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ANTIVIRALS |
Protease Inhibitors and Atypical Fat Distribution
The Crix-List, an email discussion list for users of indinavir has, for
a long time, contained many anecdotal reports of changes in body shape following
the use of indinavir. The pot-belly phenomenon seen by many had been nicknamed
Crix-belly. However, it is unlikely that this phenomenon is restricted as
a side-effect of indinavir, and may apply to the protease inhibitors as
a class. The following are the first two published reports to appear detailing
this unwanted side-effect of protease inhibitor use.
A Syndrome of Peripheral Lipodystrophy (LD), Hyperlipidaemia and Insulin Resistance due to HIV Protease Inhibitors (PIs)
Background
: We observed peripheral LD (fat wasting of the face and limbs with relative central adiposity) in HIV+ pts receiving potent PIs. This together with the known PI side effects of hyperlipidaemia and diabetes mellitus, suggest PIs cause metabolic perturbations leading to insulin resistance.Methods
: We evaluated otherwise well HIV+ pts receiving at least one PI (n=116) or who were PI naive (n=32) and matched healthy males (n=47). LD was assessed by history, physical exam and total and regional fat measured by dual-energy X-ray absorptiometry (DEXA). Fasting cholesterol, triglycerides (TG), glucose, insulin, C-peptide, free fatty acid (FFA), fructosamine, cortisol, testosterone, leptin, and TNF-alpha levels, liver enzymes, T cells and HIV RNA load were assessed.Results
: Seventy two (64%) HIV+ pts developed PI-induced lipodystrophy after a mean 10 months. LD was associated with mean weight loss of 0.51kg/month relative to PI-treated pts without LD (p=0.0005) and mean fat loss of 5.5kg in all regions except the abdomen (p=0.0001). Three (2%) pts developed new or worsening diabetes mellitus. LD pts had significantly higher TG, cholesterol, Insulin, and C-peptide levels and insulin resistance scores. LD developed earlier (8 Vs 12 months) and was more severe in pts on ritonavir/saquinavir than indinavir.Conclusions
: A syndrome of peripheral LD, hyperlipidaemia and insulin resistance is a common toxicity of potent PI therapy, particularly RIT-SAQ, but diabetes is rare.Authors: A. Carr 1, K. Samaras 2, S Burton 1, J Freund 1, DJ Chisholm 2, DA Cooper 1,3. 1. St Vincent's Hospital, 2. Garvan Institute of Medical Research, 3. National Centre in HIV epidemiology and Clinical Research, Sydney Australia.
Source: Australasian Society of HIV Medicine Conference, November 1997, Adelaide, Australia.
Benign symmetric lipomatosis associated with protease inhibitors
Unprecedented advances in the treatment of HIV-1 infection can be attributed
in a large part to the use of protease inhibitors. Protease inhibitors are
metabolised by the hepatic cytochrome P450 system of enzymes, and interactions
at this site of metabolism are a cause of the side effects associated with
these medications. Protease inhibitors can affect lipid metabolism, and
glucose tolerance. We report a patient who developed unusual fatty deposits
(benign symmetric lipomatosis) while on indinavir, lamivudine, and zidovudine.
A 34-year-old man has been seen for HIV-1 infection as an outpatient at
our clinic since May, 1995. In October 1993 he and his wife both tested
positive for HIV-1. At that time he was without symptoms and his CD4 count
was 285 106/L. Zidovudine was begun in November, 1993, and trimethoprim/sulfamethoxasole
prophylaxis in August, 1994. Other than an episode of herpes zoster he remained
well. In April and June, 1996, lamivudine and indinavir were added to his
medications. In August, 1996, myalgia and weakness prompted a measurement
of his creatine kinase (CK), which was elevated. Without any change in treatment,
his myalgia and weakness resolved within 3 weeks, although his CK has remained
elevated. At a follow up in December 1996 a "buffalo hump"--accumulation
of fat in the cervical fat pad area and across the shoulders--was noted.
He also had fatty changes in the supraclavicular area, but no other features
suggestive of Cushing's syndrome at that time. Blood tests revealed only
a minimally elevated blood glucose. Electrolytes and cholesterol were normal.
