Thanks for the URL, Paul. Given your penchant for altering documents,
I've appended the original below.

Nevirapine definitely has toxicities! No kidding. ALL drugs do. And
AIDS meds can and do cause in  many all kinds of problems.

The issue is that HIV causes people to die rather horribly. With AIDS
meds, I am not seeing my friends die from MAI, KS, PCP, CMV. No
question, I have lost friends. People die of liver toxicities, esp. if
they have Hep C coinfection. But most folks I know with HIV are
living--many FAR longer than I would have expected in the 80s and
early 90s. I remember how fast people died.

Deny all you like, my dear. But it's a heliocentric solar system--and
HIV causes AIDS.

Best of luck. I've deleted your other posts because I think you may
have distorted them....let alone your persistent attempts to distort
information to justify your need to f.ck without a condom.

        George M. Carter

**
NATAP REPORTS
8th Annual Retrovirus Conference
SPRING 2001

ADVERSE EFFECTS & COMPLICATIONS  

Section written by Gilbert Kaufmann, MD, with selected contributions
by Harvey S. Bartnof, MD, and Jules Levin

Lipodystrophy Syndrome
The lipodystrophy syndrome (fat redistribution) is one of the major
adverse events affecting a large proportion (20-80%) of individuals
with HIV who are treated. The exact cause(s), however, are still
unclear, but changes in adipogenesis (formation of fat tissue) and
adipolysis (breakdown of adipose tissue) have been reported. There is
much controversy about the diagnostic criteria (what constitutes the
syndrome) and the true incidence (rate), as well as whether it is only
one syndrome or several syndromes. Initially associated with the use
of protease inhibitor (PI) drugs, subsequent studies provided evidence
that the use of nucleoside (NRTI) drugs and non-nucleoside reverse
transcriptase inhibitor (NNRTI) drugs may similarly be associated with
this syndrome. Potential co-factors include HIV itself and affect of
HIV and therapy on immune decline and reconstitution, age,
race-ethnicity, gender (sex), genetics, co-infection with HCV,
hormones, and diabetes/insulin resistance.

Dr. C. Goujard of the Primo Group in France presented a study that
evaluated the incidence of the lipodystrophy (body changes: face,
limbs, trunk, abdomen, breast) syndrome in 121 patients with acute
(primary) HIV (recent) infection who have been treated with HAART
(highly active antiretroviral therapy) for more than 6 months
(abstract 403). Twenty-two patients (18.2%) presented with at least
one clinical sign of lipodystrophy after a mean follow-up of 24
months. The proportion of patients with lipodystrophy syndrome
increased to 30% at 36 months. This study confirms previous reports
that lipodystrophy can already occur in very early stages of treated
HIV infection and it suggests that duration of HIV infection might not
be a major cause.

Dr. L. Kingsley of the University of Pittsburgh studied the prevalence
(rate) of the lipodystrophy syndrome and metabolic abnormalities in
the Multicenter AIDS Cohort Study (MACS), consisting entirely of men
(abstract 538). A total of 868 participants underwent regular physical
examinations and laboratory testing. The results showed that changes
of body shape were detected in 33% of HIV negative and in 63% of HIV
positive men. Various studies have found lipodystrophy rates ranging
from 20%-80%. The average age of the men in this study was 47, which
likely affects some of the findings in this study as increased fat
accumulation and other body changes occur as men grow older. Due to
the high prevalence (rate) of body changes in HIV-uninfected subjects,
the investigators tried to find a better case definition of the
lipodystrophy syndrome that would allow a better "discrimination"
between the actual lipodystrophy syndrome and other, unspecific body
changes primarily associated with increasing age. A symptom
combination of moderate or severe "peripheral wasting" (thinning of
arms or legs) and central adiposity (increase in abdomen or breasts,
or loss in buttocks) was the best working definition. This resulted in
a relatively low prevalence of 20% of patients with signs of
moderate/severe lipodystrophy in the HAART-treated group, and 8% in
the mono-combo NRTI treated group. But, 42% receiving HAART, and 40%
on mono/combo NRTIs experienced "any" body changes compared to 10% of
HIV negative men. Elevated triglycerides (>400 mg/dL) was associated
with being on HAART (12%). Elevated fasting glucose was comparable
whether on HAART (11%) or mono/combo NRTIs (9%). Hyperinsulinemia was
found in 14% of men on HAART, 9% on mono/combo NRTIs, 0% for men on no
treatment, and 7.6% of HIV negative. Low HDL (the good cholesterol)
may be a hallmark of HIV-infection and not necessarily just HAART use:
0% in HIV negatives and 22%, 27%, and 29% incidence rates in
HIV-infected taking no treatment, mono/combo, and HAART, respectively.
Although finding a case definition for the lipodystrophy syndrome is
critical to estimate the true prevalence of this syndrome, it may not
be possible due to the many various contributing factors and
manifestations. A further interesting finding of this study was that
the prevalence of moderate to severe lipodystrophy reached a plateau
after 2 years, but the incidence of "any" lipodystrophy continued to
rise through the 4 year follow-up.

