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Antimicrobial Agents and Chemotherapy, December 2000, p. 3451-3455, Vol. 44, No. 12
INSERM Unité 330, 33076 Bordeaux Cedex,1
CISIH, Hôtel-Dieu, 44035 Nantes
Cedex,2 Service de Maladies Infectieuses
et Tropicales, Hôpital de l'Archet, 06202 Nice Cedex
3,3 Service des Maladies Infectieuses et
Tropicales, Hôpital Purpan, 31059 Toulouse
Cedex,4 Service de Maladies
Infectieuses, Hôpital Robert Debré, 51092 Reims
Cedex,5 Service de Médecine
Interne, Hôpital Saint-André, 33075 Bordeaux
Cedex,6 Laboratoire de Recherche en
Pathologie Infectieuse, Faculté Xavier Bichat, Paris Cedex
75018,7 and Département des
Maladies Infectieuses, Tropicales, Parasitaires et de Santé
Publique, Hôpital Pitié Salpêtrière, 75651 Paris Cedex
13,8 France
Received 7 October 1999/Returned for modification 18 January
2000/Accepted 25 August 2000
In a cohort of 1,047 human immunodeficiency virus type 1-infected
patients started on protease inhibitors (PIs), the incidence of severe
hepatic cytolysis (alanine aminotransferase concentration five times or
more above the upper limit of the normal level Several cases of acute hepatitis
have been reported after exposure to protease inhibitor (PI)-containing
regimens (2, 10, 11, 13, 19). At least two mechanisms may be
involved in drug-related hepatitis: either a toxic effect of the PIs or
other antiretroviral drugs or an enhanced inflammatory response against hepatitis B virus (HBV) or hepatitis C virus (HCV) induced by an immune
reconstitution (4, 18). Our report aims at estimating the
incidence of severe hepatic cytolysis among patients exposed to PIs in
a multicenter cohort study of human immunodeficiency virus (HIV) type 1 (HIV-1)-infected patients started on PIs, the anti-proteases cohort,
named APROCO (ANRS EP11), and assessing the determinants of the
occurrence of severe cytolysis.
APROCO was set up to study the clinical and immunovirological evolution
in HIV-1-infected patients started on PI-containing regimens. Patients
were enrolled at the initiation of PI therapy from May 1997 to July
1998 and were monitored at month 1 (M1), M4, and then every 4 months in
47 French AIDS centers. Patients eligible for this analysis were those
who had a serum alanine aminotransferase (ALT) concentration under
fivefold the upper limit of the normal value (<5N) at the baseline.
The HBV and HCV infection statuses at the time of inclusion in the
study were retrospectively recorded. Clinicians were asked to report
the most recent results. For HCV and HBV surface (HBs) antigen, this was part of routine care, but this might have been performed more often
if the patient had a potential risk of contamination.
Severe adverse events (i.e., events graded 3 or 4 according to the
grading scheme of the AIDS Clinical Trials Group [6]), had to be reported to the sponsor within 48 h after recognition. In this classification, a case of severe cytolysis was defined as an
increase in the ALT level to Among the initial cohort of 1,080 patients, 1,047 (96.9 %) had a
baseline ALT of <5N (median age, 35 years; proportion of men, 77%).
The main HIV transmission route categories were homosexuality (39%),
heterosexuality (34%), and intravenous drug use (17%). The
serological status for hepatitis viruses was known for 613 patients:
26% (n = 159) were HCV seropositive and 4%
(n = 45) had HBs antigen. After a mean follow-up of 5 months, severe cytolysis developed in 23 patients, yielding an
incidence of 5 per 100 patient-years (95% confidence interval, 3.2 to
7.6). The median time from cohort entry to an ALT of Among the 23 patients with severe cytolysis, intravenous drug use was
the most frequent HIV transmission route category (52%); 16 (70%)
were positive for HCV antibodies and 5 (22%) were positive for HBs
antigen (Table 1). The median change
between M0 and M1 was 72 × 106/liter for the
CD4+ cell count and
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Copyright © 2000, American Society for Microbiology. All rights reserved.
