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Hepatitis; Adverse Events(Lipodystrophy, hypersenstivity, hepatotoxicity,
bone problems, Newfill for lipoatrophy, clinical studies)
written by Mike Youle, MD, Royal Free Hospital, London, UK
Written for NATAP by Mike Youle, MD, Royal Free Medical Center, UK
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Co-infection with HIV and hepatitis viruses is common across Europe and this
was reflected in the number of oral and poster presentations on this subject
at this the 8th European Conference on Clinical Aspects and Treatment of HIV
Infection.
HCV Antibody Test May Be Inaccurate
One study showed that the use of HCV antibody tests has a limit in the
diagnosis of hepatitis C. 104 Spanish HIV patients with known HCV
co-infection were studied cross-sectionally [P295]. Of these 6 (6%) were
anti-HCV negative but were HCV PCR positive. All were HIV viral load
undetectable and 5 of the 6 had been HIV positive when diagnosed with HCV.
HCV & HAART
Jurgen Rockstroh's group from Bonn presented data on 44 HIV/Hepatitis C (HCV
co-infected individuals who had haemophilia) and there did not appear to be
any significant effect of HIV treatment on the levels of HCV which rose over
the 96 weeks of follow-up [P9]. A retrospective analysis of this same cohort
then looked at deaths over the period 1990-2000. Of the 285 subjects included
only 94 received HAART and 107 died. Twenty-five deaths due to liver disease
occurred only 2 of which had been on HAART (p<0.05). This study does not
support the idea that there are greater numbers of liver related deaths in
the era of HAART.
Starting HCV Therapy Before HAART
Regarding the effect of treatment of chronic hepatitis C in co-infected
individuals Uberti-Foppa and co-workers from the San Raffaele Institute in
Milan showed data that suggest pretreatment of HCV with interferon alpha (IFN
a) and ribavirin impacts significantly to reduce hepatotoxicity when HIV
therapy is subsequently commenced [O2]. In subjects who received IFNa alone
(27) and IFNa plus ribavirin (19) there was greater suppression of HCV and
less hepatotoxicity. Of the subjects who commenced antiretroviral agents
there were twice the rates of abnormal liver function in the non-treated
group. After adjusting for baseline CD4, ALT levels, histological grade at
baseline and HCV genotype (1 versus others) there was a protective effect of
anti-HCV therapy against hepatotoxicity on subsequent HIV treatment
(p<0.001).
A second oral presentation examined the link between improvement in HIV
disease status and the risk of development of liver function abnormalities to
evaluate if immune reconstitution could be a mechanism for these
abnormalities [O1]. Of the 42 subjects examined at the Carlos III hospital in
Madrid from 1997-2000 72% developed rises in transaminases and in 6 (14%)
this was severe (>5ULN). There was no difference in rates of hepatotoxicity
between those with CD4<200 compared to those above and in a multivariate
analysis no relationship was seen between episodes of hepatotoxicty and rates
of either HIV or HCV surrogate markers.
HCV Mortality in Spain
A Spanish mortality review poster showed the results of assessing cause of
deaths in 157 individuals from 1996-2000 [P275]. Fourteen per cent (23) died
of hepatopathy of whom 47% were on antiretroviral treatment, 105 subjects had
hepatitis C and 68% also had concurrent hepatitis B infections. The rates of
death due to hepatopathy increased year on year from 4%, 9%, 35%and 40% over
this 4-year period of observation suggesting rising liver-specific death
rates, a worrying trend to be watched in the future.
Liver Enzymes & PI Therapy
The data from the large comparative study of lopinavir/ritonavir versus
nelfinavir in subjects naïve to antiretrovirals (M98-863) reported that in
both arms co-infection with hepatitis B and C independently resulted in
significant risk of grade 3 liver function abnormalities with relative
hazards ranging form 1.8-10.2 [P228]. However, only 1 lopinavir/ritonavir
and 3 nelfinavir subjects, out of 115, developed grade 4 changes in liver
function.