A low-dose dexamethasone suppression test was normal, ruling out Cushing's
syndrome. His HIV-1 RNA viral load was undetectable, and he has continued
on what has otherwise been a successful regimen for his HIV-1 infection
without any worsening of fat deposition.
Benign symmetric lipomatosis is an uncommon condition seen predominantly
in male alcoholics. Apart from alcohol, associations have included glucose
intolerance, hyperlipidaemia, hyperuricaemia, and polyneuropathy. Studies
have implicated abnormal lipolytic responses of adipocytes to catecholamine
and elevated levels of lipoprotein lipase and lipoprotein. Our patient has
never drunk alcohol. The temporal association between starting his medications
and developing his "buffalo hump", the effect of protease nhibitors
on P450 enzymes, and the recent associations between indinavir use and glucose
and lipid metabolism lead us to believe indinavir may be implicated in the
development of benign symmetric lipomatosis.
[See full text article for photograph and references]
Authors: R L Hengel, N B Watts, J L Lennox. Divisions of Infectious
Diseases (R L Hengel) and Endocrinology, Department of Medicine, Emory University
School of Medicine, Atlanta, GA 30303, USA
Ref: Lancet. 1997; 350(9091)
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Lipodystrophy and diabetes are a real phenomenon of PI use the incidence
of which is unclear. DEXA Scanning is not seen as an accurate or reproducible
means of assessing body fat distribution by academic dieticians, hence
these results should be viewed with caution. What is important is
the incidence of clinically significant problems. In Munich the Ludwig-Maximilian
University (Prof. Goebel) is the referral centre for PI-induced diabetes
mellitus. The functional tests demonstrate type 2 diabetes. The preliminary
data show that all patients are at least 35 years of age, most of
them beyond 40 years. This is an age group at risk for type 2 diabetes
which is caused by peripheral insulin resistance and a secondary failure
of the endocrine function of the pancreas. Diabetes in this group
did not respond to interruption or change of PI treatment. As well
as indinavir, ritonavir and saquinavir, at least two patients have
also developed diabetes while receiving nelfinavir at this centre..
Usually the diabetes responds well to glibenclamide or other oral
antidiabetics of this class (however, see warning on troglitazone
at the end of this edition). Insulin is not normally necessary. A
difficult problem is the diet used in diabetes which may be contrary
to dietary recommendations for some protease inhibitors. |
Adefovir Results Published and US Expanded Access Announced
The results of a preliminary clinical trial indicate that adefovir dipivoxil,
an oral nucleotide reverse transcriptase inhibitor, is well-tolerated and
shows moderate anti-HIV activity, according to a multicentre group. They
report their findings in the December issue of the Journal of Infectious
Diseases.
Adefovir dipivoxil is a novel nucleotide analogue with several promising
in vitro anti-human immunodeficiency virus (HIV) characteristics,"
Dr. Steven G. Deeks of San Francisco General Hospital and colleagues explain.
Dr. Deeks' group evaluated the safety and efficacy of monotherapy with adefovir
dipivoxil in 72 patients with moderately advanced HIV infection. "Subjects
were randomly assigned in a 2:1 ratio to receive adefovir dipivoxil or placebo
as a once-daily oral dose for 6 weeks, followed by 6 weeks of open-label
adefovir dipivoxil." They evaluated two doses of adefovir dipivoxil
- 125 mg and 250 mg.
Adefovir dipivoxil was safe and well-tolerated after a 12-week course of
treatment, they report. By week 6, "...changes in absolute CD4 T cell
levels and HIV-1 RNA levels were significantly greater with adefovir dipivoxil
than with placebo," and these changes were maintained at 12 weeks.
In addition, Dr. Deeks' group detected genotypic changes from baseline in
only 1 of the 24 subjects who received 125 mg of adefovir dipivoxil. They
believe that the preliminary data indicate that "...high-level drug
resistance to adefovir dipivoxil may not be a factor limiting the long-term
use of this drug. Larger studies to characterise the clinical benefits of
adefovir dipivoxil as therapy in HIV disease are currently underway."