Hepatitis B or Hepatitis C Virus Infection Is a Risk Factor for
Severe Hepatic Cytolysis after Initiation of a Protease
Inhibitor-Containing Antiretroviral Regimen in Human Immunodeficiency
Virus-Infected Patients
ABSTRACT
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5N) was 5%
patient-years after a mean follow-up of 5 months. Only positivity for
hepatitis C virus antibodies (hazard ratio [HR], 7.95;
P < 10
3) or hepatitis B virus surface
antigen (HR, 6.67; P < 103) was
associated with severe cytolysis. Before starting patients on PIs,
assessment of liver enzyme levels and viral coinfections is necessary.
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5N. A validation committee reviewed the
cases and classified them as "not related" or "related" to PIs
(12). Cox regression models were used for the analysis of
potential determinants of severe hepatic cytolysis.
5N was 95 days
(interquartile range, 34 to 121 days). Median (minimum to maximum) ALT
and aspartate aminotransferase (AST) concentration (fold N) were 1.1 (0.5 to 4.8) and 1.1 (0.4 to 5.1) at the initiation of PI, 3.4 (0.6 to
85.6) and 1.8 (0.6 to 55.7) at M1, 5.3 (0.4 to 17.8) and 3.8 (0.7 to
7.7) at M4, 1.3 (0.4 to 7.8) and 1.2 (0.5 to 5.5) at M8, 2.0 (0.4 to
5.8) and 2.0 (0.5 to 4.9) at M12, 2.9 (0.7 to 7.7) and 2.6 (0.7 to 4.7)
at M16, 1.2 (0.4 to 3.9) and 1.2 (0.7 to 4.1) at M20, and 1.6 (0.3 to
7.4) and 1.1 (0.6 to 3.3) at M24. It was associated with at least one
clinical manifestation, mainly jaundice (n = 6) and
abdominal pain (n = 5), in 11 patients (48%).
1.84 log10 copies/ml for
the HIV RNA level. At the onset of severe cytolysis, two patients were
receiving saquinavir (SQV), five patients were receiving
ritonavir (RTV), seven patients were receiving indinavir (IDV),
five patients were receiving nelfinavir (NFV), one patient was
receiving SQV and RTV, one patient was receiving IDV and NFV, and
one patient was receiving RTV and NFV. NFV had been discontinued
17 days before severe cytolysis in one patient, and no other PI was
used at the onset of severe cytolysis. The initially prescribed PIs
were stopped after the occurrence of severe cytolysis in 17 other
patients, among whom 6 were switched to another PI and 1 was switched
to nevirapine. Among these 17 patients, the ALT concentration decreased
to <5N in the 13 patients for whom follow-up data were available.
Death occurred in one patient with HCV-related cirrhosis, despite
withdrawal of PI, 150 days after the initiation of PI therapy and 3 days after the onset of severe cytolysis. Among the five patients who
continued to take PIs, the ALT concentration decreased to <5N in two
patients and the ALT concentration remained at 5N in three patients.
Complete data for variables entered in the multivariate analysis were
available for 570 patients (Table 2). The
patients not included were comparable for HIV transmission route
category (P = 0.99) and baseline level of ALT
(P = 0.58). Positivity for HCV antibodies (hazard ratio [HR], 7.95; P < 103) and positivity
for HBs antigen (HR, 6.67; P < 103) were
identified as the only risk factors for severe cytolysis. After
adjustment for hepatitis virus status, we found no association between
severe cytolysis and the type of PI or the response at M1 in terms of
CD4+ cell count and plasma HIV RNA level. The interaction
between HCV and HBV status was not significant.
TABLE 1.
Baseline characteristics and immunological and
virological responses in 1,047 HIV-infected patients started on a
PI-containing antiretroviral regimen according to occurrence of severe
hepatic cytolysis during follow-up, APROCO, 1997 to
1999a
TABLE 2.
Effect of baseline characteristics and immunological and
virological responses on the risk of severe cytolysis in 570 HIV-infected patients started on a PI-containing antiretroviral
regimen, APROCO, 1997 to 1999
Among the present cohort of HIV-infected patients treated with PI-containing regimens, a higher incidence of severe hepatic cytolysis was detected in patients positive for HCV antibodies or HBs antigen. In large phase III trials assessing the efficacies of PI-containing regimens (3, 5, 7-9, 15), when reported, the incidences of severe hepatic cytolysis were 2 and 3% in the groups receiving IDV (7, 15) and 9% in the group receiving RTV (3). The prevalence of HBV or HCV coinfection was never mentioned, but abnormal liver enzyme levels were a common exclusion criterion. Therefore, it is likely that coinfected patients have most frequently been excluded, and this may have precluded the detection of this adverse event and its risk factors in some of these trials. Monitoring of severe adverse events after expanded use of PIs therefore seems mandatory to confirm or assess their incidence and identify risk factors in unselected population samples.