Dr. V. Joly of the ANRS in Paris, France presented the NOVAVIR study
(abstract 539). A total of 170 patients were randomized to receive
either AZT (Retrovir, zidovudine, NRTI drug) or d4T (Zerit, stavudine,
NRTI drug), in combination with 3TC (Epivir, lamivudine, NRTI drug)
and indinavir (Crixivan, PI drug). But this analysis only includes 96
of the 170. The results after 30 months revealed that the proportion
of patients with signs of lipoatrophy (fat loss under the skin) was
significantly larger and the number of clinical signs of lipoatrophy
was significantly higher in the d4T arm. There were no significant
differences between the two arms in the rates of central fat
accumulation. The study suggests that d4T increases the incidence of
lipoatrophy compared to AZT. Pretreatment with NRTI drugs (AZT, ddI,
or ddC for at least 6 months) represented a potentially confounding
co-factor. A strength of this study is that it’s randomized, but the
doctors conducting skinfold measues to detect change in lipoatrophy
were not blinded to which patients were taking AZT or d4T. See
additional review of this study in Clinical Studies (NRTI section).

As has been reported previously, 2 small studies showed that the
lipodystrophy syndrome including abdominal fat accumulation and
peripheral fat loss could affect HIV positive children taking HAART in
a similar way as adults (R.A. Amaya abstract 649 and G. Meneilly
abstract 650). Moreover, a large proportion of these children had
hypercholesterolemia (increased blood cholesterol),
hypertriglyceridemia (increased blood fats) and "insulin resistance"
(pre-diabetic state or diabetes).

A significantly higher rate of lipoatrophy was observed among HIV/HCV
(hepatitis C virus) co-infected patients taking HAART than among HIV
mono-infected patients taking HAART (abstract 654). Differences in
"insulin resistance" also were reported. For more information, see
this section.

Lipodystrophy Changes Associated with Changes in Blood Markers
One of the more interesting posters about lipodystrophy and lipid
levels at the Retrovirus Conference was presented by Dr. Nevena
Christeff of the Pasteur Institute in Paris, France (abstract 660).
Dr. Christeff found that in a prospective study of 31 HIV positive men
taking anti-HIV therapy (94% HAART with a PI and NRTI drugs), changes
in certain blood markers were associated with worsened, improved or
the development of lipodystrophy (LD, fat redistribution). Twenty HIV
negative, control men were also included. The men were followed
prospectively up to 24 months. At baseline, 20 of those with HIV did
have LD, as determined by CT (computed tomography) scans and physical
examination, while the remaining 11 HIV positive men did not.