Meanwhile, last week, Gilead Sciences, Inc., based in Foster City, California,
announced an expanded access program for adefovir dipivoxil (Preveon) in
the USA. The company plans to make the drug available to patients in the
US with advanced HIV infection as an antiretroviral therapy and prophylaxis
for cytomegalovirus disease.
Ref: J Infect Dis 1997;176:1517-5223
Source: CDC NCHSTP Daily News Update
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It should be commented that it is shameful that monotherapy studies
are still being conducted in HIV-infected people. Concerns also exist
that nucleotides as a class (ie. cidofovir, adefovir, PMPA) may possess
renal toxicity problems which may not become apparent in such a low-dose
short term study. The low dose may also explain the lack of resistance
seen (no selective pressure was being exerted). Phase I/II studies
showed a viral load activity of adefovir of around - 0.3 to 0.5 log.
There is concern that a proper dose for this agent has yet to be determined,
and adequate dose ranging studies should be performed BEFORE compassionate
access. |
More Discussion on Latent HIV Despite Potent Antiretroviral Treatment
The following is an extract from an article by Dave Gilden published in
the New York based treatments newsletter Treatment Issues. The full article
is available from the Gay Mens Health Crisis on the Web at:
http://www.gmhc.org
This article discusses the recent publications detailing recovery of replication
competent HIV from individuals who have undergone potent suppressive antiretroviral
therapy for up to 3 years (see ATPs Doctor Fax Issues 35
& 36 for details of these publications).
Does Residual Virus Equal Residual Replication?
The NIH investigators raised an important issue: Is the pool of latently
infected cells slowly turning over, i.e., are the cells slowly dying and
being replaced by newly infected ones? Or are the latently infected cells
very long-lived, like uninfected resting CD4 cells? They would then represent
a viral reservoir left over from the pretreatment period when HIV was running
rampant. The NIH investigators did find significant quantities of "unintegrated"
viral DNA that had not yet merged with the chromosomes in the surrounding
cell. Because the strands of unintegrated DNA are unstable, they presumably
derive from new HIV that has recently penetrated the cells containing them.
The Johns Hopkins group noted in their paper that in the one individual
with undetectable viral load who was tested, the frequency of activated
CD4 cells releasing infectious HIV was a miniscule but detectable 0.0002%.
(That incidence was ten times higher in patients with viral loads of 200
to 1,000 -- just over the quantification threshold.) Nonetheless, most researchers
are confident that even if a few cells do release HIV in patients considered
"fully suppressed," those virions are going nowhere because the
antiviral drugs are blocking them. Dr. Joseph Wong of the University of
California San Diego argued, "The lack of emergence of drug resistance
[in these patients' HIV] indicates a vanishingly (sic) low rate of replication.
Since the genetic makeup of the pre- and post-therapy virus is very similar,
the latent HIV probably was there from the beginning."
Still, the evidence that a few cells are producing HIV demonstrates that
the highly artificial conditions that promoted the activation of latent
HIV in the lab does have some relevance to the processes in the body. Presumably
as different populations of resting cells are activated to fight new infections
during the natural course of events, any cells that harbour competent, integrated
HIV genes will start churning out virus. This possibility raises the prospect
that antiviral therapy will have to be continued even in patients with undetectable
viral loads until all the latently infected resting cells are cleared from
the body.
But how long is that? No one seems to know at this point. It is of course
widely remarked that people who interrupt therapy in the first couple of
years have very rapid HIV rebounds. This resurgence is probably mainly due
to chronically producing cells such as infected macrophages. The present
findings extend the treatment horizon by adding a new long-lived HIV reservoir.
The new reservoir greatly postpones the point at which HIV eradication might
be achieved even in people whose viral loads approach zero under treatment.
Ref: Treatment Issues - Volume 11, Number 11, November 1997.
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OPPORTUNISTIC ILLNESSES |
Radiology Research Suggests that Protease Inhibitor Containing Regimens
Can Reverse AIDS Dementia
Research presented recently at the Radiological Society of North America
suggests that antiretroviral drug cocktails can halt, or possibly reverse,
dementia caused by the disease. According to researchers from the Albert
Einstein College of Medicine in New York, brain scans prove that protease
inhibitors combined with other antiviral drugs change the course of AIDS
dementia complex enough to permit some terminally ill patients to return
to their jobs. Christopher Filippi, an investigator on the study, said many
patients included in the trial had less than a year to live and were nurse-dependent
when they started treatment. Fourteen months later, he said, they were alive
and, in some cases, enough improved to return to work.