Although an increase in the ALT concentration greater than 5N may not be considered severe from a hepatologist's point of view, it seems to be a reasonable threshold considering that it provides an assessment of hepatocellular necrosis and seems to be a reasonable threshold in the context of adverse events surveillance from international standardized toxicity tables (6).
Severe cytolysis in HIV-infected patients may be related to several causes such as drug treatment regimens that include PIs and other antiretroviral drugs, concomitant infections or neoplasms, and immune restoration, which may interact with each other. Drug-related hepatitis may be suggested by a decrease in ALT levels after withdrawal of PI treatment, a positive response upon rechallenge, and the presence of an hepatic eosinophilic infiltrate (1, 2, 10). In the present study, ALT levels decreased to normal after the withdrawal of PI treatment in some patients; however, the observation of a return of ALT levels to normal levels in other patients who continued PI treatment suggests that the drug may not have been the only cause of cytolysis.
The first cases of severe cytolysis were described in patients receiving IDV only (2, 10, 13, 19). We did not confirm these results in our study, and we suggest that a selection bias might have occurred in previous studies, related to clinical habits for prescription. Through its wide composition, APROCO may be considered fairly representative of the French population of HIV-infected patients routinely started on a PI-containing regimen and is a particular contributor to the surveillance for these adverse events. However, all patients in APROCO were started on a PI, and it was therefore not possible to compare them to patients not receiving a PI. Moreover, as patients were not randomized to receive each PI, confounding by indication may exist, so comparisons were adjusted for other potential risk factors to avoid confounding as much as possible.
Another limitation was that only those patients with a known serologic status could be included in the multivariate analysis and a potential selection bias could tend to overestimate the excess risk associated with hepatitis status. In fact, the proportion of patients with known serologic HCV status on entry into the study was the same (both 61%) for the group of patients with AST or ALT levels of at least >1N (n = 305) and the group with normal liver enzyme levels (n = 742). It is therefore unlikely that only patients with abnormal liver enzyme levels underwent HCV antibody testing. Moreover, we performed a robustness analysis in which patients with unknown serologic status were considered HCV positive: the HR for HCV antibody-positive patients versus HCV antibody-negative patients was 2.1, which could be considered the minimal HR for severe cytolysis associated with the presence of HCV. Thus, our results clearly confirm the relationship between severe cytolysis in patients started on a PI-containing regimen and HBV or HCV infection (2, 4, 11, 18).
It was an hypothesis that restoration of immune status in patients coinfected with HIV and HCV or HIV and HBV may lead to an enhanced inflammatory response against hepatitis viruses mediated by CD8+ and CD4+ cells (4, 14, 18). Our data do not support the hypothesis that in patients positive for HBs antigen or HCV antibodies the likelihood of severe hepatic cytolysis is related to the intensity of the immunological response to highly active antiretroviral therapy (HAART). Nevertheless, our study had several limitations. First, a 1-month delay may be too short to assess the immunological response, and markers other than the peripheral CD4+ cell count might be more relevant for study of the HCV-specific immune response (20). Second, HCV or HBV status was assessed only by serology and did not take the plasma HCV RNA or HBV DNA concentration into consideration, the latter of which is not determined as part of routine care. Nevertheless, several studies have shown that HAART does not significantly modify HCV replication (16, 21). Third, without assessment of histopathological lesions by liver biopsy, the discussion of the underlying pathologic mechanism remains speculative.
In conclusion, because nearly 90% of HCV-infected patients did not develop severe hepatic cytolysis, our data do not question the recommendation that patients coinfected with HIV and HCV be treated with HAART, according to recent guidelines on the management of HIV-infected patients (17). However, before starting these patients on a PI, assessment for liver enzyme levels and viral coinfections is necessary. In patients with HIV and HBV or HCV coinfection, careful monitoring of liver enzyme levels is suggested during the first months after the initation of such treatments. It may be hypothesized that other markers, such as HCV RNA or HBV DNA levels, might be useful to provide a better understanding of the pathophysiology of acute cytolysis in antiretroviral-treated patients coinfected with HIV and HBV or HIV and HCV.