After the follow-up interval, those with LD at baseline were
classified as "unchanged" (9 of 20), "aggravated" (worsened, 5 of 20),
or "improved" (6 of 20). Those without LD at baseline were classified
as "evolution" to LD (2 of 11) or "absence of evolution (9 of 11).
Evolution of LD was determined by physical examination by the
physician, patient report and "anthropomorphic" measurements including
waist-hip ratio and skin-fold thickness. The major conclusions of the
study were that:

Among men with LD at baseline, worsening of LD was significantly
associated with a decrease in blood "DHEA" (dihydroepiandrosterone,
steroid hormone precursor), "dramatic increase in cortisol: DHEA
ratio," persistently high levels of "interferon alpha," (cytokine,
intercellular messenger) and persistently high levels of blood lipids
(triglycerides and "VLDL" (very low density lipoprotein cholesterol).
(Note cortisol is a natural "stress" hormone released from the adrenal
gland on top of each kidney; cortisol measurements were all "fasting"
levels.)

Among men with LD at baseline, LD improvement was significantly
associated with an increase in the DHEA levels leading to a normalized
cortisol: DHEA ratio, and a normalization of interferon alpha and
lipid levels.

Among men without LD at baseline, LD development (only 2 patients) was
associated with a decrease in DHEA, an increase in the cortisol: DHEA
ratio, and increased interferon alpha and lipid levels.

Among men without LD at baseline, the absence of developing LD was
associated with elevated cortisol, "highly elevated DHEA…leading to a
normal cortisol: DHEA ratio," and normal interferon alpha and lipid
levels.

The authors concluded, “This study demonstrates that clinical
evolution of lipodystrophy and lipid changes associated [with] this
syndrome are related to changes in both [the] cortisol: DHEA ratio and
interferon-alpha concentrations…[and] also confirms our previous
observations suggesting that the concomitant action of cortisol, DHEA,
particularly the cortisol:DHEA ratio and interferon alpha is one of
the mechanisms responsible for lipid perturbations and fat mass
distribution in [the] lipodystrophy syndrome.”

This study raises more questions than it answers, but might represent
the next step in our understanding fat redistribution and lipid
alterations in HIV patients taking HAART. Most of the studies to date
about LD are cross-sectional studies; however, this one is
prospective. The main question that arises is why did some patients in
the current study have or develop abnormal (or normal) levels of
cortisol, DHEA and interferon alpha? And, are those abnormal levels a
direct cause of fat redistribution or merely a marker that occurs
simultaneous to (associated with) LD? The authors reported, "none of
the patients tested received any complementary treatment, including
glucocorticoids [steroids] or ketoconazole [Nizoral, antifungal
drug]." There is an assumption that none were prescribed male sex
hormones or growth hormone. But is it possible that some were using
illicit steroids outside of the study? Also, DHEA is available as a
"dietary supplement" in the US. Were any patients taking supplementary
DHEA not known by the study authors? Would taking supplementary DHEA
improve or prevent lipodystrophy? Would "stress reduction"
interventions that lead to decreased cortisol levels improve or
prevent LD? The authors do not address these questions and others that
are raised by their findings. The association with interferon alpha is
quite interesting, since this is an approved agent to treat chronic
hepatitis C and B and some HIV/HCV co-infected patients have taken it.

It is noteworthy that one study at this Conference found a higher rate
of LD among HIV/HCV co-infected patients taking HAART than
HIV-infected patients taking HAART (see this section). Again, this
study does not establish cause & affect (that DHEA imbalances causes
LD). Other potentially confounding factors in the current study
include: duration of HAART at study baseline; duration of LD at study
baseline; adherence to therapy; CD4 counts and HIV RNA levels (that
might correlate with adherence); pre-HAART levels of cortisol, DHEA,
interferon alpha and lipids; types of ART in the HAART regimens; types
of fat redistribution (lipoatrophy versus fat accumulation); and
exercise regimens. Notwithstanding these limitations and various
unanswered questions, the study was rather provocative and certainly
will lead to further studies and much discussion.

Are Elevated Lipid Levels Associated With an Increased Risk for
Coronary Heart Disease (CHD)?
Based upon HIV negative populations, it must be assumed that HIV
positive patients with elevated cholesterol levels are similarly at
risk for CHD (coronary heart [artery] disease). For many HIV positive
persons, HAART (highly active antiretroviral therapy) appears to
increase lipid (blood fat) levels. Several reports at the Retrovirus
Conference addressed this issue.

