease inhibitors or combining protease inhibitors with newer non-nucleoside RT inhibitors (nevirapine, delavirdine, DMP-266).
Sometimes resistance can be overcome simply by finding any two or more new, highly potent drugs that arent cross-resistant. And some times, viral load only reappears temporarily, then becomes
undetectable again probably in response to some secondary infection.
Beyond these points, there are a number of new drugs coming, some of which might be
useful despite current resistance. For example, one new protease inhibitor in early clinical trials from is very different from
all current protease inhibitors and offers the potential of being active despite resistance to the earlier drugs. Also, several
new classes of drugs are now in clinical trials. These include T-20 (a fusion inhibitor), integrase inhibitors, zinc-finger inhibitors,
etc. Some new research is also re-emphasising the potential of hydroxyurea. Of course, theres also the whole field of immune restoration to look to.
One important ray of hope came from another study presented at the ICAAC meeting.
It showed that, although the longest duration of success came with "undetectable" viral levels, this goal was not essential for
preventing short-term progression to AIDS. Instead, this study suggested that the ability to prevent short-term progression simply
depended on lowering the viral low and keeping it below baseline.
Is there a bottom line here?
If so, its to re-emphasise the critical importance of adherence and using therapy aggressively
enough to fully suppress viral replication. This is the only proven way to get the greatest possible benefit from the available
therapies. Another bottom line is to re-state the importance of the principles of prevention, which have sometimes been left
on the sidelines in the wake of talk about "undetectable virus." Perhaps this new public discussion will encourage people and the
media to take a more realistic look at where we are in the fight against AIDS and to adjust behaviours accordingly. Euphoria
over the success of treatment has had an unfortunate side effect in diminishing the sense of threat people felt from HIV infection.
This has lead to an increase in risky behaviour among the uninfected, and to the trend toward "barebacking" (condomless fucking)
among a small faction of the gay community. We must all do what we can to help the public and the media achieve a realistic
perspective on where we are and what we need to do to make the best of a still imperfect situation. Finally, we must get on with
the business of AIDS activism to make sure that better, safer, and easier to use therapies become available as quickly as possible.
Ref:
Project Inform: Discussion Paper on Treatment Failure. Date: Sept 29, 1997 by Martin
Delaney, Founding Director, Project Inform
Source:
"From Project Inform, for more information contact the Project Inform National HIV/AIDS
Treatment Hotline, 800-822-7422."
This article raises a number of issues which are hotly debated amongst people infected
with HIV, researchers and clinicians:
Although theoretically plausible, is early treatment feasible given the length of time on demanding therapies (barring eradication,
one must assume life-long) and the toxicitys of currently available antiretrovirals?
Does return of measurable viral load on treatment inevitably lead to clinical deterioration
(does virologic failure mean clinical progression)?
Can viral replication be only partially suppressed and durability of clinical benefit
still be obtained?
Given the considerable side-effect profiles of currently available antiretrovirals
(NAs, NNRTIs and PIs) means that many physicians who encouraged or allowed patients to treat asymptomatic
HIV-infection may have inflicted considerable toxicitys when that individuals risk of HIV related illness was low. It would be a great tragedy
if people infected with HIV started on therapies whose toxicitys caused morbidity or even mortality sooner than HIV-infection would have done. When
treatment is a life-long commitment we must be confident of the need to make that commitment. With the inadequacies of currently
available antiretrovirals, therapy for HIV is a matter of risk management: balancing the risks of therapy against the risks
of no therapy. In later stage, progressive and life-threatening disease, the risk of no treatment is clear - death, but we are still
in need of careful consideration when looking at treatment when the short-term outcome of no treatment is not as clear cut
and the long-term benefit of treatment is unknown.
Regarding detectable virus while on treatment and its relation to clinical failure,
again a lack of long-term data frustrates any conclusions. In 3TC studies over one year of follow-up, rates of disease progression
were the same in undetectable and less than 5000 copies/ml plasma RNA groups. Long term non-progressors (LTNPs) frequently have low but detectable levels of viral RNA. However, low viral load in the absence of drug pressure cannot be compared to that of viral load
kept low by mechanisms other than host resistance (ie. antiretrovirals). There is also much speculation that the continued clinical
benefit seen in those patients who have not maintained viral suppression on sub-optimal regimes (double nucleoside analogue)
will not continue but is a time-lag effect from the initial viral suppression.
The inherent dangers in the evolution of genotypically resistant HIV populations to
both personal and public health and a lack of longer term evidence that a burden of such mutated viruses can be sustained without
pathology highlights the need to prevent such populations arising. At present the only strategy which has been shown to achieve
such a goal is maximally potent antiretroviral combination therapy with the aim of reducing viral load to less than 50 copies/ml.
Limited data has shown that in individuals who are able to achieve such a goal viral evolution appears to be halted (see following
article).
|
Return to Contents
The Twilight of the Eradication Hypothesis
After the 3rd International Consensus Symposium on Novel Developments in Antiviral
Therapy held during September 1997 in Istanbul, Turkey, New Yorks Treatment Action Group (TAG) Mark Harrington wrote this report.
The Discovery of a Third Phase of Viral Decay
Doug Richman of the University of California at San Diego and Ashley Haase of the
University of Minnesota each presented data which suggest that the time-to-eradication estimates previously generated by Alan Perelson
and David Ho, based on two phases of viral decay under maximal therapeutic suppression, may need to be lengthened considerably.
Apparently at least three papers now under review at Science will document the reasons for extending if not suspending altogether
the estimated time-to-eradication. (This new work was prefigured by a paper delivered by Bob Siliciano at St. Petersburg
in June, which suggested that the half life of the latently infected CD4 T cell population might have to be doubled, extending
the time-to- eradication estimate from Ho & Perelson's three years to at least six.)
Richman began his presentation by commenting that current data suggest that antigen
presenting cells (APCs) such as monocytes and macrophages, dendritic cells, and other APCs appear more likely sources of second-phase
HIV decay than do latently infected CD4 T cells. While the first phase of viral decay appears invariable, the second phase
appears proportional to CD4 count at baseline. Those with lower CD4 counts at baseline appear to have a shorter second phase
half- life. If there are only two phases of HIV decay, the half-life to eradication depends on the number of infected cells and
the half-life of the second compartment:
Assuming the worst case scenario of the Ho/Perelson model of 1012 infected cells and a half-life of second phase viral decay of 4 weeks gives you an
estimated time to eradication of 3 years
However, the high total body infected cell count, the rapid nature of virus turnover,
the high mutation rate of HIV and the very slow turnover of latently infected cells, taken together, mean that the effectiveness
o therapy is always threatened by the potential emergence of resistance to therapy. All possible single point mutations are
generated daily somewhere in the body by HIV, as with other single-stranded RNA viruses such as hepatitis C, influenza and polio.
At Richman's lab, Joe Wong did lymph node biopsies on a number of patients enrolled
in Merck 035. The results confirmed Ashley Haase's 1996 Science paper using a different technology. Lymph node HIV RNA levels
correlate well with peripheral blood RNA, and the amount of lymph node (LN) and peripheral blood (PB) HIV DNA provirus correlates
well with RNA levels. Replication competent DNA provirus was easily recoverable from peripheral blood mononuclear cells (PBMCs)
and lymph tissue (LT) in subjects with a suboptimal response to treatment. However, even after 36 weeks of therapy among individuals
whose plasma RNA fell to below 20 copies/mL, RNA was still found in lymphoid tissue. Two individuals took drug holidays,
during which their plasma RNA levels rose four logs (from 104-108), after which their lymph nodes were re-seeded with drug-resistant
HIV. Wong used the Affymetrix assay to determine the occurrence of resistance mutations in different tissue compartments (plasma
versus LT) and found that resistance to AZT and 3TC was the same in both compartments.
There was a tremendous concordance between mutant genotypes in peripheral blood and
lymphoid tissue. After up to a year of therapy, there were no resistant genotypes found among individuals who maintained a peripheral
blood HIV RNA count below 20/mL, while resistance was found in all compartments in those with over 3.7 log10 plasma HIV
RNA.
Wong and Richman also quantified multiply spliced and unspliced HIV RNA in the various
compartments. Multiply spliced RNA occurs only after a virus has integrated and is replicating; it indicates transcriptional
activation. Unspliced RNA could exist before integration and before a cell was infectious. In patients with RNA below 20 copies/mL
there was no evidence of viral evolution in any compartment by either RNA or DNA, and no evidence of transcription. However,
when RNA was above 200 copies/mL, some replication, and hence some viral evolution, was going on. In some cases, while HIV DNA
remained wild-type, RNA was drug- resistant. This reflects sampling limitations (the resistant virus was coming from another infected
cell, while the wild-type DNA was archival, pre-treatment virus).
Among patients receiving minimal suppression (AZT/3TC) the genetic distance between
baseline and one year viral genotypes was smaller than among non-compliant patients on triple therapy, confirming Wolinsky's finding
that there is more viral homogeneity with limited suppression (Wolinsky found this among rapid progressors, whose limited
immune response, rather than therapy, was the determinant of the minimal suppression).
In summary, among individuals whose HIV RNA remains over 50 copies/mL:
1. HIV replication is ongoing,
2. New mutants appear,
3. Viral evolution is detectable,
4. Multiply spliced RNA in lymphoid tissue indicates ongoing transcription, and
5. It is easier to isolate HIV from PBMCs
This confirms Dale Kempf's finding, presented at St. Petersburg, that the nadir of
viral load reduction predicts the duration of suppression.
Richman moved on to describe new work which directly addresses the time-to-eradication
estimates, and indeed the very viability of the eradication hypothesis. Referring to Chun and Siliciano's June paper on latently
infected lymphocytes and DNA provirus, Richman stated that reverse transcription can take place before CD4 T cell activation,
but that actual integration requires cellular activation. Most cells which experience activation and integration then undergo
mitosis (cell division), in the process of which HIV copies are made. The cell is either killed by direct cytolytic effects of
the virus or by antiviral effector mechanisms of the immune system (CD8+ cytotoxic T lymphocytes or CTLs, antibodies, macrophages,
etc.). However, a small minority of infected cells may survive with integrated HIV DNA. Of these, only a small subset are replication
competent. Of one million PBMCs taken from an infected individual, 1,000- 100,000 cells may have detectable HIV DNA provirus,
but only 10-100 of these cells will have integrated provirus and only 1-10 of these will be replication competent. One to
ten cells out of one million cells may be replication competent. (However, the other cells may remain targets for the immune mechanisms
mentioned above if any viral proteins, even defective ones, are made.)
Resting memory CD45RO+ cells are the major reservoir for integrated HIV-1 provirus
in resting CD4 T cells. Two studies (Finzi/Siliciano and Spina/Richman 1997) show that there is no apparent decrease in the number
of latently-infected resting CD4 cells over two to 32 months of potent antiretroviral therapy. Even among individuals with fewer
than 200 RNA copies/mL, one to ten infectious units per million cells (IUPM) can be detected after up to 32 months of treatment.
The assay is imprecise (with up to one log variation) but this suggests that there may be a very slow half-life for decay
of this infected cell population, confirming estimates made by Angela McLean. In April, Richman and Celsa Spina published a paper
in the Journal of Clinical Investigation which demonstrated that memory CD4 cells with a CD45RO+ phenotype are easier to activate
than naive cells with a CD45RA+ phenotype. According to Chun and Siliciano, they are also easier to infect with HIV and more
susceptible to its cytopathic effects.
Spina and Richman refined the standard PBMC co-culture assay to eliminate CD8 cells,
which exert antiviral effects of their own (either by direct anti-HIV CTL activity or by the CD8 antiviral factor, Jay Levy's
CAF), and then stimulated the cells with anti-CD3 and anti-CD28 antibodies, which are more potent than the standard mitogens IL-2
and PHA.
Using this new assay, they looked for HIV in the cells of patients whose HIV was undetectable
(<50/mL) after two years (100 weeks) of combination therapy. They removed the CD8 cells from the donor cells and stimulated
the donor cells with allogeneic, CD8 depleted lymphoblasts. Virus levels rose in culture from 0-10,000 per million cells
within 21 days.
Using this enhanced PBMC co-culture method, all samples studied were culture positive
for HIV after up to two years of treatment. However, in all patients studied, the virus isolated was wild- type. The lack of
drug resistance demonstrated that despite viral persistence in latently infected CD4 cells, viral evolution and the emergence of
drug resistance was not taking place (with two exceptions, one patient with K70R and one with K219Q).
In summary, Richman declared that this was evidence for a third phase of viral decay
among latently infected CD4 cells with integrated provirus. These cells are predominantly CD45RO+, and their isolation requires
CD8 cell depletion and CD4 cell activation. The half-life of this third compartment will be many months to years, but the virus
isolated from these cells taken from patients with very low HIV RNA levels (<50/mL) after two years of treatment showed no evidence
of viral evolution or the emergence of drug resistance.
Thus, hopes for short term eradication of HIV from an individual within three to six
years are "clearly unrealistic," according to Richman, unless we can figure out a way to shorten the third phase, perhaps by
stimulating the latent infection out of the CD4 cells. Richman joked that inducing toxic shock might be one way of shortening the
third phase. "Conceivably," he continued, "one could eradicate in ten years or more".
Richman concluded that, "It would be wrong to be discouraged about anything but the
prospect for short term eradication, however, we have achieved suppression of viral evolution, which bodes well for maintenance."
Source: Treatment Action Group, 200 East 10th Street, #601 New York, NY 10003
Data on the prediction of the durability of viral load response to treatment was corroborated
by a presentation by Montaner at the Hamburg conference showing that a longer term response was achievable only by those
patients in the INCAS trial who maintained a viral load < 20 copies/mL. Patients with a viral load between 20 - 500 copies
showed no superior durability compared to individuals with higher viral load (>500 copies/mL). Ref: Abstract 105, Sixth European Conference on Vlinical Aspects of HIV-Infection,
Hamburg, Oct. 11-15, 1997).
|
Return to Contents
|
ANTIVIRALS
|
The Early Promise of DMP-266
DMP-266 (generic name efavirenz; trade name Sustiva) belongs to the class of anti-HIV
drugs known as non-nucleoside reverse transcriptase inhibitors (NNRTI). DMP-266 is being developed by DuPont Merck (DuPont Pharma
in Europe). Forty-eight-week data from an ongoing study of 59 individuals taking DMP-266 in a double combination with the
protease inhibitor indinavir show that 88% achieved undetectable HIV viral load (less than 400 copies/mL). In addition, CD4 cell
counts rose an average of 240 cells/mm3 in these study participants. In the control arm of the study, 42 participants took indinavir
alone for 12 weeks, then added DMP-266 and d4T. Of these individuals, 68% achieved undetectable HIV viral load and an average
increase of 150 CD4 cells/mm3. These findings were presented at the 35th annual meeting of the Infectious Diseases Society of
America held in San Francisco, September 13-16, 1997 (see ATPs Doctor Fax issue 31).
Below are examples of 3- and 4-drug combinations containing DMP-266 that are now under
study:
- DMP-266 plus nelfinavir plus 2 nucleoside analogues
- DMP-266 plus indinavir plus 2 nucleoside analogues
- DMP-266 plus indinavir plus 1592
- DMP-266 plus 1592 plus adefovir plus GW 141*
GW 141 is an experimental protease inhibitor and 1592 an experimental nucleoside analogue
both from Glaxo Wellcome.
The most frequently reported adverse side effects of DMP-266 are headache, dizziness,
nausea and vomiting. About 24% of individuals on the DMP-266/indinavir combination have experienced headache, rash, diarrhoea,
dizziness, sinusitis, nausea and flu-like symptoms. The intensity of these side effects appears to diminish over a 2-week period.
To date about 300 patients have been treated with DMP-266 for more than 6 months.
Like other NNRTI and some of the protease inhibitor drugs, DMP-266 is an inducer of
the cytochrome P450 enzyme system. This results in interactions with other commonly used HIV/AIDS medications. For example, DMP-266
decreases blood levels of indinavir by 35%. To achieve best results when using DMP-266 in combination with indinavir, DuPont
Merck advises increasing the standard indinavir dose (800 mg every 8 hours) to 1,000 mg every 8 hours.
Co-administration of DMP-266 with clarithromycin (Klaricid) reduces blood levels of
the latter drug by 30%. DuPont Merck says that DMP-266 does not affect blood levels of AZT, 3TC or fluconazole (Diflucan). DMP-266
also does not appear to significantly affect blood concentrations of the protease inhibitor nelfinavir (Viracept). The effect
of DMP-266 on saquinavir is dose-dependent with a decrease of SQV at lower doses and an increase at higher doses. Interaction
studies of DMP-266 with the new, improved formulation of saquinavir (Fortovase) and other drugs are ongoing.
In addition to its potent anti-HIV activity, DMP-266 possesses another distinct advantage:
once daily dosing is sufficient to maintain adequate blood concentrations of the drug. DMP-266 at 600 mg daily appears
to be the optimal dose based on pharmacokinetic considerations.
Resistance data to date are limited possibly showing a interesting difference from
other NNRTIs. DMP-266 at adequate plasma levels may overcome single resistance mutations against
nevirapine or delavirdine as indicated by in vitro results. Nothing is known so far for multiple mutations in vivo, as they
might occur in pre-treated patients.
Source: Adapted from an article by BETA.
Return to Contents
DMP-266 Compassionate Access
DuPont Pharma are making limited supplies of DMP-266 available in the UK and across
Europe on a named-patient basis starting on Monday October 20th 1997. A wider expanded access programme will be in place for the
first quarter of 1998.
Although DMP-266 can be made available to any physician who decides its use is in the best interest of their patient, DuPont, in association with treatment
activist groups, have formulated physician guidelines which should provide for optimal use of this drug according to current
knowledge. These guidelines are:
- Confirmed HIV positive patients > 13 years of age.
- Patients with plasma HIV-RNA levels > 30,000 copies per mil who are protease inhibitor
naive but nucleoside experienced.
- Patients who are not failing their current anti retroviral regime who are being treated
with triple therapy but are intolerant to one agent may have efavirenz substituted for either a nucleoside or a protease inhibitor.
- Patients who are not failing their current nevirapine anti retroviral regime but who
are intolerant to nevirapine.
- Efavirenz must not be used as monotherapy.
- Efavirenz must be used with at least one
or more nucleoside analogue or protease inhibitor drug to which the patient has had no prior exposure. Efavirenz may not be added
on by itself to existing therapy. Patients must be given at least one other drug to which they have not developed resistance.
- Patients must be able to understand & give informed consent.
- Minors must have the approval of a parent or legal guardian.
The freephone number for physicians to request a supply of efavirenz is operational
from October 20, the free phone and fax numbers for DuPont Pharma countries are:
UK - 0800 731 4341 (tel) / 0800 731 3706 (fax)
Germany - 0130 82 75 74 / 0130 82 75 73
Spain - 900 97 33 53 / 900 96 33 49
Italy - 167 780 564 / 167 790 564
Ireland - 1800 55 33 85 / 1800 55 33 84
The responsibility for efavirenz distribution in other European countries is that
of Merck, Sharp and Dohme (MSD). As of going to press, MSD has informed Doctor Fax that they will have a similar protocol driven
programme for these countries starting in a few weeks. Doctors in these countries should contact their local MSD representative
for details of how to access the drug.
|
Return to Contents
|
PAEDIATRICS
|
Paediatric Treatment Guidelines Released
A draft version of treatment guidelines for paediatric HIV infection are now
available on line at the site "Clinical Care in HIV" (www.healthcg.com).
Developed by the Working Group on Antiretroviral Therapy and Medical Management of
HIV-infected Children, these guidelines attempt to address specific issues related to HIV treatment in infants, children and adolescents.
They are intended as a companion document to the National Institutes of Health guidelines released in June 1997.
The 44-page document, including references and numerous tables, identifies concepts
necessary to understanding the particular care required by children with HIV. Considerable detail is given to the issues of pregnancy
and vertical transmission, as well as the need for drug formulations intended especially for children. One section addresses
the question of how to manage the adverse side effects observed in young patients. In addition, the responsibility that must
be assumed by caregivers in ensuring strict adherence (compliance) with treatment is discussed at length. Finally, a number of
tables are included which outline specific recommendations regarding treatment regimens, as well as the dosing schedules, side
effects and possible drug interactions related to the various antiretrovirals used to treat paediatric HIV.
These guidelines can be viewed at
http://www.healthcg.com/hiv/guidelines/pediatrics/
* The Working Group was convened by the National Paediatric and Family HIV Resource
Center (USA) and the Health Resources and Services Administration.
Source: CATIE-News
Return to Contents
|
MICRONUTRIENTS
|
Study Finds Selenium Affects Survival in HIV/AIDS
Scientists at the University of Miami School of Medicine, Center for Disease Prevention,
report in the Journal of AIDS that deficiency of selenium, an essential trace element for maintaining a healthy immune system,
has a profound effect on survival in HIV infected men and women. The researchers, led by Dr. Marianna K. Baum, found that
HIV-1 infected patients with selenium deficiency were 19.9 times more likely to die of HIV related causes than those with adequate
selenium levels.
The dramatic results of this NIH funded study in 125 HIV infected men and women, published
on September 30 in the Journal of Acquired Immune Deficiency Syndrome, demonstrate that selenium plays a critical role
in HIV-1 disease. The researchers also found that while other nutrients (vitamins A, B12, and zinc) affect survival, these nutrients
produce a substantially lower risk for mortality. In fact, when the nutrients were examined together, selenium had the strongest
impact upon mortality.
The authors suggest that the striking relationship between selenium deficiency and
mortality could be related to selenium's antioxidant function and/or action in gene regulation which may affect HIV replication.
As proposed in a report of Dr. Will Taylor, of the University of Georgia, published in the same issue of the Journal of AIDS,
selenium, as part of selenoproteins, could have an important role in regulating HIV expression. He has proposed a novel viral mechanism
that contributes to a decline in selenium levels accelerating disease progression, while adequate selenium would be expected
to prevent HIV replication, and thus, delay the course of disease progression.
Based on this research, Dr. Baum's team is developing a study to determine whether
selenium treatment can slow disease progression and improve survival over time in HIV infected men and women.
Source: Aegis
It remains to be proven that selenium deficiency is causal in HIV disease progression
and not the epiphenomenon of high level oxidative stress due to rapid HIV turnover. Assesment of selenium levels in patients
before and during effective antiretroviral therapy might shed more light on this. Additionally, treating deficiency may be substantially
different to supplementing in a person with adequate levels.
In a recent British Medical Journal leader (Dietary selenium: time to act. BMJ 314:387-388
), Dr Margaret Rayman, suggests that Britain should consider the problem of low (and
still falling) intakes of selenium. Average British intakes have dropped from 60g/day in 1975 to 34 g/day in 1994. The recommended intake is 75 g/day for men and 60 g/day day for women. Soil levels of selenium in Britain and Europe are low and bioavailability
is further reduced by acid rain and artificial fertilisers. Changes in trading patterns have reduced imported foods
rich in selenium such as Canadian hard wheats. Dr Rayman advises food supplementation or a daily helping of Brazil nuts to ensure
adequate intake of this important micronutrient.
|
Return to Contents
Vitamin B12 and Cognitive Impairment
A study by the Johns Hopkins University component of the Multicenter AIDS Cohort Study
(MACS) followed B vitamin blood levels in 310 HIV-positive men for nine years. In a report last winter,1 the MACS investigators noted that those with abnormally low serum levels of cobalamin
(B12) in their blood progressed to AIDS almost twice as fast as those with normal levels. Another study2 presented this year was a follow-up of similar observations made earlier by an HIV
nutrition research group at the University of Florida. The new data documented a correlation between low vitamin B12 levels and
cognitive impairment in 108 HIV-positive volunteers -- and this association increased as time passed. The particular areas where
problems appeared were semantic (verbal) memory, cognitive efficiency, delayed visual recall and short-term memory.
The original Florida study of cognitive function3 was confined to persons with HIV who were relatively asymptomatic or in the early
stages of the disease. It found that approximately 25% of the participants demonstrated either marginal or overt vitamin B12 deficiency.
When cognition was assessed, those participants with low B12 levels performed more poorly than did those with normal vitamin
B12 levels (at least 180 pmol/l). Participants were tested on information processing speed and visuo-spatial problem-solving
skills.
These findings suggest that concurrent vitamin B12 deficiency may be a factor in cognitive
changes observed in both the early and late stages of HIV infection, even when blood abnormalities are not yet apparent.
Ref:
1. Tang AM et al. Journal of Nutrition. February 1997; 127(2):345-51.
2. Posner G et al. Nutrition and HIV Infection. April 23-25, 1997; Cannes, France (abstract
O-23).
3. Beach RS et al. Archives of Neurology. May 1992; 49(5):501-6.
Source: Treatment Issues -- September 1997, Volume 11 Number 9; published by GMHC
The lack of blood abnormalities in the presence of neurological symptoms due to vitamin
B12 deficiency is well documented outside of HIV-infection. This means that the use of full blood counts to detect megaloblastic
anaemia are not an adequate indicator of deficiency. Patients may be well advised to supplement with B12 to attempt to maintain
adequate blood levels.
|
Return to Contents