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APPENDIX |
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Members of the APROCO Study Group are as follows:
Scientific Committee: Steering Committee, principal investigators C. Leport and F. Raffi; methodology, G. Chêne and R. Salamon; social sciences, J.-P. Moatti and J. Pierret; virology, F. Brun-Vézinet and H. Fleury; pharmacy, G. Peytavin; Other members of the Scientific Committee, D. Costagliola, P. Dellamonica, C. Katlama, L. Meyer, M. Morin, D. Sicard, A. Sobel, and F. Vincent-Ballereau; Events Validation Committee of the Scientific Committee, M. Dupon, V. Le Moing, B. Marchou, T. May, P. Morlat, A. Waldner-Combernoux; observers to the Scientific Committee, F. Agid, F. Bourdillon, J.-F. Delfraissy, J. Dormont, J.-Y. Lacut, Y. Souteyrand, and J.-L. Vildé. Monitoring and statistical analysis were conducted by V. Cailleton, D. Carricaburu, C. Deveaud, G. Dupouy, S. Dutoit, J.-L. Ecobichon, C. Egouy, C. Jadand, P. Joly, V. Journot, S. Lawson-Ayayi, C. Lewden, B. Masquelier, W. Nouioua, G. Palmer, M. Savès, and M. Souville. Promotion was done by the Agence Nationale de Recherches sur le Sida (ANRS, Action Coordonnée no. 7). Other support was provided by the Association des Professeurs de Pathologie Infectieuse et Tropicale and associated pharmaceutical companies: J. P. Chauvin (Abbott), D. Delavelle (Boerhinger-Ingelheim), E. Dohin (Roche), B. Gallet (Bristol-Myers Squib), M.-C. Gervais (Merck Dohm Chibret), and D. Lapierre (Glaxo-Wellcome).
Clinical centers (coordinators) were as follows: Amiens (J. L. Schmit); Angers (J.-M. Chennebault), Belfort (J.-P. Faller), Besançon (J.-M. Estavoyer, R. Laurent, and D. Vuitton), Bordeaux (J. Beylot, J.-Y. Lacut, M. Le Bras, J.-M. Ragnaud), Bourg-en-Bresse (P. Granier), Brest (M. Garré), Caen (C. Bazin), Compiègne (P. Veyssier), Corbeil Essonnes (A. Devidas), Créteil (A. Sobel), Dijon (H. Portier), Garches (C. Perronne), Lagny (P. Lagarde), Libourne (J. Ceccaldi), Lyon (D. Peyramond), Meaux (C. Allard), Montpellier (J. Reynes), Nancy (P. Canton), Nantes (F. Raffi), Nice (J.-P. Cassuto and P. Dellamonica), Orléans (P. Arsac), Paris (F. Bricaire, C. Caulin, J. Frottier, S. Herson, J.-C. Imbert, J.-E. Malkin, W. Rozenbaum, D. Sicard, F. Vachon, and J.-L. Vildé), Poitiers (B. Becq-Giraudon), Reims (G. Rémy), Rennes (F. Cartier), Saint-Etienne (F. Lucht), Saint-Mandé (R. Roué), Strasbourg (J.-M. Lang), Toulon (D. Jaubert), Toulouse (P. Massip), and Tours (P. Choutet).
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ACKNOWLEDGMENTS |
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We thank all patients and investigators at the clinical sites. We are grateful to Nicholas Moore and Hervé Zylberberg for valuable discussions during the preparation of the manuscript, to Sylvie Lawson-Ayayi for special contribution to data collection, and to Valérie Journot for contribution to the statistical analysis.
This study was supported by grants from the Agence Nationale de Recherches sur le Sida (ANRS) through the Action Coordonnée no. 7 (cohorts), which was the sponsor, and received additional grants from the following pharmaceutical companies: Abbott, Boerhinger-Ingelheim, Roche, Bristol-Myers Squibb, Merck Dohm Chibret, Glaxo-Wellcome.
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FOOTNOTES |
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* Corresponding author. Mailing address: Laboratoire de Recherche en Pathologie Infectieuse, Faculté Xavier Bichat, 16 rue Henri Huchard, 75870 Paris Cedex 18, France. Phone: 00 33 144 85 61 79 or 00 33 140 25 78 03. Fax: 00 33 144 85 62 46 or 00 33 140 25 88 60. E-mail: leport{at}bch.ap-hop-paris.fr.
Member of the APROCO Study Group.
Members of the APROCO Study Group are listed in the Appendix.
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