Results of a magnetic resonance imaging (MRI) study of the effects of protease
inhibitors on patients with HIV-encephalopathy -- a disease of the white
matter of the brain that can cause loss of mental and motor function --
were presented at the 83rd Scientific Assembly and Annual Meeting of the
Radiological Society of North America (RSNA).
"Until now, HIV-encephalopathy has been considered to be relentlessly
progressive. This is the first study that demonstrates clinical neurologic
improvement with the use of protease inhibitors that correlates with an
improvement seen on brain MR scans," said Christopher G. Filippi, M.D.,
assistant professor of radiology and director of neuroradiology at the Weiler
Hospital, Albert Einstein College of Medicine, New York City.
Sixteen patients were studied. The MR scans of eight of nine patients (89
percent) who took protease inhibitors showed stabilisation (four patients)
or near complete regression (four patients) of white matter disease. These
changes correlated with clinical improvements in their symptoms. One patient
showed slight progression of disease. The MR scans of six of seven patients
(86 percent) not on protease inhibitors showed disease progression. These
findings corresponded with decline in mental function. One patient showed
no change. The study was conducted at Yale-New Haven Medical Center, New
Haven, Conn.
The seven patients in the control group were not given protease inhibitors
for clinical reasons, ranging from elevated liver function tests to a history
of non-compliance with medication regimens, according to Dr. Filippi. MR
scans were performed at intervals ranging from two to 12 months, he said.
"Our study showed a statistically significant improvement with protease
inhibitors and suggests that many more patients may benefit from these drugs,"
he said, adding control of the disease with protease inhibitors also may
avoid even more costly medical interventions.
Patients in the study were end stage AIDS patients with abnormal MR scans
that showed a significant amount of white matter disease, Dr. Filippi said.
In HIV-encephalopathy, the HIV virus invades the brain. All of the patients
(nine men and seven women) also were on nucleoside analogue therapy, such
as ZDV, d4T, ddI and 3TC. Nine patients were started on protease inhibitor
therapy (ritonavir, indinavir or saquinavir) by their primary care providers
after an initial MR scan.
Source: CDC NCHSTP Daily News Update
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Is there added value from PIs over NAs in the prevention and treatment
of AIDS dementia? ZDV monotherapy apparently improves ADC. However,
Farthing et al (ICAAC 97) showed that 12/13 patients with undetectable
viral load in plasma, on RTV/SQV only, also had undetectable CSF viral
load, suggesting a PI effect. A study presented by Moyle et al. in
Hamburg this year suggested that some patients with low viral load
in plasma on dual PI therapy had > 1 log higher viral load in CSF
and that those with NAs in their regimen were more likely to have
undetectable VL in CSF. |
Two New Reports On hCG Treatment for Kaposis Sarcoma
In the journal Nature, British scientists have reported early data that
could lead to a treatment for Kaposi's sarcoma. According to David Adams
of the University of Leeds, the research indicated that ribonuclease enzyme
contained in a commercial preparation of the hormone human urinary chorionic
gonadotrophin (hCG) reacts against the cancer cells and causes cell death.
Adams identified the enzyme as the active ingredient that appears to cause
tumours to regress. "We think hCG and the associated ribonuclease may
have [the] most potent anti-cancer activity in combination," Adams
commented.
Ref: Ribonuclease inhibits Kaposi's sarcoma (Scientific Correspondence)
S J Griffiths, D J Adams & S J Talbot 568 11 December 1997 Vol 390,
No 6660
New research published in the December 3 issue of the Journal of the National
Cancer Institute suggests that a preparation of human chorionic gonadotropin
administered subcutaneously to AIDS patients with Kaposi's sarcoma is safe
and exhibits anti-KS activity. According to Parkash S. Gill of the University
of Southern California in Los Angeles, evidence of anti-tumour activity
against KS following the use of certain preparations of human chorionic
gonadotropin has been reported before. Researchers in the current trial
used Wyeth-Ayerst's A.P.L., which had shown the most activity against KS
cells in vitro. They found that six of 18 patients had major responses to
the preparation, while two achieved biopsy-confirmed complete remissions.
