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  8th European Conference on Clinical Aspects and treatment of HIV-Infection (ECCATHI)
Athens, Greece - October 2001
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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
  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.
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 na´ve 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 na´ve 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.
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 na´ve 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.