The story is not all bad news, though, since it appears that extra-hepatic
manifestations of HCV may be lower in co-infected individuals. An Italian
study by Bruno and co-workers showed that although extra-hepatic events are
seen in 24% of 200 individuals cryglobulinaemia was milder than seen in HIV
negative individuals carrying HCV. There were no cases of cryoglonuliaemic
syndrome with arthralgia, purpura or weakness [P281] which would be unusual
in for a cohort of this size.
B: Adverse events
Abacavir Hypersensitivity
The safety of re-utilizing abacavir subsequent to a treatment interruption
was examined by Berenguer and co-workers [P82]. Fourteen subjects had brief
interruptions of abacavir therapy (13 had one interruption and 1 had 6
interruptions). Mean time off abacavir was 6 days and no evidence of
hypersensitivity reaction occurred in a mean follow-up of 85 days after
recommencing the drug.
NNRTIs: Hepatotoxicity, Hypersensitivity; Efavirenz and Pre-existing
Depression
Data on the side effects of non-nucleoside reverse transcriptase inhibitors
was shown in a number of presentations. One group from Spain carried out a
prospective study of all 182 subjects who received efavirenz from 1997 at
their centre [P128]. Ten per cent were naïve to antiretrovirals, 34% were
co-infected with hepatitis C and 58% had prior AIDS. Median follow-up was 6.2
months with a total observation of 10,945 patient years. Hepatotoxicty
developed in 11(6%) of subjects of whom 82% had co-infection with hepatitis C
(=0.003). No other risk factors were seen. Another prospective study in 427
consecutive subjects starting NNRTI containing regimens assessed the risk of
severe hepatotoxicity (SH) and also hypersensitivity over a 4-year period
[P129]. Six percent were hepatitis B surface antigen positive and 54% had
active hepatitis C. In a multivariate analysis there was no difference in the
risk of these adverse events between nevirapine and efavirenz containing
regimens. Four percent showed SH at a median of 22 weeks after starting the
regimen and there appeared to be a greater risk of SH in patients co-infected
with hepatitis C (RH 4.5, 95%CI 1.4-16.8) and zidovudine use (RH 3.2, 95%CI
1.1-9.2). Finally a further study of the central nervous system side effects
of efavirenz linked a history of depressive symptoms to subsequent problems
with the drug [P149]. In 105 subjects 52 (49%) had a prior history of
depression and of these 25% discontinued treatment due to CNS toxicity
whereas only 1.9% of those with no known prior history stopped the drug for
these reasons (p=0.0005).
Lipodystrophy in Italian Women
Massimo Galli and his group from Milan, Italy always presents good long term
data and this time he has examined a cohort of 264 women on antiretroviral
therapy for changes related to lipodystrophy over a three year period from
1998 [P105]. They had anthropometric measurements performed every 12 months
and during that time the group showed rates of morphologic alteration of 12%,
41% and 58% at the one, two and three year examinations. Breast enlargement
was a factor on 87%, 26% and 30% on these occasions with a 20-30% reduction
at years two and three in those who had reported enlargement the previous
year. Associated with improvement in breast size was a significant rebound in
viral load (adjusted RH4.7; 1-21, p=0.045) suggesting perhaps poorer
adherence in these women or less effective regimens. Finally the only clear
association with body shape change was duration of antiretroviral treatment.
Lipodystrophy-Adherence
A companion poster from a Roman unit suggested in 175 patients that good
adherence was related to the development of lipodystrophy but that over time
this relationship declined [P106]. Agreement between physician assessment of
the condition and that of the patient appeared to be good.
Bone Mineral Density
Several presentations concerning bone changes continued to build on the
evidence that significant alterations in bone metabolism occur in HIV. For a
proportion of patients these will have physical symptomatic relevance. A long
term study of a small number of Greek patients [N=22], showed a progressive
loss of bone mineral content over the five years using DEXA scanning although
no clinical disease was reported [P119]. However a similar study from the UK
but with only a one year follow-up in 28 patients showed no significant
changes but a proportion of subjects worsening and some improving [P138].
These data suggest that large numbers with long follow-up may be required to
accurately map what is happening, especially since in both cohorts studied
treatment changes were frequent.
Avascular Necrosis
Avascular necrosis is a particularly disabling condition where the
blood-supply of the head of a bone, usually the femur is compromised
resulting in dead of tissue and resorption of bone. This leads to pain and
deformity and eventually requires joint replacement. Valenica and colleagues
showed data from the Carlos III Hospital cohort in Madrid that revealed a
rate of 0.36% over 4 years, 6 cases in 1650 [P120]. They were all being
treated with antiretrovirals including protease inhibitors and 4 had
triglyceridaemia, whilst one was on corticosteroids. In 4 the protease
inhibitors were changed with two getting relief of symptoms whilst the other
4 progressed.
A case report of bony exostoses and osteosclerosis in a patient on
antiretroviral was shown to further complicate matters in the bone field,
suggesting that bone growth and overproduction may sometimes occur [P150].
The subject had his protease inhibitor, indinavir stopped and there was a
reported improvement. Clearly the importance of the case report in HIV
remains.
NEWFILL for Lipoatrophy
A fascinating presentation was made by Camille Aubron-Olivier on the use of
polylactic acid (Newfill) used as a filling agent for patients with hollowing
of the cheeks due to facial wasting. This product is a synthetic polymer that
has been approved since 1999 in the European Union by the licensing agency
G-Med as a medical device for the treatment of scars and in aesthetic
surgery. Fifty subjects with severe facial wasting (<2mm subcutaneous fat by
ultrasound) were entered into a study where they received 4 injections of
1vial (0.15g) into each cheek at baseline and weeks 2, 4 and 6, by the same
experienced dermatologist. If 8mm of fat was not seen on repeat ultrasound at
week 8 a fifth pair of injections were given. Four subjects had 3
injections, 29 had 4 and 17 had 5. The mean increase in subcutaneous fat was
from 2.9mm to 8.1mm at week 8 and 9.5mm at week 24 (P<0.001). Quality of life
as measured by visual analogue scale improved from 6.4 at baseline (N=24) to
7.5 at week 24 (P<0.014). So this seems a highly successful intervention
although the data out to 2 years when it is available will bring durability
and also help define any long-term problems with the technique.
C: New therapeutic data
Sharon Walmsley presented Canadian trial data from a chart review of subjects
given salvage therapy with either lopinavir (LPV/r) N=35, or amprenavir plus
lopinavir (AMP/LPV/r) N=33 with no significant differences in baseline
variables between the two groups [P66]. After various time-points to 12
months 33% of the combination group compared to 37% of the LPV/r only group
had HIV RNA <50copies/mL where as T4 rises were greater in the combination
arm. There does not appear to be a significant advantage or disadvantage as
revealed in this study of either approach in salvage treatment. An intensive
metabolic study of amprenavir in 12 men and 2 women showed this agent when in
combination with abacavir and lamivudine to be associated with worsening oral
glucose tolerance and increased fasted lipids [P103]. A decrease in insulin
sensitivity occurred, associated with truncal fat accumulation but no fat
loss. The insulin resistance appeared only when fat accumulated suggesting a
different mechanism than the early IR seen with indinavir.
The first data from the long awaited MaxCmin study run by the Copenhagen HIV
program was presented by Ulrik Bak-Dragsted [O10]. In this study both
experienced and naïve patients were enrolled who had not had a ritonavir
boosted protease inhibitor regimen. They were randomised to either saquinavir
1000mg bid or indinavir 800mg bid with ritonavir 100mg bid as a
pharmacokinetic enhancing agent to push up the drug levels of the other
agents. The data on 306 subjects shown were to 24 weeks and as an interim
analysis no formal statistics were performed. However there did not appear to
be any difference in terms of vial load suppression or CD rise in either arm
and although slightly higher rates of adverse events were seen in the
indinavir arm there were no differences in discontinuations between the two
groups. The data out to 48 weeks will be fascinating as will be the next
study, MaxCmin 2 which pitches lopinavir/ritonavir against saquinavir
/ritonavir data for which will be available late 2002.
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