DOCTOR FAX
ISSUE 33 27th March 1998
Sourced Compiled and Edited by Paul Blanchard
Medical Advisor - Dr Graeme Moyle,
Chelsea & Westminster Hospital.
Dr Stefan Mauss
, Munich.
Contents
VIROLOGICAL FAILURE
|
Recently physicians have noticed that some patients, being treated with a protease-inhibitor-containing
regimen which failed to control the virus, still maintained a better CD4 (T-helper)
count, and seemed to be doing better clinically, than would have been expected given their viral load. The most extensive report yet on this observation--from
a cohort of 143 "virologic failure" patients followed for a median of 18 months at
San Francisco General Hospital--was presented as a poster at the 5th Conference on Retroviruses and Opportunistic Infections in Chicago.(1) AIDS TREATMENT
NEWS interviewed lead author Steven G. Deeks, M.D. on the findings of this study,
and also on the current practices of physicians at San Francisco General Hospital
in treating patients whose viral load could not be reduced to undetectable levels by antiretroviral
therapy.
Summary of the Poster Presented at the Retroviruses Conference
(also see report in DocFax 40)
The study by Deeks and others was a retrospective review of the medical records of
a cohort of patients at San Francisco General who met a strict definition of "virologic
failure." To be included in this cohort, patients had to (1) have had more than 24
weeks of continuous treatment with regimen containing a protease inhibitor (either indinavir,
ritonavir, nelfinavir, or ritonavir plus saquinavir), (2) have had two consecutive
viral load measurements of greater than 500 copies/ml (using the branched DNA test) at their last two clinic visits, and (3) have received ongoing care at San Francisco
General Hospital.
143 patients met these criteria and were included in the review. Of the 108 who had
a viral load test available before starting protease inhibitors, the median baseline
viral load was 4.84 logs (about 70,000 copies), and the median baseline CD4 count
was 82.
In the entire cohort of 143, followed for a median of 18 months, there were seven
deaths: four were not AIDS related, two were from AIDS-related dementia which preceded
the protease inhibitor treatment, and one was from invasive aspergillus. In the entire
cohort, there were only eight new AIDS-defining events during the follow-up period:
two cases of non-Hodgkin's lymphoma, two pneumocystis, one cryptococcal meningitis,
one cutaneous Kaposi's sarcoma, one PML, and one invasive aspergillus. There were
no new cases of CMV or MAC. More analysis was possible on the 108 patients who had a baseline
viral load. Before the analysis, the patients were divided into three mutually exclusive
groups: (1) Non-responders, with no viral load reduction greater than one log below the baseline (meaning that the antiretroviral regimen never reduced the amount
of virus in their blood to a tenth or less of its pre-treatment level); (2) Transient
responders, who did have at least one viral load measurement one log below baseline,
but whose viral load had returned to within one log of baseline at their last visit;
and (3) Durable responders, who had a greater than one log reduction in viral load
at their last visit (but who, like all the others, still met the strict "failure"
definition of not being below 500 copies on either of their last two visits). By these measures
of response, there were 22 non-responders, 45 transient responders, and 41 durable
responders (total 108).
At 18 months, even the "non-responders" had a median CD4 count increase of approximately
50. The transient responders had a median CD4 increase of more than 100, and the
durable responders had over 150. The median CD4 increase for all 108 of these "virologic failure" patients was approximately 100. The following conclusions are quoted from
the poster: "Despite a median duration of 18 months since initiating a potent PI-containing
[protease inhibitor containing] regimen, and greater than 12 months since the emergence of virologic failure, the median absolute CD4 T-cell level in this cohort
remained approximately 100 cells/mm3 above the pre-PI baseline.
"A significant proportion of patients with an incomplete response to a PI-containing
regimen had a durable 1 log or greater decrease in viral load. This durable suppression
was associated with a sustained increase in the absolute C4 T- cell count. "Patients who had a transient virologic response to a PI- containing regimen had also significant
and sustained increase in the absolute CD4 T-cell count. "New AIDS related events
were uncommon in this cohort of 143 patients 'failing' a potent PI containing regimen (n=8). There were no new cases of CMV or MAC.
"These observations suggest that failure of a PI-containing regimen, defined virologically,
may not be predictive of subsequent CD4 T-cell decline (over the following 12 months).
"These observations must be considered in light of the retrospective nature of this study, and the limited duration of follow-up. Long-term follow-up of this cohort
is needed to further examine the clinical implications of PI failure."