Daniel Klein, MD of Oakland, California reported an update about the
rate of coronary heart disease (CHD) events in 4,541 HIV-infected men
receiving PI drugs in the Kaiser Permanente HMO (health maintenance
organization) in Northern California (abstract 655). The cases were
compared to 43,118 randomly selected, age- and sex-matched control
members not known to be HIV-infected. The CHD incidence was 5.2 events
per 1,000 patients per year for individuals taking anti-HIV therapy
without PI drug therapy and 5.8 for patients taking a protease
inhibitor. The rate in HIV-uninfected men was significantly lower at
3.4. Regarding other CHD risk factors, HIV positive patients had a
significantly lower rate of hypertension (high blood pressure, 13%
versus 21%), a non-significantly higher rate of increased cholesterol
levels (21% versus 15%) and similar rates of diabetes (6%) and smoking
(29%) as control members. The study suggests that PI drug use does not
increase the short-term risk for CHD, when compared to anti-HIV
therapy without a PI drug. However, the higher rate of CHD events
among HIV-infected persons taking ART remained unexplained. Whether
other possible co-factors for CHD, including cytomegalovirus (CMV) and
chlamydiae, or HIV itself might explain the difference, is unknown.

Dr. M. Mary-Krause of INSERM in Paris, France studied the course of
CHD in the French Hospital HIV Database. Myocardial infarction ("heart
attack") was diagnosed in 84 of 42,787 men exposed to PI drug therapy,
so the risk of heart attack was low. The incidence rate of myocardial
infarction increased in parallel with the time of exposure to PI drug
therapy (after 18 months of therapy, up to 30 months) and was 3-fold
higher among those with at least 30 months of PI drug exposure than
the expected incidence in the general population of HIV-negative men.
However, the statistical analysis was not adjusted for CHD co-factors.
Although this study provides some preliminary evidence that the risk
for CHD is increased in patients with long-term exposure to PI drug
therapy, a longer follow-up period is required to estimate the full
impact of long-term elevations of lipid levels on the development of
CHD in this cohort of patients.

Genetic Risk for Increased Cholesterol Associated with Anti-HIV Drugs
Dr. Andre R. Miseraz of University of Basel in Switzerland reported
that a genetic variation was significantly associated with an increase
in total blood cholesterol after starting a protease inhibitor drug
(abstract 500). A naturally occurring "polymorphism" (variation,
"genotypes 11/12") of SREBP (sterol-regulatory element
binding-protein)-1c was significantly associated with an increase in
blood cholesterol after starting PI drug therapy, when compared to
"homozygous" (the same two gene doses) "genotype 22." A total of 67
HIV positive patients were included in the study. While the results
would need to be confirmed in larger studies, they suggest that
testing for the altered gene one day might help to predict who will
develop high cholesterol after starting a PI drug and that that
information would be useful when constructing an optimal anti-HIV drug
regimen. Additionally, there might be implications for designing new
drugs to treat high cholesterol for HIV-positive and HIV-negative
populations.

