Advocacy
By Ronald Baker, PhD
Unusual Side Effects Due to HIV Therapy?
The widespread use of highly active antiretroviral therapy (HAART) has significantly
improved survival rates and quality of life for many individuals living with HIV disease,
including those with advanced AIDS. In addition to a greater than 50% decline in death
rates, hospitalization and opportunistic infection rates also have fallen dramatically
since the advent of potent 3-drug therapy that usually includes a protease inhibitor.
Along with these improved outcomes resulting from treatment advances, some people are
experiencing abnormal metabolic changes that appear linked to anti-HIV therapy. The
unusual effects have alarmed many patients and have adversely affected their quality of
life. In the absence of any treatment to prevent or reverse these adverse developments,
there is a growing concern among treatment advocates that people may stop or not initiate
anti-HIV therapy, even when treatment is clearly indicated . The following briefly
summarizes what is currently known about these side effects and comments on the potential
implications for HIV treatment.
Changes in
Body Composition and Redistribution of Fat
These unusual side effects are related to an abnormal distribution of fat in the body.
Among patients, the effects are known by descriptive names such as "protease
paunch" and "buffalo hump." The most notable visible changes involve (1) an
increase in waist size (fat on the lower belly and flanks, called "protease
paunch" or truncal obesity), accompanied by a loss of muscle tissue in the arms and
legs; and (2) a raised area behind the neck (a fatty mass at the base of the neck, called
"buffalo hump" or dorsocervical fat pad). Among women, the most visible changes
involve increased waist size and breast enlargement. Other visible characteristics may
include a thinning of the skin on the arms and legs and abnormal, sometimes severe
wrinkling of the facial skin.
A rapid increase in waist size and the development of "buffalo hump" were the
first unusual metabolic side effects to be recognized by patients and their doctors. The
effects were first seen and described in early 1997 among people who had been taking
protease inhibitor-containing regimens for several months. Shortly afterwards, the U.S.
Food and Drug Administration (FDA) sent an alert to physicians summarizing reports from
physicians of diabetes mellitus in certain individuals taking protease inhibitor therapy,
some of whom also had developed truncal obesity.
Other individuals using protease inhibitors have developed abnormally high triglyceride
levels (hypertriglyceridemia). Triglycerides are lipids (fats) which at high levels
(greater than 1,000) may increase the risk of developing pancreatitis or cardiovascular
disease. Some patients taking protease inhibitors have developed high cholesterol levels
(greater than 400) that may put them at increased risk for heart and circulatory disease.
A recent letter to The Lancet (May 2, 1998) notes that a chart review of 124
patients taking protease inhibitor therapy found that 33% had high enough lipid
concentrations to warrant treatment with either a lipid-lowering drug or with diet and
exercise.
What Causes These Side Effects?
Medical experts are uncertain about the cause(s) of these metabolic side effects.
Australian researchers have documented increased truncal fat in 64% of study participants
using protease inhibitors. Their study also found that there may be a direct effect of
protease inhibitors on fat metabolism, i.e., the protease inhibitor drugs themselves may
cause these metabolic disturbances. However, not all people experiencing these effects
have taken protease inhibitor drugs. Doctors in New York City and San Francisco report
that the development of "buffalo hump" also occurs in people not using
protease inhibitors. In addition, physicians have described altered fat distribution in
HIV positive patients prior to the development of protease inhibitors. Of course, this
does not eliminate the possibility that protease inhibitors may play a role in the
development of these unusual side effects.
Management of Side Effects
There are no known treatments to prevent or reverse the fat redistribution that results
in conditions such as "protease paunch," "buffalo hump" or facial
wrinkling. However, there are standard, effective medical treatments for diabetes,
hypertriglyceridemia, high blood cholesterol and cardiovascular disease.
Implications for Treatment of HIV
Currently there is not enough information to identify the full extent of this (new?)
phenomenon. It is not known whether these metabolic changes are a direct effect of
protease inhibitor therapy, or a result of all anti-HIV drug treatment, or a
syndrome caused by HIV infection itself. There are few answers at this point, only
questions. Given the many uncertainties associated with the syndrome, physicians are
unlikely to recommend a discontinuation or change in current HIV treatment guidelines.
Not surprisingly, the situation is generating controversy among patients and doctors
about the value of potent HIV therapy, especially in relation to quality of life. As
reports of these adverse events have increased, so has the anxiety of patients. Some
individuals with disfiguring changes in body composition have undergone liposuction and
plastic surgery in an attempt to mitigate the effects of these abnormal metabolic changes.
There is a growing concern that patients may stop anti-HIV therapy in order to avoid or
rid themselves of these unwanted side effects. Moreover, as reports of these potentially
treatment-related phenomena increase, untreated HIV positive individuals may ignore
recommendations to start HIV therapy because they fear disfiguring side effects.
It is important for patient groups, physicians, researchers, drug manufacturers and FDA
to work together quickly to address the questions raised by the increasing incidence of
these side effects among people taking HIV therapy. A task force composed of researchers,
clinicians, patients and their advocates should be formed immediately to examine closely
what is occurring, and to make recommendations for coordinated action, including
formulation of a case definition of the syndrome and a blueprint for appropriate
monitoring and clinical studies.
Treatment advocates, community physicians, researchers, FDA and the protease inhibitor
manufacturers have a common interest in quickly implementing steps to better characterize
this new syndrome, to learn its cause(s) and to develop treatments to prevent and reverse
its unwanted effects. The longer the delay in pursuing these issues, the greater the risk
for a backlash against the use of anti-HIV therapy. The San Francisco AIDS Foundation
urges prompt action by all concerned parties in order to avoid a possible erosion of
confidence in current HIV therapy guidelines.
FDA Panel Rejects Drug for Cryptosporidial Diarrhea
The FDA's Antiviral Advisory Committee voted on May 6, 1998 against approval of
nitazoxanide (NTZ; brand name Cryptaz), from Unimed Pharmaceuticals, for the treatment of
cryptosporidial diarrhea. NTZ is the first anti-cryptosporidiosis drug to be reviewed by
FDA. During the public hearing on the company’s approval application, the San
Francisco AIDS Foundation, as well as other AIDS groups, urged the FDA panel to approve
the drug. Although NTZ appears safe and reasonably well-tolerated, the data presented by
Unimed failed to convince the committee that the drug produced a significant decrease in
crypto-associated diarrhea. A major reason for the lack of convincing data on NTZ stemmed
from the premature closure of a placebo-controlled study (ACTG 336) designed to test the
drug’s effectiveness. ACTG 336 was closed in April due to insufficient enrollment.
The widespread use of potent anti-HIV regimens has produced a dramatic reduction in the
incidence of opportunistic infections, including cryptosporidiosis. This fortunate
development has a flip side, evidenced by the shutdown of ACTG 336: there are now so few
people with cryptosporidiosis that it has become impossible to recruit enough volunteers
for an efficacy trial of drugs to treat the disease (a similar situation has developed
with recruitment of studies for CMV disease). In addition, the relatively small number of
people currently affected by cryptosporidiosis has created little incentive for
manufacturers to develop drugs for the condition.
Unimed wants FDA to approve NTZ so that the company can market it and begin to recover
its costs for developing the drug. Community advocates would like to see NTZ become more
widely available to people with cryptosporidiosis, but following the debacle at the May
FDA review, many no longer support standard or even conditional approval of the drug.
Although the data from several small NTZ studies are encouraging, there is no chance of
FDA approval unless a new study is conducted that produces clearer evidence of efficacy,
as well as more information on the optimal dose of the drug.
To achieve this objective, Linda Grinberg and Martin Delaney of Project Inform have
drafted a consensus statement that presents an option which may break the current logjam
on access to NTZ:
"We urge Unimed to apply for a Treatment Investigational New Drug (IND), with cost
recovery, for the use of Cryptaz for the treatment of cryptosporidial diarrhea.
Additionally, we call upon the FDA and the sponsor to work together immediately to agree
upon the design of an additional study which would more clearly answer the question of
efficacy and thus permit later replacement of the Treatment IND with New Drug Application
(NDA) approval, if warranted by study results."
Under Treatment IND regulations, when a drug sponsored by a small company with limited
financial resources fails to meet FDA approval standards, yet demonstrates a significant
promise of effectiveness, the company may apply for "cost recovery" for
supplying the drug to patients. In this scenario, although the drug is not approved for
widespread marketing, the company can charge for it. This arrangement gives small,
cash-strapped manufacturers an incentive to make the drug available to patients in need of
an unapproved therapy. The cost to patients (or insurers) is negotiated between FDA and
the manufacturer.
It is uncertain whether Unimed and FDA can agree on how to proceed to make NTZ
available to patients with cryptosporidial diarrhea. The Project Inform consensus
statement offers a rational, productive blueprint for moving toward a resolution of this
important matter. The San Francisco AIDS Foundation urges Unimed and FDA to negotiate a
cost recovery IND for NTZ as soon as possible.
If your organization would like to support the community consensus statement on NTZ,
please contact Linda Grinberg (310-471-6565) or email Linda_Grinberg@prodigy.com.
How to Obtain NTZ
NTZ is currently available in the U.S. through 2 mechanisms. For individuals already
enrolled in the Cryptaz compassionate use program, Unimed will continue to supply free
drug. However, no new patients will be admitted to this program (physicians can reach
Unimed at 800-864-6330). The only other reliable source for NTZ in the U.S. is New York
City’s People with AIDS Health Group, which imports the drug from Mexico. At a dose
of 1,000 mg daily, a month’s supply of NTZ will cost approximately $150 through the
PWA Health Group (telephone 212-255-0520).
Revisions to Federal Guidelines for Treatment of HIV
The U.S. Department of Health and Human Services published revisions to its Guidelines for the Use of
Antiretroviral Agents in HIV-Infected Adults and Adolescents in the April 24, 1998
issue of Morbidity and Mortality Weekly Report. The guidelines were originally
released in June 1997 (see BETA, June 1997). The most
significant changes to the original recommendations are summarized here. For a complete
summary of the revisions, see Research Notes.
The Panel on Clinical Practices revised its guidelines on recommended, preferred drugs
for the treatment of HIV to include Fortovase, the new soft-gel capsule formulation of
saquinavir. This action places Fortovase on a par with the other protease inhibitor
drugs--indinavir, nelfinavir and ritonavir--as a first-line HIV treatment option, when
used in combination with 2 nucleoside analog drugs. In addition, as recommended, preferred
treatment options, the panel has added the combination of ritonavir plus either hard-gel
capsule saquinavir (Invirase) or Fortovase, also when used in combination with 2
nucleoside analog drugs. The panel notes that gastrointestinal toxicity may be greater
when using Fortovase than with Invirase. Invirase use is no longer recommended, except
in combination with ritonavir.
Regarding the criteria for changing a drug regimen due to treatment failure, the panel
has added the following recommendation: "In some cases, regimens identified as
suboptimal for initial therapy are rational due to limitations imposed by toxicity,
intolerance or non-adherence. This especially applies in late-stage disease. For patients
with no rational alternative options who have virologic failure with return of viral load
to baseline (pre-treatment levels) and a declining CD4 T-cell count, discontinuation of
antiretroviral therapy should be considered."
The panel also lists several new regimens as options for patients whose current therapy
has failed. These include the following: if failing on 2 nucleoside analog reverse
transcriptase inhibitors (NRTI), switch to 2 new NRTI plus ritonavir
plus saquinavir; or switch to 1 new NRTI plus 1 non-nucleoside reverse
transcriptase inhibitor (NNRTI) plus a protease inhibitor; or switch to 2 protease
inhibitors plus 1 NNRTI.
Regarding use of the NNRTI drugs, the panel notes the following: "Of the 2
available [FDA-approved] NNRTI, clinical trials support a preference for nevirapine
(Viramune) over delavirdine (Rescriptor) based on results of viral load assays. These 2
agents have opposite effects on the CYP450 [liver enzyme] pathway, and this must be
considered in combining these drugs with other agents." Editor’s Note:
prior to making any decisions regarding first-time use of an NNRTI, BETA advises
patients and physicians to watch for reports on new data on the NNRTI efavirenz (Sustiva)
to be presented at the 12th World AIDS
Conference in Geneva.
25% of HIV Positive Individuals Not Treated According to Federal Guidelines
Approximately 1 in 4 individuals starting HIV drug therapy are prescribed drug regimens
that are not consistent with federal guidelines for HIV treatment, according to a recent
survey conducted by Louis Harris and Associates and funded by a grant from Merck and
Company.
The survey evaluated HIV-treating physicians' current use of HIV drug therapy, their
general awareness and acceptance of the federal guidelines, and how closely they followed
the guidelines. The survey revealed that physicians with the least experience treating HIV
waited longer to begin treatment and prescribed fewer medications than recommended by the
guidelines.
A smaller percentage of women, African-Americans and Hispanics receive care from the
most experienced physicians than do white men, according to the survey. "Many of the
more experienced physicians are not always easily accessible to this growing segment of
the population most affected by HIV," said Paul Volberding, MD, Professor of Medicine
at the University of California at San Francisco.
Physicians with less treatment experience tend to treat the greatest proportion of
women and people of color with HIV, and start antiretroviral therapy later for their
treatment-inexperienced patients. The survey results show that more women and minorities
are HIV-symptomatic when beginning HIV therapy (36% of women, 42% of African-Americans,
43% of Hispanics) compared to white men (27%), and have higher viral load measures and
lower CD4 cell counts at the start of therapy.
Based on the survey of 476 physicians who prescribe treatment for HIV patients,
Volberding called for more physician education on the guidelines through the International
AIDS Society-USA, an organization he heads and which sponsors numerous national HIV
education programs.
For a copy of the survey report, contact Corinna Kaarlela at 415-476-3804 or Bill
Martin at 917-769-5619.
FDA Proposes New Rules for Off-Label Use of Prescription Drugs
FDA has proposed new regulations to allow more flexibility regarding information about
off-label use of prescription drugs. "Off-label" refers to the use of
FDA-approved drugs, biologics or medical devices for purposes other than the specific
approved use. For example, the use of amitriptyline (Elavil) for control of
HIV-related peripheral neuropathy pain is an off-label use of that drug, which is
FDA-approved only for use as an antidepressant.
When finalized, the new rules will allow drug, biologic and device manufacturers to
disseminate certain types of information about off-label use to healthcare providers,
pharmacy benefits managers, health insurers, and federal and state agencies (such as
MediCal), but not to patients or media. FDA will require the manufacturers to
submit a supplemental application for FDA approval of the new use within 6 months of
starting information dissemination about the new indication.
FDA will also restrict the type of information that the company can distribute. Such
information must be in the form of "an unabridged reprint or copy of a peer-reviewed
scientific or medical journal article, or an unabridged reference publication, about a
clinical investigation that is considered scientifically sound by qualified experts."
The manufacturer also would have to submit a copy of the information to FDA for review
prior to dissemination.
These proposed new regulations should satisfy opponents of off-label information
distribution who fear manufacturers will disseminate false or misleading information which
could pose a significant safety risk to consumers. The proposed new rules tightly control
the type of information and the method of distribution.
The FDA proposal may be too restrictive concerning information distribution on
off-label use, because it requires the manufacturer to seek FDA approval for the new
indication. In cases where data are scant or insufficient for the unapproved use, the
agency may be interfering in a patient’s fundamental right to take a potentially
beneficial medication. In addition, FDA’s tight restrictions on off-label drug use
may be particularly harmful to patients seeking relief for illnesses for which there are
no other viable treatment options.
It also appears counterintuitive to forbid manufacturers to provide to patients
information on off-label use that is published in professional journals. Many patients are
well informed consumers capable of making sound judgments about medication use in
consultation with their physicians. They do not require a federal agency to control what
information they may or may not access, especially when the source material has already
appeared in a scientific publication or presented at a scientific conference.
Efavirenz (Sustiva) on Fast-Track for FDA Accelerated Approval
DuPont Merck has submitted to FDA a New Drug Application (NDA) for accelerated approval
of its NNRTI drug efavirenz. FDA has agreed to speed up its review of the drug in order to
make it available by prescription before the end of this summer (assuming FDA grants
approval).
Efavirenz is a unique anti-HIV drug that is taken once daily. DuPont Merck is expected
to present data at the AIDS conference in Geneva showing that efavirenz produces
undetectable HIV levels when the drug is used with or without a protease inhibitor. It is
possible that the combination of efavirenz plus 2 nucleoside analogs (e.g., AZT/3TC,
d4T/3TC or d4T/ddI) may lead to potent and durable suppression of HIV. These 3-drug
combinations have the advantage of sparing the use of protease inhibitors. The critical
question is whether these non-protease inhibitor-containing regimens can produce a
reasonably durable response. The company’s presentations on efavirenz in Geneva may
help to answer this question.
Efavirenz is currently available through an expanded access program open to people with
HIV who cannot construct a viable treatment regimen without the drug. For more information
about this program in the U.S. and Canada, which has enrolled over 6,000 people, call
DuPont Merck at 800-998-6854. Editor's Note: DuPont has bought out Merck and
Company’s 50% interest in DuPont’s pharmaceutical drug development program. When
the $2.6 billion deal is finalized, the new entity will be called the DuPont
Pharmaceuticals Company.
Efavirenz and Fortovase
DuPont Merck recently sent a letter to physicians regarding the results of analyses
from an interaction study of the combined use of efavirenz and Fortovase (the new soft-gel
formulation of saquinavir manufactured by Roche Laboratories). Preliminary results suggest
that the combination of 600 mg per day of efavirenz plus 1,200 mg 3 times per day of
Fortovase produces a 10% decline in plasma concentration of efavirenz and a 60% decline
in plasma concentration of Fortovase.
DuPont Merck believes that the 60% decline in Fortovase concentration warrants the
recommendation that clinicians not use Fortovase as the only protease inhibitor in
combination regimens that include efavirenz unless no other regimen is possible. "All
other saquinavir-containing double protease inhibitor regimens are strongly discouraged
with the possible exception of ritonavir/saquinavir," according to DuPont Merck.
However, DuPont Merck states that "the use of Sustiva with Norvir [ritonavir] and
Fortovase is not recommended, pending data on drug-drug interactions. There are no data to
support any dosing recommendation or even the use of these drugs together."
Roche sent a letter to community treatment advocates on June 12, 1998 commenting on the
DuPont Merck communication about the Sustiva/Fortovase interaction. "DuPont Merck
provided preliminary data on interactions between efavirenz and Fortovase. However, it
should be noted that preliminary research indicates that efavirenz also triggers a decline
in plasma concentration with the protease inhibitors Crixivan [indinavir] and
amprenavir….Often results from teratogenicity, mutagenicity, carcinogenicity and
other safety studies, as well as drug-drug interactions, do not become apparent until
further study is concluded, particularly with drugs in expanded access or accelerated
approval." Roche apparently agrees with DuPont’s conclusions regarding use of
efavirenz in combination with ritonavir plus Fortovase: "We [Roche] do not have any
activity data to support the case [sic] of efavirenz in combination with ritonavir and
Fortovase in salvage therapy. So at this point, Roche cannot responsibly advise any
specific patient on a course of action or make any dosing recommendations [regarding this
combination]." The bottom line: until more data become available, it may be
prudent to avoid using efavirenz in any regimen that includes Fortovase, based on
DuPont’s preliminary data suggesting that Fortovase concentrations decline by 60%
when the 2 drugs are combined at standard doses.
Kidney Dysfunction: A Safety Update on Adefovir (Preveon)
Adefovir dipivoxil (Preveon) is the nucleotide analog drug from Gilead Sciences now
available on expanded access for individuals who cannot construct a viable treatment
regimen without it (for information on the program, call 800-GILEAD-5). Approximately
2,800 patients have enrolled in the adefovir expanded access program, which provides the
drug free to those who qualify. Another 2,200 patients are participating in clinical
trials of the drug. Gilead Sciences is expected to file an application with FDA for
accelerated approval of adefovir before the end of 1998.
Gilead reports that 366 serious clinical adverse side effects or grade III (moderate)
laboratory abnormalities have been noted in 216 patients as of March 31, 1998, primarily
asymptomatic elevations in hepatic transaminase (liver enzyme) or creatinine levels.
After 48 weeks of treatment, 32% of patients taking 120 mg once daily adefovir
developed 3 or more laboratory abnormalities suggestive of a condition called proximal
renal tubular dysfunction (PRTD), a disorder of the kidneys. These abnormalities
include hypophosphatemia (low blood levels of phosphate), glycosuria, proteinuria (sugar
and protein, respectively, in the urine), low serum bicarbonate levels and elevated
creatinine levels. The PRTD-related abnormalities were generally mild to moderate (grade I
or II) in severity. The onset of this syndrome occurred after approximately 24-28 weeks of
adefovir therapy; no cases were reported earlier than 20 weeks after starting the drug.
The abnormalities were reversed following dose reduction or temporary or permanent
discontinuation of adefovir. The median time to resolution of laboratory abnormalities was
8 weeks following dose modification or discontinuation, according to Gilead.
The 2 most common lab abnormalities associated with PRTD are (1) elevated serum
creatinine (a greater than 0.5 mg/dL increase from baseline value), and (2) decreased
serum phosphate (less than 2.0 mg/dL). While other abnormalities such as proteinuria and
glycosuria may also occur, and should be routinely monitored during treatment with
adefovir, they are less specific and sensitive indicators of PRTD.
It is important that physicians remain alert to the potential onset of these
laboratory abnormalities in their patients taking adefovir. Observation of any of
these potential manifestations of PTRD in a patient taking adefovir warrants further
evaluation using other appropriate laboratory tests to confirm PTRD. Complete data on
PTRD-related abnormalities will be presented by Gilead Sciences at the Geneva AIDS
conference.
FDA Approves New Combination Treatment for Hepatitis C
Many HIV positive individuals are co-infected with hepatitis C, a liver infection that
can lead to cirrhosis, liver cancer, liver failure and death. FDA has approved a
combination of 2 drugs for the treatment of the disease, ribavirin (Rebetol) plus
interferon-alpha. The newly approved combination works better than interferon-alpha
injections alone (the standard treatment). The downside of the combination is its high
cost and potentially serious side effects, which may include severe anemia, birth defects
and psychiatric problems. The most common side effect of interferon-alpha is flu-like
symptoms.
The interferon-alpha/ribavirin combination regimen consists of a 6-month course of
interferon-alpha injections and ribavirin capsules. Depending on the doses used, a course
of treatment will cost $6,400 to $8,600. About 50% of people using interferon-alpha alone
do not respond at all. Thirty to forty percent respond to interferon-alpha, but then
relapse. FDA approved the combination for these patients, although physicians are free to
prescribe the drug as they see fit.
Ronald Baker, PhD, is Editor-in-Chief of BETA and Director of Treatment Advocacy
at the San Francisco AIDS Foundation.
Page last updated 10 July 1998
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