The Interview
We asked Dr. Deeks about this study, and about treatment of such patients at San Francisco
General Hospital, which is widely recognised as a leader in AIDS care. The interview
took place on February 12, 1998.
AIDS TREATMENT NEWS
: In this study of clinical consequences of virologic failure of protease inhibitor
therapy, why were the "durable responders" counted as treatment failures?
Dr. Deeks
: They did not meet the strict criterion that has become the gold standard of therapy,
which is to achieve sustained undetectable viral load. They had a clear response;
the viral load went down and stayed down, but at least in the last two visits it
was detectable (greater than 500 copies/ml using standard bDNA assay).
ATN
: In this study, were there predictors of who would do poorly--predictors that might
be helpful for clinicians in managing patients?
Dr. Deeks
: Our presentation was only meant to report, "This is what we saw." To take this observation
and conclude how clinicians should use viral load and CD4 data would be premature.
Our data simply state that the patients we identified as having "failed" protease inhibitor treatment still clearly had a sustained CD4 increase. That is a major
point of this presentation. We are not saying that patients will not progress eventually.
But as far as we can tell, over the 12 to 18 months after we recorded failure, for
the vast majority of patients, CD4 decrease or clinical progression did not occur.
We did have a small group who developed opportunistic infections: only eight in this
cohort of 143. What was constant with most of them is that even though they may have
had a viral load response to their therapy, they never had a CD4 count response. This
was consistent with what Dr. Judy Currier reported in her analysis of ACTG 320; (2)
that analysis showed that for patients who received AZT and 3TC, or AZT, 3TC and
indinavir, just a small increase in CD4 count above their baseline (after eight weeks of treatment)
was highly associated with a good clinical outcome. Our data were consistent with
their observations.
One possible take-home message is that if patients do get even a small T-cell response,
that may translate into prolonged clinical benefit. Patients who do not see a T-cell
response to protease inhibitor therapy might benefit from more aggressive prophylaxis of opportunistic infections. Yet our results cannot prove that if you fail protease
inhibitor therapies virologically then you should stay on that particular regimen--or
even that you should necessarily stay on therapy. To answer those questions would
require a prospective clinical trial comparing the different options that patients have:
stopping therapy, switching therapy, or staying on therapy.
ATN
: What are the risks of staying on therapy despite virologic failure?
Dr. Deeks
: By allowing viral replication in the face of a selective pressure, high-level drug
resistance may develop. This process may continue to occur long after the viral load
starts to increase. It may limit future options with so- called "salvage therapy"
down the line. A second risk is continued side effects, which for some patients may outweigh
any durable benefit from these therapies. And the cost of these drugs will be a factor
for some. In our clinic the vast majority of patients, once they failed the protease inhibitor virologically, either stayed on that therapy or switched to a second
protease inhibitor containing regimen. And virologically, those groups basically
did about equally well. We have not had many patients achieve durable viral suppression
after switching to a second protease inhibitor containing regimen. Whether or not these
people would have done as well had they stopped all their drugs, we do not know.
Of note, clinical investigators at Johns Hopkins University have reported reasonable
success in patients who switch early to a second protease inhibitor containing regimen.
(3) The fact that some of their patients switched early may be critical. Delaying
the switch for months, which was common in most of the patients we studied, may allow
for the development of high-level resistance.
ATN
: Is there any observation from those who did choose to stop everything?
Dr. Deeks
: We only had about half a dozen patients who chose to stop antiretrovirals because
of virological treatment failure. Among clinicians at San Francisco General Hospital,
there is a strong sense that stopping therapy is not a good thing to do. So we do
not have data to make a comparison. One possible criticism of our data is that only those
patients who did well stayed on therapy. We do not believe this was a significant
issue in our analysis, since very few patients stopped therapy--and all patients,
including those who stopped, remained in the analysis. So again, we can only offer the observation
that virological failure is not necessarily equal to clinical failure, over 12 to
18 months. But people should not take this and say, "I failed my protease inhibitor, but I should stay on it." We really do not know that, and certainly there are risks
in staying on the drugs.
ATN
: Have you seen increased viral resistance in these patients?
Dr. Deeks
: We have not looked for it yet, and do not have much resistance data on these patients
now. We need to do this analysis.
ATN
: What research ought to be done next?
Dr. Deeks
: The virologists and immunologists need to take a close look at this phenomenon,
and try to determine if there is any underlying reason to think that virologic failure
and resistance to a protease inhibitor confers loss of virologic virulence. This
is a major question clinicians have been asking. There are some small studies suggesting
that it may be true. A paper published a few months ago suggested that resistance
could result in a switch from a syncytium inducing phenotype (SI) to a non-syncytium
inducing phenotype (NSI)(4); this could explain why resistant virus would be less destructive
to T-cells. Other observations along those lines would also suggest that resistance
to a protease inhibitor comes at some significant cost to the virus. These are the
kinds of virologic studies that need to occur. I am told that it is very difficult,
however, to test a virus for virulence in the laboratory. We are interested in working
on this problem here at the Gladstone Institute [a privately funded non-profit research facility associated with San Francisco General Hospital].
The other issue is what exactly is happening in the immune system--which goes back
to the fundamental question of how HIV causes immune destruction. Is it a direct
effect of the virus on the CD4 T-cell, or is it something much more fundamental earlier,
a view many investigators are coming to support?
ATN
: In other words, not the virus killing the CD4 cells, but doing something that prevents
the cells from being produced in the first place?
Dr. Deeks
: Yes. And it is possible that the transient virologic response to a protease inhibitor
could lead to a sustained immunologic benefit. If the problem caused by the virus
occurs early in the development of the mature immune system, one could envision that
even a brief period of time when the virus was not around could let the immune system
regenerate itself. Therefore immune function could be more sustained in the face
of the virus coming back up, and that could lead to a sustained clinical benefit.
The implication, however, is that eventually progression will occur. But when that may happen
is unknown.
If you look closely at the data from the nucleoside analogue trials, the CD4 count
response is more sustained than the virologic response. So what we have reported
may not be associated with protease inhibitor failure specifically. It may be a phenomenon
of antiretroviral drug failure.
ATN
: What would we need to answer the question of whether people should stay on treatment,
or go off? Would a clinical trial be necessary?
Dr. Deeks
: I doubt that people would support such a trial now--taking patients who "have no
clear options to switch to" and randomly assigning them to go off all antiretroviral
treatment, or to recycle drugs that had not worked for them. My sense has been that
many clinicians and patients would not participate in such a study. So we will always have
inconclusive data.
What needs to happen for these patients is not to answer the question of stop, or
change, or recycle--but to develop new and better drugs.
Caution on Starting NNRTI Drugs After Protease Inhibitor Failure
Dr. Deeks
: At San Francisco General Hospital, for our patients who have failed more than one
protease inhibitor--and they are very common here--one approach has generally been
to keep them on whatever drug combination is best tolerated, and avoid adding or
changing to any of the newer drugs, particularly the non-nucleoside reverse transcriptase inhibitors.
The goal here is to save these drugs for when we know how best to use them in "salvage"
regimens. Until then, the goal of therapy for patients who have failed their first-line therapies is to move from seeking viral suppression, toward seeking sustained
clinical benefit. It can be difficult to distinguish between these two. But a strong
feeling of physicians here is not to play the non-nucleoside RT inhibitor card for these patients until you have to--that is, until patients are progressing clinically.
Perhaps over the next year we will have clinical evidence on how best to approach
patients no longer responding virologically to protease inhibitor therapy. Presumably,
the non-nucleoside reverse transcriptase inhibitors will be a critical component of
that strategy.
ATN
: Do you mean efavirenz in particular?
Dr. Deeks
: Or nevirapine or delavirdine. These are very potent drugs--but they rarely do much,
unless they can be given with two other drugs which will be very effective. And for
these patients who have gone through the first line of antiviral therapies, there
probably are not one or two other drugs that are going to be effective enough to lead to
complete suppression.
Viral Load: How Low Is Low Enough?
ATN
: Do you have any thoughts on the issue of whether a viral load below 400 copies is
good enough, or do you really want to be below 50, 40, or even less?
Dr. Deeks
: This is one of the questions that clinicians are going to struggle with over the
next year. The data that Dale Kempf from Abbott Laboratories presented about a year
ago clearly shows that the lower you get, the longer you stay down; (5) that makes
sense. So the goal of therapy will be to get the viral load as low as possible; the way
to measure that would be with one of the new ultrasensitive assays. The problem is,
what do you do when the viral load does not go so low? This is a fundamentally different
question. If you get down to very low levels, less than 400 copies, but the virus is
still detectable, and it stays at this low level, what do you do then? Do you add
drugs? Do you change the entire regimen? Do you continue to follow patients and watch
what happens? The problem is that these new tests provide you with powerful information,
but we do not know how to use it. So I myself do not see a dramatic need right now
for access to the ultrasensitive assays. They will cause more confusion when they
become more widely available.
The data from Keith Henry, from his clinic at the University of Minnesota, would suggest
that a large proportion of patients who are "undetectable" with the standard assays
will be detectable with the ultrasensitive assays. (6) So it will be a real concern.
Some other posters at the Retroviruses meeting are relevant here. One looked at five
vs. four vs. three drugs (7); this was a relatively small study done in Europe. Researchers
looked at viral decay rates over the first two weeks [how fast the virus decreases when combination antiretroviral treatment is first started], and observed that
as you increase the number of drugs the patients begin with, the decay increased
substantially. To me this suggested that the three-drug combinations now used, for
example the classic AZT plus 3TC plus indinavir, might not be enough to fully suppress viral
replication--since if you go to four or five drugs, you get more rapid decline. This
would suggest that current three-drug regimens may be suboptimal for some patients,
which may be why we see drug failures even in patients who are completely adherent to
these regimens. How important is it to get the viral load to extremely low levels?
Obviously the gold standard test for answering this question would be lack of clinical
progression. But in people who get to these very low levels, we see very little clinical
progression; it would take years to distinguish between those under 400, for example,
vs. those under 40. In practice we will never know the answer for sure.
So it comes back to the theory. Theory drives much of what we do, and probably it
should. Here theory would suggest that the less viral replication you have, the less
resistance you will develop, and the longer these drugs will work. So getting the
viral load as low as possible should be a central goal of therapy.
References:
Deeks SG, Beatty G, Cohen PT, Grant R, and Volberding P. Viral load and CD4 + T Cell
Changes in Patients Failing Potent Protease Inhibitor Therapy. 5th Conference on
Retroviruses and Opportunistic Infections, Chicago, February 1-5, 1998 [abstract
#419].
Currier JS, Williams PL, Grimes JM, Squires KS, Fischl MA, and Hammer SM, for the
ACTG 320 Study Team. Incidence rates and risk factors for opportunistic infections
in a phase III trial comparing indinavir + ZVD + 3TC to ZVD + 3TC. 5th Conference
on Retroviruses and Opportunistic Infections, Chicago, February 1-5, 1998 [abstract #257].
Gallant JE, Hall C, Barnett S, Raines C. Ritonavir/Saquinavir (RTV/SQV) as Salvage
Therapy after Failure of Initial Protease Inhibitor (PI) Regimen. 5th Conference
on Retroviruses and Opportunistic Infections, Chicago, February 1-5, 1998 [abstract
427].
Ercoli L and others. HIV phenotype switching during antiretroviral therapy: emergence
of saquinavir-resistant strains with less cytopathogenicity. AIDS. August 1997; volume
11, number 10, pages 1211-1217.
Kempf D, Molla A, Sun E, Danner S, Boucher C, and Leonard J. The duration of viral
suppression is predicted by viral load during protease inhibitor therapy. 4th Conference
on Retroviruses and Opportunistic Infections, Washington, January 22-26, 1997 [abstract #603].
Henry K and others. Levels of plasma HIV RNA measured by the Roche Ultrasensitive
assay in HIV infected individuals with RNA levels below the bDNA detection limit.
5th Conference on Retroviruses and Opportunistic Infections, Chicago, February 1-5,
1998 [abstract #529].
De Wolf F, Lukashov VV, Danner SA, Goudsmit J, and Lange JMA. Clearance of HIV-1 following
treatment with three, four, and five anti-HIV drugs. 5th Conference on Retroviruses
and Opportunistic Infections, Chicago, February 1-5, 1998 [abstract #384].
Source: AIDS Treatment News Issue #289 - February 20, 1998; published twice monthly;
Subscription and Editorial Office: P.O. Box 411256 San Francisco, CA 94141
Return to Contents
The Swiss HIV Cohort Study has found rates of virologic failure in advanced and drug-experienced
patients similar to that found at San Francisco General and other study centres.
About 49% of people in this cohort taking HAART (highly active antiretroviral therapy) did not achieve undetectable viral loads, that is, viral loads below 500
copies per ml.
Their letter to the Lancet described all 101 patients in their study who started HAART
before February 1997 and received the drugs for at least three months. The baseline
for this group was an average T-cell count of 162; 66% had shown evidence of virologic failure on their previous mono- or dual-therapy regimens. After 12 months, 93% of
the whole group had higher T-cell counts than they began with, but 49 of them had
detectable viral loads.
At the end of one year, those who became undetectable and stayed that way had an average
increase of 138 T-cells. Those who were transiently undetectable did almost as well
with an average T-cell rise of 130.
The real surprise came in looking at the 49 who were never undetectable the whole
year. For the 33 who continued taking their medications anyway, the average T-cell
increase was 105 - not that far below those who reached undetectability. Even the
16 who stopped or interrupted treatment (for an average of 55 days) had an average rise at
the end of the year of 57 T-cells.
The study compared these rises to their cohort's experience before the coming of HAART.
The average number of T-cells lost per year was 60. With double-combination nucleoside
therapy, the decline stopped, but the gains were small - no more than 40 T-cells
after one year. The authors rightly inferred from this comparison that something else
must be going on with HAART besides viral suppression.
They looked at 15 of the patients with continued detectable viral loads but T-cell
rises and found that all 15 had quite an accumulation of drug-resistance mutations.
They speculate, therefore, that heavily-mutated viruses may be less "fit" for reproduction or causing damage to the immune system and/or that small reductions in viral load
and a break in the killing of T-cells may allow time for the immune system to make
small but significant restorations.
Ref: Kaufmann D, Pantaleo G, Sudre P, and Telenti A. CD4-cell count in HIV-1-infected
individuals remaining viraemic with highly active antiretroviral therapy (HAART).
The Lancet. March 7, 1998; volume 351, pages 723-724.
Author: Walt Senterfitt
Source: Being Alive, Los Angeles; April 1998
Published by Being Alive Los Angles; 3626 Sunset Blvd., Los Angeles, CA 90026
In practical terms, these studies give new hope to those who have exhausted all their
antiviral drug choices and still have detectable viral loads. They give reason to
stay on therapy, if one can tolerate it and if no better options are available as
yet, even if viral loads are rising. We cannot expect these benefits in T-cell counts to
last indefinitely, but they may well give tens of thousands of people enough immune
system boost to hang on until more drugs are available and we know how to use them
better.
What these studies do not do, however, is negate the primary objective of striving
for as low a viral load as possible when initiating antiretroviral therapy. This
should still be the primary imperative. Plasma viral loads of below 50 copies/ml
while on antiretroviral treatment are strongly associated with prolonged durability of suppression
and lack of genotypic evolution of HIV.
This study does not answer the question of whether the still- replicating virus will
be able to become more resistant later and fully negate the value of the drugs--or
whether the drug- resistant virus is damaged or less pathogenic in some way, allowing
the treatment to be of value indefinitely even if undetectable viral load is not reached
or maintained. Clearly long-term data will be needed.
|
Return to Contents
|
ANTIRETROVIRAL DRUGS AND STRATEGIES
|
Potent antiretroviral therapy can reduce human immunodeficiency virus (HIV) in plasma
to levels below the limit of detection for up to 2 years, but the extent to which
viral replication is suppressed is unknown. To search for ongoing viral replication
in 10 patients on combination antiretroviral therapy for up to 1 year, the emergence of
genotypic drug resistance across different compartments was studied and correlated
with plasma viral RNA levels. In addition, lymph node (LN) mononuclear cells were
assayed for the presence of multiply spliced RNA. Population sequencing of HIV-1 pol
was done on plasma RNA, peripheral blood mononuclear cell (PBMC) RNA, PBMC DNA, LN
RNA, LN DNA, and RNA from virus isolated from PBMCs or LNs. A special effort was
made to obtain sequences from patients with undetectable plasma RNA, emphasising
the rapidly emerging lamivudine-associated M184V mutation. Furthermore, concordance of drug
resistance mutations across compartments was investigated. No evidence for viral
replication was found in patients with plasma HIV RNA levels of <20 copies/ml. In
contrast, evolving genotypic drug resistance or the presence of multiply spliced RNA provided
evidence for low-level replication in subjects with plasma HIV RNA levels between
20 and 400 copies/ml. All patients failing therapy showed multiple drug resistance
mutations in different compartments, and multiply spliced RNA was present upon examination.
Concordance of nucleotide sequences from different tissue compartments obtained concurrently
from individual patients was high: 98% in the protease and 94% in the reverse transcriptase regions. These findings argue that HIV replication differs significantly
between patients on potent antiretroviral therapy with low but detectable viral loads
and those with undetectable viral loads.
Ref: Guenthard,H.F., Wong,J.K., Ignacio,C.C., Guatelli,J.C., Riggs,N.L., Havlir,D.V.,
Richman,D.D.: J.Virol.,72 (3):2422-2428 (1998 Mar)
This abstract supports both the concept of ultra-sensitive viral load testing and
the "low as you can go" viral load target for treatment. This study suggests that
reducing viral load below 20 copies per ml does effectively stop or at least dramatically
slow viral replication and the development of resistance. The authors found a significant
difference in the development of resistance between those with viral load under 20
copies and those with viral loads between 20-400 copies. This does not negate the
significant clinical improvements seen in people with viral loads between 20 and 400,
but it may suggested that the long term maintenance of clinical improvements is dependent
on achieving very low viral load values.
|
Return to Contents
The US Department of Health and Human Services (HHS) have announced its decision to
designate saquinavir soft gel capsule (SQV-sgc, FortovaseTM) as "preferred" therapy in revised federal government AIDS treatment guidelines soon
to be released on the world wide web (www.hivatis.org). According to the recommendations,
Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents, SQV-sgc, when taken with two nucleoside analogues, demonstrates "strong evidence
of clinical benefit and sustained suppression of plasma viral load."
The original formulation of saquinavir (hard gel capsule), known as InviraseTM , was excluded from earlier versions of the guidelines due to concerns over poor
potency. SQV-sgc is a more bioavailable formulation of saquinavir that provides greater
antiviral activity. To ensure adequate potency SQV-sgc is also dosed at 1200mg tid,
double the dose of the original InviraseTM formula.
Roche pharmaceuticals have recently announced named patient access for saquinavir
soft gel capsules (FortovaseTM). Eligibility for access is suggested for:
Patients who are currently stable on the existing hard gelatine capsule formulation
of saquinavir (InviraseTM).
Protease-naïve patients suitable for initiating treatment with saquinavir.
Patients who have failed clinically or virologically on any other protease inhibitor(s).
The programme co-ordinators may be contacted by calling the numbers below:
Ben Willis: 01707 365 707
Neil Delmas: 01707 365 756
Maggie Strack: 01707 365 699
|
Return to Contents
Researchers from the Medical College of Wisconsin and the U.S. Food and Drug Administration
report incidence of Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis
(TEN) in an HIV-positive patient receiving zidovudine, lamivudine, and nevirapine. The patient had tender oral ulcers and haemorrhagic crusts, which were believed
to be a result of using nevirapine. The researchers also note 19 other cases of
nevirapine-associated SJS and TEN reported to the FDA since the drug's approval in
June 1996. There has been only one published report of zidovudine-mediated TEN since the drug
was approved in 1987, and there are no reports of lamivudine-induced SJS or TEN since
its 1995 introduction. The researchers note that the likelihood of severe mucocutaneous side effects related to use of nevirapine in persons infected with HIV-1 appears
to be among the highest reported for any medication.
Ref: Lancet (21/02/98) Vol. 351, No. 9102, P. 567; Warren, Kelly J.; Boxwell, Debra
E.; Kim, Nancy; et al.
Source: CDC NCHSTP Daily News Update
Return to Contents
February 18th, 1998
Dear Investigator
RE : EFAVIRENZ (DMP 266) SAFETY REPORT
The clinical development program of efavirenz (DMP 266) in HIV-infected individuals
has continued to be supported by developmental toxicology studies in various animals.
This letter provides an interim report of findings from an ongoing efavirenz (DMP
266) developmental toxicology study in cynomolgus monkeys. Pregnant cynomolgus monkeys
were dosed with 30 mg/kg bid of efavirenz from gestational day 20 through day 150.
This dose of efavirenz was selected because pregnant cynomolgus monkeys did not
tolerate higher doses. A dose of 30 mg/kg bid of efavirenz is anticipated to achieve plasma
drug concentrations in pregnant cynomolgus monkeys which are similar to those in
humans given 600 mg/day.
Gross malformations have been observed in 3 of 13 foetuses upon Caesarean sectioning
of efavirenz-treated mothers. Anencephaly and unilateral anophthalmia were observed
in one fetus, microophthalmia was observed in another foetus, and cleft palate was
observed in a third foetus. No gross malformations have been observed in 13 foetuses
upon Caesarean sectioning from the vehicle control group. No clinical signs of toxicity,
effects on body weight gain, differences in the number of aborted, lost or stillborn foetuses have been observed in the pregnant monkeys given 30 mg/kg bid of efavirenz
compared to the vehicle-treated controls.
In completed developmental toxicology studies, no efavirenz-related foetal malformations
occurred in efavirenz-treated pregnant rabbits or rats given up to 75 mg/kg/day and
up to 100 mg/kg bid, respectively. The only notable finding in pregnant rats given 100 mg/kg bid was a slight, non-statistically significant increase in the incidence
of foetal resorptions. Plasma efavirenz concentrations in pregnant rats and rabbits
given these doses approximated those in humans given 600 mg/day. Foetal exposure
to efavirenz at these doses has been documented in pregnant rabbits and rats.
In conclusion, while results of a series of reproductive toxicology studies showed
no evidence of efavirenz-related foetal malformations in rats or rabbits, treatment-related
malformations did occur in foetuses of cynomolgus monkeys. These findings do not affect our ongoing trials as female patients are required to undergo pregnancy testing
as part of entry criteria and at every study visit. In addition, patients must be
willing to use an effective medically-accepted (including barrier) method of contraception. In all healthy volunteer studies, females must be of a non-child bearing potential
defined as being post-menopausal (ovarian failure documented with a 2-year history
of amenorrhea and a serum FSH >30 units/mL) or surgically sterile by hysterectomy, bilateral oophorectomy or tubal ligation in excess of 2 years as documented by medical
records.
Please submit this safety report to your IRB, as required, and provide DuPont Merck
with a copy of the correspondence to your IRB informing them of these events.
Please contact me at (302) 992-4638 if you have any questions.
Sincerely,
Donald W. Nibbelink, M.D.
Drug Safety Officer
A teratology study is a normal part of new drug development & determines the effect
of a drug on a developing embryo. To facilitate the evaluation of the effect of Sustiva
on women in the early stages of pregnancy, DuPont Merck has conducted teratology
studies on animals. In studies of rats and rabbits given doses of efavirenz which approximate
the exposure achieved in humans given 600mg/day, no embryo malformations were observed.
In an effort to better understand the potential effects in humans, an additional species,
cynomolgus monkeys, was studied, given doses of efavirenz which approximate the exposure
achieved in humans given 600mg/day. This marks the first time any pharmaceutical company studying an antiretroviral treatment for HIV and AIDS has examined the
effect of the drug in pregnant monkeys. In this study of 60 monkeys, malformations
in three of 13 foetuses delivered by Caesarean section have been observed. DuPont
Merck is continuing to monitor the natural deliveries in this ongoing study. The malformations
observed are a result of exposure very early in pregnancy. There was no effect
on the mother monkeys.
A letter has been sent to all investigators informing them of this finding. In addition,
the informed consent form has been modified to reflect this information.
In all clinical studies of Sustiva to date, patients have had to be willing to use
an effective, medically-accepted (including barrier) method of contraception. In
addition, women are required to have pregnancy testing at study entry and at each
visit. In Phase I studies women were required to be of non-child-bearing potential. To date,
more than 4000 patients, of which 20% are women, have received efavirenz. Two women
became pregnant while on study and both women elected to terminate their pregnancies.
To our knowledge, no other women have become pregnant. If a woman who is taking
efavirenz becomes pregnant or is considering pregnancy, she needs to weigh the risks
and benefits carefully in consultation with her doctor.
These findings do not rule out plans to conduct mother-to-child transmission studies
where dosing will occur in the last trimester of pregnancy. Paediatric studies with
children age three and older are ongoing, and no unexpected side effects have been
observed. In summary, these findings will have no impact on ongoing studies or the clinical
development plan for Sustiva.
This finding will likely require that the Sustiva labelling contain a pregnancy class
C designation (US label), which indicates that it should be used during pregnancy
only if the potential benefit of treatment justifies the potential risk. Most of
the currently marketed antiretrovirals also carry a pregnancy class C designation.
|
Return to Contents
Australian researchers have determined that combination antiretroviral therapy that
includes a protease inhibitor can aid in the treatment of HIV-1 related Enterocytozoon
bieneusi and Cryptosporidium parvum. The bacteria can induce microsporidiosis and
cryptosporidiosis infections in the gastrointestinal tracts of HIV-1-infected individuals,
causing persistent diarrhoea, weight loss, and abdominal pain. The scientists administered
medical regimens of combination therapy that included at least one HIV-1 protease inhibitor to five patients with microsporidiosis, three with cryptosporidiosis,
and one with both infections; all nine men were infected with HIV. The researchers
saw complete clinical responses in all nine subjects, who gained an average of 15
kg in weight and ceased taking all antidiarrhoeal and antimicrobial treatments. Moreover,
follow-up stool microscopy found that eight of eight men tested showed neither pathogen,
while all five patients tested by endoscopy were also negative for the pathogens. Five of the nine patients remained symptom free for an average of 13 months, while
four of the patients had recurring diarrhoea between seven and 13 months. The researchers
noted that while neither infection was eliminated, combination that includes an HIV-1 protease inhibitor can effect "complete and sustained clinical, microbiological,
and histological resolution of HIV-1-associated opportunistic infections."
Ref: Lancet (24/01/98) Vol. 351, No. 9098, P. 256; Carr, Andrew; Marriott, Deborah;
Field, Andrew; et al.
Source: CDC NCHSTP Daily News Update
Return to Contents
New research published in the February issue of the Journal of Medical Virology indicates
that a high maternal level of HIV RNA is a risk factor for transmitting HIV to the
infant, and is also linked with an elevated risk of premature birth. The researchers investigated vertical transmission factors in 95 HIV-positive pregnant women, evaluating
the women's viral load, clinical status, and CD4 cell count, as well as the HIV status
of the 94 children born to the women. Dr. Siobhan O'Shea of the United Medical and Dental Schools of Guy's and St. Thomas's Hospitals in London and colleagues
found that the mother's viral load was a better indicator of vertical transmission
than CD4 cell counts; the estimated rates of transmission were 2 percent for women
with 1,000 HIV RNA copies/mL, 11 percent for 10,000 copies, and 40 percent at 100,000 copies.
The researchers also found that the mean gestation at delivery dropped by an average
of 1.3 weeks for every 10-fold increase in HIV RNA load in the mother.
Source: CDC NCHSTP Daily News Update
Return to Contents
The Clinical Management of HIV/AIDS: Drug-Drug Interactions, by Charles Flexner, M.D.,
and Steven Piscitelli, Pharm. D.
This new module, written for physicians, pharmacists, and nurses but available to
anyone through the World Wide Web, provides background on drug interactions as well
as lists of what to watch out for. You can also submit your own regimen for an immediate
computerised report on known potential interactions.
Most drug interactions fall into one or more of several classes, making them somewhat
more predictable than might be expected. The background section of this training
module--"How Drugs Interact: What You Need to Know" explains how most drugs are metabolised, and lists the five most important kinds of pharmacokinetic interactions, in which
one drug affects the concentration of another ("inhibition of metabolism; induction
of metabolism; altered drug absorption; inhibition of renal excretion; and displacement from plasma protein binding sites"). There are also pharmacodynamic interactions
("synergism or antagonism of drug effects, without alterations in the concentrations
of either drug"). This section also describes the cytochrome P450 system, an important
part of one of the two major ways the liver metabolises drugs.
This drug interaction guide is published by HealthCare Communications Group, and is
available at
http://www.healthcg.com
The entire course can be printed easily, so if you do not have online access yourself,
someone else could print the material for you.
Project Inform's Drug Interactions Fact Sheet, by Ben Cheng
This simpler drug interaction guide has one page of introduction written for patients,
and 17 pages of drug-drug interactions listed alphabetically by generic drug names.
There is also a short glossary of terms used in describing the side effects.
You can obtain a copy from Project Inform.
http://www.projinf.org
The latest version, dated February 1998, will include information from the Retroviruses
conference (Chicago, February 1-5).
Source: AIDS Treatment News
In addition to the Doctor Fax AIDS Treatment Project also runs a Treatment Information
phoneline on Monday and Wednesday evenings (6 -9 pm).
0645 47 00 47
(National Local Rate Calls)
|
Many doctors have found it useful to refer their patients to the ATP phoneline. Patients
are able to discuss treatment options anonymously with knowledgeable positive people
without any time pressures.
We would like to remind Doctor Fax subscribers that each issue of the Doctor Fax is
available by email delivery in a Microsoft Word format.
This is the most cost-effective method for AIDS Treatment Project to distribute this
document.
If you are able to receive Doctor Fax by email please email us at
admin@atp.org.uk
requesting an email subscription and detailing how
you currently receive Doctor Fax.
Return to Contents