"Mitochondrial Toxicity" & "Lactic Acidemia:" New Classification
System
Andrew Carr, MD of St. Vincent’s Hospital in Sydney, Australia
presented a State-of-the-Art lecture on "mitochondrial" (energy
producer of cell) toxicity (session 64, no abstract). Different
nucleoside reverse transcriptase inhibitor (NRTI) drugs are thought to
inhibit mitochondrial "polymerase gamma" enzyme to varying degrees,
resulting in toxicity. Elevated "lactate" levels (lactic academia,
increased blood acid level) may be one of the consequences of
mitochondrial toxicity. He proposed the following classification of
lactic acidemia: normal less than 2 millimoles per liter (mmol/L),
mild increase: 2-5, moderate increase: 5-10, and severe: greater than
10 mmol/L. Subjects with mild lactic acidemia may be asymptomatic (no
symptoms), whereas patients with moderate lactic acidemia may show
symptoms such as fatigue, malaise, and gastrointestinal
(stomach-colon) symptoms including nausea. The severe form of lactic
acidemia is often acidotic (lactic acidosis syndrome, grouping of
abnormalities), which is associated with a high mortality (death
rate), particularly in women who are overweight. With regard to these
serious consequences, Carr recommended that NRTI drug therapy should
be discontinued when lactate levels increase above 5-10 mmol/L.
However, he did not recommend routine testing of lactate levels.
Nonetheless, clinicians and patients should be alerted by symptoms
associated with this syndrome. Dr. S.M.E. Vrouenraets of the Academic
Medical Center in Amsterdam, The Netherlands reported that increased
blood lactate levels in persons taking NRTI drug therapy were not
consistent in the same individuals, with a wide intra-patient
variability (abstract 625). This Netherlands study underscores the
recommendation that testing lactate levels is difficult.

Dr. J.T. Lonergan of the University of California at San Diego found
that the incidence of lactic acidemia was more than 10-fold higher for
any d4T (Zerit, stavudine, NRTI drug)-containing regimen compared with
a regimen without d4T (abstract 624). Patients were included if he/she
had an increased ALT (liver enzyme) and/or gastro-intestinal
(stomach-colon) symptoms. The greatest risk occurred when ddI (Videx,
didanosine, NRTI drug) or ddI/3TC (Epivir, lamivudine, NRTI drug) was
combined with d4T. However, patients with lactic acidemia could be
safely rechallenged (newly started) with other NRTI drugs such as
abacavir (Ziagen) or ZDV (zidovudine, Retrovir) or both after
discontinuing the original NRTI drugs and the acidemia had resolved.

Dr. Vrouenraets (referenced above) found a 22% prevalence (rate) of
elevated blood lactate levels among 223 patients taking NRTI drug
therapy and 8% among untreated patients. Consistent with the Lonergan
study above, they found a significantly increased risk for
d4T-containing regimens ("odds ratio" or OR of 12), and a trend
towards a decreased risk for 3TC-containing regimens (OR 0.19). In a
"multivariate" analysis, the other 4 NRTI drugs were not significantly
associated with an increased lactate. Neither hepatitis virus
co-infection (hepatitis C or B) nor increased liver enzyme (ALT) was
statistically associated with increased lactate levels.

Treatment for Metabolic Complications and Lipodystrophy
Dr. J. Miller of the University of New South Wales in Sydney,
Australia evaluated the safety and efficacy of gemfibrozil (Lopid) to
treat elevated triglyceride (blood fats) levels (abstract 540).
Gemfibrozil was well tolerated and did not appear to be associated
with additional PI drug toxicity, but had only a modest effect on
hypertriglyceridemia. Gemfibrozil is FDA-approved to treat high blood
triglyceride levels in HIV negative persons.

Dr. E. Martinez of Hospital Clinica in Barcelona, Spain studied the
impact of substituting efavirenz (Sustiva, NNRTI drug) for a PI drug
in combination therapy (abstract 668). The randomized study involved
93 HIV-infected adults with lipodystrophy syndrome. At 12 months after
switching, patients on efavirenz had significant decreases in measured
severity scores of several types of lipodystrophy, as well as
improvements of "insulin sensitivity" and HDL-(high density
lipoprotein or "good") cholesterol. However, the efavirenz arm did
still have a further decrease in fat under the skin (worsened
lipoatrophy), but less of a decrease than the PI drug arm. Therefore,
the substitution of efavirenz (after 12 months) for a PI drug appears
to slow the evolution of body fat changes except for fat loss,
although it does not prevent or reverse them. Both arms maintained
undetectable HIV viral loads.

In contrast, Dr. D. Estrada of Clinica de San Carlos in Madrid, Spain
found somewhat different results in a non-randomized study of 41
patients with lipodystrophy syndrome (abstract 671). One year after
switching to an efavirenz-based from a PI drug-based regimen, there
were no significant changes in insulin sensitivity. Also, waist-to-hip
ratio (one measurement of abdominal obesity) did not change
significantly. HIV viral load remained undetectable in all but one
patient.

Yet, Dr. R. Walli of Ludwig-Maximillians University in Munich, Germany
showed that switching from a PI- to an abacavir (Ziagen, NRTI)-based
regimen results in an improvement of insulin sensitivity and a
decrease in both total cholesterol and triglycerides in the majority
of patients up to 12 months. Changes in fat redistribution were not
reported. These results are consistent with results seen from previous
studies.

Although some of these reports might appear somewhat promising, it
appears that some body shape changes may not be easily reversed.

"Osteopenia" and "Osteoporosis" (Loss of bone mineral density)
Several cross-sectional studies evaluated the incidence of osteopenia
(mild loss of bone mineral density) and osteoporosis (severe loss).
Osteoporosis is common in elderly, HIV-negative women and some
elderly, HIV-negative men and increases the risk of bone fractures.
Several studies at the Conference reported increased rates of bone
mineral loss associated with HIV infection and not necessarily due to
anti-HIV therapy. For example, Dr. Ian McGowan of Gilead Sciences
reported a 24% osteopenic rate and a 2% osteoporotic rate among 151
HIV positive patients who were antiretroviral-naïve (never took any
treatment) (abstract 628).

Similarly, Dr. H. Knobel of Hospital del Mar in Barcelona, Spain found
osteopenia in 25% of therapy-naïves, in 40% of protease inhibitor
treated, in 33% of non-protease inhibitor treated and in 16% of
healthy adults (abstract 629). In this study of 80 patients, the
association between the use of HAART and reduced bone mineral density
was not statistically significant.

Similarly, Dr. K. Chang of Yonsei University in Seoul, South Korea
reported that osteoporosis and osteopenia were not more prevalent in a
HAART-experienced group than in a HAART-naïve group of patients
(abstract 630). Yet in this study of 109 Asians (Korean), rates of
decreased bone mineral density in the lumbar spine (low back) were
quite similar when comparing HIV negative controls, HIV-positive,
HAART-naïve and HAART-experienced patients (18-24% range).
Interestingly, in a separate report, Dr. Chang also reported that
lipodystrophy was not detected in a study of 122 Koreans, including 45
HIV patients taking HAART, 32 treatment-naïve patients and 45 healthy
controls (abstract 648). Lipodystrophy was measured using DEXA (dual
energy x-ray absorptiometry). The length of HAART treatment was not
stated in the abstract. Metabolic changes were observed in the HAART
patients, including significantly increased triglycerides, decreased
HDL (high density lipoprotein or "good") cholesterol and insulin
resistance. The findings suggest that manifestations of HIV and/or
adverse events of anti-HIV drugs are not always identical when
comparing race-ethnic groups. A lower rate of lipodystrophy has been
reported previously among HIV positive African-Americans taking HAART.

Dr. A. Lawal of St. Luke’s-Roosevelt Hospital Center in New York City
reported that the rate of osteopenia among HIV positive men in 1993
(pre-HAART era) was similar to the rate among HIV positive men taking
HAART in 1998 (abstract 627). DEXA scanning was used. However, bone
mineral density in both groups was significantly lower than
case-matched, HIV negative, control patients. The 36 men from 1993 had
HIV-related wasting and were being treated with oxandrolone (Oxandrin)
steroid hormone. The 22 HAART patients from 1998 included were being
treated with recombinant (manufactured) human growth hormone
(Serostim) to treat abdominal obesity.

In another study, Dr. S. Arpadi of Columbia University in New York
measured the total body bone mineral content in 51 HIV-infected
children and 282 healthy controls (abstract LB8). Significant
reductions in bone mineral density were observed among the HIV
positive children, which progressively increased with age, but were
independent of PI drug treatment. Only 6% of the HIV-positive children
were treatment-naïve.

These studies suggest that there is no clear relationship between
HAART and reduced bone mineral density. Also, there appears to be
increasing information that HIV by itself might increase the risk of
losing of bone mineral content. However, the cross-sectional design of
these studies represents a major limitation. The preliminary results
require therefore confirmation in longitudinal, prospective,
well-controlled trials. Additionally, people with HIV may also have
increased incidence of risk factors for osteopenia. Potential
confounding cofactors that can contribute to developing osteopenia
include being sedentary, cigarette smoking, nutrition (including
inadequate calcium intake), current or past steroid hormones (prior
exposure to steroid treatment for PCP, use of Megesterol acetate for
appetite stimulation, post-menopausal hormone deficiency), excessive
alcohol intake, genetics, elevated lipids, possibly lower body mass.

"Avascular Necrosis" (Bone Death Due to Inadequate Blood)
Dr. J.C. Keruly of Johns Hopkins University reported 15 cases of
"avascular hip necrosis" in their HIV Clinic Cohort (abstract 637).
This condition may have no symptoms (diagnosed by x-ray or other
imaging study) or may be painful. If required, the treatment is
hipbone replacement with a metal "prosthesis" during surgery. The
"incidence" rate in the current study was 47-fold higher than in the
general HIV negative population. There was a significant trend in that
the annual number of cases increased from 1995 through 2000 at their
institution. Risk factors associated with this specific adverse event
included steroid drug (prednisone, cortisone, others) use, low CD4
count (less than 200 cells per microliter) and a longer time since HIV
diagnosis, but not treatment for HIV. Nearly half of the cases had
never taken a PI or NNRTI drug. Similarly, Dr. D.M. Gaughan of Harvard
School of Public Health reported 5 cases of "avascular necrosis" in
HIV-infected children (abstract 638). The incidence rate was much
higher in this cohort than in the HIV negative, general pediatric
population.

Hepatotoxicity (Liver toxicity)
Dr. D. Boxwell from the US FDA (Food and Drug Administration) reported
that the combination of hydroxyurea (HU, Hydrea, Droxia) and NRTI
drug(s) may increase the risk for serious hepatotoxicity (abstract
617). Hydroxyurea is an FDA-approved drug to help treat certain
cancers and sickle cell anemia. Among 34 reported cases of
hepatotoxicity associated with NRTI drug and HU usage, 25% were fatal.
Among all of the cases, ddI (didanosine, Videx) was reported in 91%.
The combination of ddI/ d4T/HU combination may further increase the
risk of fatal outcome (61% rate). The authors concluded, "Patients
taking HU and NRTIs, in particular ddI and d4T, should therefore be
aggressively monitored for hepatotoxicity." Regular testing of liver
enzymes (ALT, AST), in addition to pancreas gland enzyme (amylase, see
"pancreatitis" below) would be reasonable for patients taking NRTI
drugs, and particularly when combined with hydroxyurea. Liver and/or
pancreas toxicity associated with NRTI drug usage also is associated
with increased blood lactate levels and life-threatening lactic
acidosis (see reports above in this Section). One limitation of the
study is the voluntary nature of the reporting system. As a result of
these findings, the FDA has supplemented the "Black Box" warnings of
the drug product information (package inserts) for hydroxyurea, ddI
and d4T (stavudine, Zerit). See below: Sulkowsky and Bartlett studies
for more on hepatoxicity.

Pancreatitis (Inflammation of the Pancreas Gland)
Dr. John Moore of Johns Hopkins University reported that the risk for
pancreatitis (inflammation of the pancreas digestive gland) increased
4-fold in patients treated with hydroxyurea (HU, Hydrea, Droxia).
Again, the large Hopkins HIV Clinic Database was used. HU is an
FDA-approved drug to treat certain cancers and sickle cell anemia. The
combination of hydroxyurea with other agents such as ddI and d4T has
been associated with pancreatitis in the current and previous studies.
The authors concluded, "Use of [hydroxyurea] and ddI should probably
be discouraged."