Source: CDC NCHSTP Daily News Update
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Potent combination therapy including a protease inhibitor is known
to have a significant impact itself on KS. Most oncologists would
suggest initiation of such antiretroviral therapy rather than specific
anti-KS treatment. Liposomal doxorubicin and daunorubicin are the
treatments of choice for patients with disseminated, progressive KS
despite PI treatment. Such patients are rare (6 of approximately 900
patients in a Munich clinic).For patients with limited disease and
the need for treatment, local therapy with intralesional injection
or radiotherapy is preferred. |
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OBSTETRICS |
Incidence and Consequences of Pregnancy in Women With Known Duration of
HIV Infection
To determine the incidence and outcome of pregnancy in HIV-infected women,
as well as the rate of disease progression in pregnant women, Maria Alliegro
and colleagues for the Italian Seroconversion Study Group conducted a prospective
study of 331 women who seroconverted between 1981 and 1994. Using a follow-up
of 5.5 years for each subject, the researchers found that 94 of the women
had developed HIV-related diseases, 47 had developed AIDS, and 53 had CD4
counts of under 100. At the time of seroconversion, 38 of the women were
pregnant, while 31 became pregnant within an average of eight years after
seroconversion. Although only 45 of the 69 pregnancies were carried to term,
the researchers found no significant differences in terms of the rate of
disease progression. The researchers conclude that HIV-positive women do
continue to become pregnant even after seroconversion, and pregnancy does
not affect the rate of HIV progression.
Ref: Archives of Internal Medicine (12/08/97-12/22/97) Vol. 157, No.
22, P. 2585; Alliegro, Maria Barbara; Dorrucci, Maria; Phillips, Andrew
N.; et al.
Source: CDC NCHSTP Daily News Update
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PATHOGENESIS |
Vigorous HIV-1-Specific CD4+ T Cell Responses Associated with Control
of Viraemia
A study published November 21 in SCIENCE is generating considerable scientific
interest, and suggests possible treatment strategies for both early and
more advanced HIV infection. While this study itself is one small building
block among a number of important advances toward the understanding of how
the body first controls HIV infection but later usually fails to do so,
its publication seems to mark a time of change toward integration of virological
and immunological approaches, away from the relative neglect of immunology
and domination of HIV research by virology.
The picture emerging from this and other studies is that in most cases of
HIV infection, the T-helper cells which respond specifically to HIV (and
help to bring down the very high viral load which develops during primary
HIV infection) seem to be lost or stop working early in the disease process.
The new study examined long-term nonprogressors, and found that in them,
this specific T-helper response against HIV remained strong. In other persons
with HIV who were tested, this response correlated strongly with low viral
load (much more strongly than CD4 count correlated with viral load), suggesting
that specific T-helper response to HIV is important in the body's control
of the virus. Why the specific anti-HIV activity is lost is unknown; it
is possible that the cells which recognise HIV are activated and therefore
easily infected at the time of high viral levels during primary infection.
Two practical consequences have been suggested by a number of researchers:
(1) Effective antiretroviral treatment early enough--probably during primary
infection with a regimen including protease inhibitors--may allow the specific
anti-HIV responses to be preserved, as they seem to be in long-term nonprogressors.
Early experience from treatment of patients during primary infection supports
this possibility.
(2) Later in HIV disease, antiviral treatment which results in undetectable
viral load generally does not lead automatically to the return of these
specific anti-HIV T- helper cells. However, there is reason to believe that
they still could be induced by vaccination while the infectious virus is
suppressed by antiretrovirals. Several approaches-- killed-virus vaccine,
certain HIV antigens produced by genetic engineering, or DNA vaccines--are
feasible to try now.
Source: AIDS Treatment News No. 284, December 5, 1997. Subscription
and Editorial Office: P.O. Box 411256 San Francisco, fax 415/255-4659 Internet: