Hepatitis: Gatell JM

Hammer SM, Eron JJ, Reiss P, Schooley RT, Thompson MA, Walmsley S, Cahn P, Fischl MA, Gatell JM, Hirsch MS, Jacobsen DM, Montaner JS, Richman DD, Yeni PG, Volberding PA, Anonymous00064. · Division of Infectious Diseases, Columbia University College of Physicians and Surgeons, 630 W 168th St, New York, NY 10032, USA. · JAMA. · Pubmed #18677028 links to  free full text

Abstract: CONTEXT: The availability of new antiretroviral drugs and formulations, including drugs in new classes, and recent data on treatment choices for antiretroviral-naive and -experienced patients warrant an update of the International AIDS Society-USA guidelines for the use of antiretroviral therapy in adult human immunodeficiency virus (HIV) infection. OBJECTIVES: To summarize new data in the field and to provide current recommendations for the antiretroviral management and laboratory monitoring of HIV infection. This report provides guidelines in key areas of antiretroviral management: when to initiate therapy, choice of initial regimens, patient monitoring, when to change therapy, and how best to approach treatment options, including optimal use of recently approved drugs (maraviroc, raltegravir, and etravirine) in treatment-experienced patients. DATA SOURCES AND STUDY SELECTION: A 14-member panel with expertise in HIV research and clinical care was appointed. Data published or presented at selected scientific conferences since the last panel report (August 2006) through June 2008 were identified. DATA EXTRACTION AND SYNTHESIS: Data that changed the previous guidelines were reviewed by the panel (according to section). Guidelines were drafted by section writing committees and were then reviewed and edited by the entire panel. Recommendations were made by panel consensus. CONCLUSIONS: New data and considerations support initiating therapy before CD4 cell count declines to less than 350/microL. In patients with 350 CD4 cells/microL or more, the decision to begin therapy should be individualized based on the presence of comorbidities, risk factors for progression to AIDS and non-AIDS diseases, and patient readiness for treatment. In addition to the prior recommendation that a high plasma viral load (eg, >100,000 copies/mL) and rapidly declining CD4 cell count (>100/microL per year) should prompt treatment initiation, active hepatitis B or C virus coinfection, cardiovascular disease risk, and HIV-associated nephropathy increasingly prompt earlier therapy. The initial regimen must be individualized, particularly in the presence of comorbid conditions, but usually will include efavirenz or a ritonavir-boosted protease inhibitor plus 2 nucleoside reverse transcriptase inhibitors (tenofovir/emtricitabine or abacavir/lamivudine). Treatment failure should be identified and managed promptly, with the goal of therapy, even in heavily pretreated patients, being an HIV-1 RNA level below assay detection limits.

Hammer SM, Saag MS, Schechter M, Montaner JS, Schooley RT, Jacobsen DM, Thompson MA, Carpenter CC, Fischl MA, Gazzard BG, Gatell JM, Hirsch MS, Katzenstein DA, Richman DD, Vella S, Yeni PG, Volberding PA, Anonymous00173. · Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA. · JAMA. · Pubmed #16905788 links to  free full text

Abstract: CONTEXT: Guidelines for antiretroviral therapy are important for clinicians worldwide given the complexity of the field and the varied clinical situations in which these agents are used. The International AIDS Society-USA panel has updated its recommendations as warranted by new developments in the field. OBJECTIVE: To provide physicians and other human immunodeficiency virus (HIV) clinicians with current recommendations for the use of antiretroviral therapy in HIV-infected adults in circumstances for which there is relatively unrestricted access to drugs and monitoring tools. The recommendations are centered on 4 key issues: when to start antiretroviral therapy; what to start; when to change; and what to change. Antiretroviral therapy in special circumstances is also described. DATA SOURCES AND STUDY SELECTION: A 16-member noncompensated panel was appointed, based on expertise in HIV research and patient care internationally. Data published or presented at selected scientific conferences from mid 2004 through May 2006 were identified and reviewed by all members of the panel. DATA EXTRACTION AND SYNTHESIS: Data that might change previous guidelines were identified and reviewed. New guidelines were drafted by a writing committee and reviewed by the entire panel. CONCLUSIONS: Antiretroviral therapy in adults continues to evolve rapidly, making delivery of state-of-the-art care challenging. Initiation of therapy continues to be recommended in all symptomatic persons and in asymptomatic persons after the CD4 cell count falls below 350/microL and before it declines to 200/microL. A nonnucleoside reverse transcriptase inhibitor or a protease inhibitor boosted with low-dose ritonavir each combined with 2 nucleoside (or nucleotide) reverse transcriptase inhibitors is recommended with choice being based on the individual patient profile. Therapy should be changed when toxicity or intolerance mandate it or when treatment failure is documented. The virologic target for patients with treatment failure is now a plasma HIV-1 RNA level below 50 copies/mL. Adherence to antiretroviral therapy in the short-term and the long-term is crucial for treatment success and must be continually reinforced.

Rubio R, Berenguer J, Miró JM, Antela A, Iribarren JA, González J, Guerra L, Moreno S, Arrizabalaga J, Clotet B, Gatell JM, Laguna F, Martínez E, Parras F, Santamaría JM, Tuset M, Viciana P. · Hospital 12 Octubre, Madrid, Spain. · Enferm Infecc Microbiol Clin. · Pubmed #12084354 links to  free full text

Abstract: OBJECTIVE: To provide an update of recommendation on antiretroviral treatment (ART) in HIV-infected adults.Methods. These recommendations have been agreed by consensus by a committee of the spanish AIDS Study Group (GESIDA) and the National AIDS Plan. To do so, advances in the physiopathology of AIDS and the results on efficacy and safety in clinical trials, cohort and pharmacokinetics studies published in biomedical journals or presented at congresses in the last few years have been reviewed. Three levels of evidence have been defined according to the data source: randomized studies (level A), case-control or cohort studies (level B) and expert opinion (level C). Whether to recommend, consider, or not to recommend ART has been established for each situation. RESULTS: Currently, ART with combinations of at least three drugs constitutes the treatment of choice in chronic HIV infection. In patients with symptomatic HIV infection, initiation of ART is recommended. In asymptomatic patients initiation of ART should be based on the CD41/mL lymphocyte count and on the plasma viral load (PVL): a) in patients with CD41 lymphocytes < 200 cells/mL, initiation of ART is recommended; b) in patients with CD41 lymphocytes between 200 and 300 cells/mL, initiation of ART should, in most cases, be recommended; however, it could be delayed when the CD41 lymphocyte count remains close to 350 cells/mL and the PVL is low, and c) in patients with CD41 lymphocytes > 350 cells/mL, initiation of ART can be delayed. The aim of ART is to achieve an undetectable PVL. Adherence to ART plays a role in the durability of the antiviral response. Because of the development of cross-resistance, the therapeutic options in treatment failure are limited. In these cases, genotypic analysis is useful. Toxicity limits ART. The criteria for ART in acute infection, pregnancy and postexposure prophylaxis and in the management of coinfection with HIV and hepatitis C and B virus are controversial. CONCLUSIONS: The current approach to initiating ART is more conservative than in previous recommendations. In asymptomatic patients, the CD41 lymphocyte count is the most important reference factor for initiating ART. Because of the considerable number of drugs available, more sensitive monitoring methods (PVL) and the possibility of determining resistance, therapeutic strategies have become much more individualized.

Bruguera M, Torres M, Campins M, Bayas JM, Segura A, Barrio JL, Esteban R, Gatell JM, Martínez M, Monés J, Plans A, Planas R, Serra C, Tural C, Villalbí JR. · Servicio de Hepatología, Hospital Clínic, Barcelona, España. · Med Clin (Barc). · Pubmed #17878027 No free full text.

This publication has no abstract.

Laguno M, Sánchez-Tapias JM, Murillas J, Forns X, Blanco JL, Martínez E, Larrousse M, León A, Loncá M, Milinkovic A, Miró JM, García F, Gatell JM, Mallolas J. · Servicio de Enfermedades Infecciosas, Hospital Clínic-Universitari de Barcelona-IDIBAPS, Universitat de Barcelona, Spain. · Enferm Infecc Microbiol Clin. · Pubmed #15701331 links to  free full text

Abstract: The chronic infection by the hepatits C virus represents a serious sanitary problem affecting 1-3% of the world-wide population. It is transmitted by sexual route, vertical route and mainly after blood exposure by percutanea route. While HIV shares similar routes of transmission, the co-infection HCV-HIV is very frequent and the chronic hepatopathy and complications associated with its clinical course are an important cause of morbi-mortality in this population. The gold standard of the treatment for the HCV, has been the interferon and later the combination therapy of interferon plus ribavirine. Currently, the combination of ribavirine and a new pegilated formulation of the interferon has become the standard in the treatment reaching rates of sustained viral response around 40-80%.

Soriano V, Miró JM, García-Samaniego J, Torre-Cisneros J, Núñez M, del Romero J, Martín-Carbonero L, Castilla J, Iribarren JA, Quereda C, Santín M, González J, Arribas JR, Santos I, Hernández-Quero J, Ortega E, Asensi V, del Pozo MA, Berenguer J, Tural C, Clotet B, Leal M, Mallolas J, Sánchez-Tapias JM, Moreno S, Gatell JM, Téllez MJ, Rubio R, Ledesma E, Domingo P, Barreiro P, Pedreira J, Romero M, González-Lahoz J, Lissen E. · Service of Infectious Diseases, Hospital Carlos III, Madrid, Spain. · J Viral Hepat. · Pubmed #14738553 No free full text.

Abstract: Chronic hepatitis B and C represent a leading cause of morbidity and mortality among human immunodeficiency virus (HIV)-infected patients worldwide. New treatment options against both hepatitis B (HBV) and C (HCV) viruses have prompted us to update previous recommendations for the management of coinfected individuals. Fifteen topics (nine related to HCV, five to HBV and one to both viruses) were selected for this purpose. A panel of Spanish experts in the field was invited to review these areas and propose specific recommendations, which were scored according to the Infectious Disease Society of America (IDSA) grading system. These guidelines represent a comprehensive and updated overview on the management of hepatitis B and C in HIV-infected patients.

Laguno M, Murillas J, Blanco JL, Martínez E, Miquel R, Sánchez-Tapias JM, Bargallo X, García-Criado A, de Lazzari E, Larrousse M, León A, Loncá M, Milinkovic A, Gatell JM, Mallolas J. · Infectious Diseases Unit, the Pathology Service, Hospital Clínic Universitari de Barcelona-IDIBAPS, University of Barcelona, Spain. · AIDS. · Pubmed #15316335 No free full text.

Abstract: BACKGROUND: Current therapies for chronic hepatitis C virus (HCV) in HIV co-infected patients have a low success rate and are poorly tolerated. We have evaluated the efficacy and safety of interferon alfa-2b (IFN) + ribavirin (RBV) versus pegylated interferon alfa-2b (PEG-INF) + RBV. METHODS: Randomized, single-centre, open-label clinical trial including patients with: detectable HCV-RNA, alanine aminotransferase > 1.5-fold upper limit of normal, abnormal liver histology, CD4 cell count > 250 x 10/l and HIV RNA < 10 000 copies/ml. Patients were assigned to INF (3 x 10 units three times/week) or PEG-IFN (100-150 microg/week) plus RBV (800-1200 mg/day). Duration of treatment was 48 weeks (only 24 weeks for HCV genotypes 2 or 3 and baseline HCV RNA < 800 000 IU/ml). The primary endpoint was a sustained virological response (SVR). RESULTS: Ninety-five patients were randomized (43 INF + RBV, 52 PEG-INF + RBV), 68% males, 82% injecting drug users; 63% genotypes 1 or 4 and 36% genotypes 2 or 3; 62% fibrosis index grade >/=2 and 30% bridging fibrosis/cirrhosis. SVR was significantly higher in the PEG-INF + RBV arm, 44% versus 21% (intent to treat; P = 0.017). Among patients with genotypes 1 or 4, SVR were 38% versus 7% (P = 0.007) and 53% versus 47% (P = 0.730) for genotypes 2 or 3. CD4 cell count but not its percentage dropped in both arms and HIV RNA viral load did not change from baseline. Side effects were very frequent in both arms leading to treatment discontinuation in 14 patients without statistical differences between arms (P = 0.565). CONCLUSION: PEG-INF + RBV was significantly more effective than INF + RBV for the treatment of chronic hepatitis C in HIV co-infected patients, mainly of genotype 1 or 4.

Podzamczer D, Olmo M, Sanz J, Boix V, Negredo E, Knobel H, Domingo P, Pineda JA, Vilades C, Quero JH, Force L, Lahoz JG, Muñoz P, Llibre JM, Mariño A, Ortega E, Dalmau D, Gatell JM, Antón E, Sola J, Galindo MJ, Pedrol E, Sanz J, Lima JT, Flores J, Anonymous00075. · Hospital Universitari de Bellvitge, L'Hospitalet, Barcelona, Spain. · J Acquir Immune Defic Syndr. · Pubmed #19214120 No free full text.

Abstract: BACKGROUND: The strategy of switching nevirapine (NVP) twice daily to once daily was evaluated. METHODS: Forty-eight-week randomized, open, multicenter trial. Stable HIV-infected patients on NVP twice daily for >12-18 weeks with alanine aminotransferase (ALT) <2.5, the upper normal limit were randomized to continue their regimen or switch to NVP 400 mg once daily. Primary end point was the proportion of ALT/aspartate transaminase (AST) > or =grade 3. RESULTS: Two hundred eighty-nine patients were included, mean CD4 620 cells per microliter. Noninferiority was demonstrated in the per protocol analysis, with 97.9% (once daily) and 99.3% (twice daily) of patients event free (difference, 1.4%; 95% confidence interval, -1.95% to 5.4%), whereas 81.8% vs. 93.8% were event free by intent-to-treat switch = toxicity analysis (difference, 12%; 95% confidence interval, 4.6% to 19.4%). Only 4 patients (3 once daily, 1 twice daily) had NVP-related grade 3/4 ALT/AST increases, but in 2 of them (once daily), transaminases decreased despite continuation with NVP. Two other once daily patients presented grade 3/4 ALT/AST increase due to well-documented acute hepatitis A virus or hepatitis C virus infection. Grade 2 ALT/AST increases occurred in 11.2% (once daily) vs. 10.3% (twice daily) of patients (P = 0.80). A larger number of once daily patients were lost to follow-up/violated protocol (15% vs. 5%). CONCLUSIONS: In patients on standard twice daily NVP-containing regimens for at least 12-18 weeks, per protocol analysis showed that switching to once daily NVP was not inferior to continued twice daily NVP in terms of the predefined noninferiority margin of 10% for hepatotoxicity.

Laguno M, Cifuentes C, Murillas J, Veloso S, Larrousse M, Payeras A, Bonet L, Vidal F, Milinkovic A, Bassa A, Villalonga C, Pérez I, Tural C, Martínez-Rebollar M, Calvo M, Blanco JL, Martínez E, Sánchez-Tapias JM, Gatell JM, Mallolas J. · Infectious Diseases Service, Hospital Clínic, Barcelona, Spain. · Hepatology. · Pubmed #19085908 No free full text.

Abstract: Although two pegylated interferons (Peg-IFN) are available to treat chronic hepatitis C virus (HCV) infection, no head-to-head comparative studies have been published. We aim to compare the efficacy and safety of PEG IFN alfa-2b (PEG 2b) versus PEG IFN alfa-2a (PEG 2a), plus ribavirin (RBV). A prospective, randomized, multi-center, open-label clinical trial including 182 human immunodeficiency virus (HIV)-hepatitis C virus (HCV) patients naïve for HCV therapy was performed. Patients were assigned to PEG 2b (80-150 mug/week; n = 96) or PEG 2a (180 mug/week; n = 86), plus RBV (800-1200 mg/day) for 48 weeks. The primary endpoint was sustained virological response (SVR: negative HCV-RNA 24 weeks after completion of treatment). At baseline, both groups were well balanced: 73% male; 63% HCV genotype 1 or [corrected] 4; 29% had fibrosis index of 3 or greater. The overall SVR was 44% (42% PEG 2b versus 46% PEG 2a, P = 0.65). Among genotypes 1 or [corrected] 4, SVRs were 28% versus 32% (P = 0.67) and 62% versus 71% (P = 0.6) in genotypes 2 or [corrected] 3 for PEG 2b and PEG 2a, respectively. Early virological response (EVR; >or=2 log reduction from baseline or negative HCV-RNA at week 12) was 70% in the PEG 2b group and 80% in the PEG 2a group (P = 0.13), reaching a positive predictive value of SVR of 64% and a negative predictive value of 100% in both arms. Side effects were present in 96% of patients but led to treatment discontinuation in 10% of patients (8% on PEG 2b and 13% on PEG 2a, P = 0.47). Conclusion: In patients with HIV, HCV therapy with PEG 2b or PEG 2a plus RBV had no significant differences in efficacy and safety.

Laufer N, Laguno M, Perez I, Cifuentes C, Murillas J, Vidal F, Bonet L, Veloso S, Gatell JM, Mallolas J. · Infectious Diseases Unit, Hospital Clinic, Barcelona, Spain. · Antivir Ther. · Pubmed #19043930 No free full text.

Abstract: BACKGROUND: The combination of pegylated interferon (PEG-IFN) plus ribavirin (RBV) is the standard of care for hepatitis C virus (HCV) treatment in HIV-coinfected individuals. In 2007, abacavir (ABC)-based antiretroviral therapy was, for the first time, reported to be associated with early virological failure during HCV treatment. The aim of our study was to evaluate the effect of ABC on the response rate to HCV therapy. METHODS: A retrospective analysis of HIV-HCV-coinfected patients treated with PEG-IFN and weight-adjusted RBV in four hospitals in Spain was performed. An analysis of baseline descriptive variables was conducted. Logistic regression models were used to test possible associations between non-response and pretreatment characteristics, including antiretroviral drugs. RESULTS: A total of 244 HIV-HCV-coinfected patients treated with PEG-IFN and RBV were included. Overall, 85% of patients were on highly active antiretroviral therapy; of these patients, 24% received ABC-based regimens. The most frequent genotypes were 1 and 3. RBV dosing was 213.2 mg/kg/day in 97% of the patients. In the global intent-to-treat analyses, 46.3% of patients reached a sustained virological response (SVR; 46.2% in ABC group versus 46.7% in non-ABC group, P=1). The only two factors in the multivariate analysis that were statistically associated with an increased risk of failure to achieve SVR were HCV genotypes 1 or 4 and older age. The use of ABC was not associated with failure to achieve SVR at any of the other time points evaluated. CONCLUSIONS: Our data suggest that the use of ABC-based regimens in the context of HCV therapy does not negatively affect the outcome of this treatment.

Laguno M, Larrousse M, Blanco JL, Leon A, Milinkovic A, Martínez-Rebozler M, Loncá M, Martinez E, Sanchez-Tapias JM, de Lazzari E, Gatell JM, Costa J, Mallolas J. · Infectious Diseases Unit, Hospital Clinic, Villarroel, 170, Barcelona, Spain. · AIDS Res Hum Retroviruses. · Pubmed #18393687 No free full text.

Abstract: Occult hepatitis B virus (HBV) infection is diagnosed when HBc antibodies (HBcAb) and HBV DNA are detectable in serum while hepatitis B surface antigen (HBsAg) is not. This situation has been frequently described in patients with chronic hepatitis C virus (HCV) infection. The objective of this study was to evaluate the prevalence of occult hepatitis B in HIV-HCV-coinfected patients and its clinical relevance in liver histology and viral response after interferon therapy for HCV. A total of 238 HIV-HCV-infected patients,negative for HBsAg, were included. Serum samples were analyzed for the presence of HBV DNA and HBcAb.HBV DNA quantification was determined with the Cobas TaqMan HBV Test (detection limit 6 IU/ml).Data from liver biopsy and laboratory tests were also analyzed. HBcAb resulted in 142 (60%) patients, being the independent associated factors: male gender, previous history of intravenous drug use, age, CD4 count,and HAV antibody presence. Among 90 HBcAb patients that we could analyze, HBV DNA was positive in 15 (16.7% of occult hepatitis B infection in this group, and 6.3% in the whole HIV-HCV cohort studied). No baseline factors, liver histology, or HCV therapy response were related to the presence of HBV DNA. We found that occult hepatitis B is a frequent condition present in at least 6.3% of our HCV-HIV patients and in more than 16% of those with HBcAb. Despite the high prevalence, this phenomenon does not seem to affect the clinical evolution of chronic hepatitis C or modify the viral response to interferon-based HCV therapies

Jaén A, Esteve A, Miró JM, Tural C, Montoliu A, Ferrer E, Riera M, Segura F, Force L, Sued O, Vilaró J, Garcia I, Masabeu A, Altès J, Coltet B, Podzamczer D, Murillas J, Navarro G, Gatell JM, Casabona J, Anonymous00385. · Centre d'Estudis Epidemiològics sobre ITS/VIH/SIDA de Catalunya, Badolona, Spain (CEEISCAT, coordinating center). · J Acquir Immune Defic Syndr. · Pubmed #18297762 No free full text.

Abstract: OBJECTIVE: We analyze the factors related to progression to AIDS or death in HIV-infected patients from the Proyecto para la Informatización del Seguimiento Clínico epidemiológico de los pacientes con Infección por VIH/SIDA (PISCIS) Cohort and we assess the optimal time to initiate highly active antiretroviral therapy (HAART) taking lead time into account. METHODS: We selected naive patients who were AIDS-free and initiated HAART after January 1998. Statistical analyses were performed using Cox proportional hazards models. Lead time was defined as the time it took the deferred group with an early disease stage to reach the later stage. The analysis accounting for lead time was performed using multiple imputation methods based on estimates from the pre-HAART period as described elsewhere. RESULTS: Multivariate analysis on 2035 patients (median follow-up = 34.3 months) showed significantly higher hazard ratios (HRs) for a CD4 count <200 cells/microL (HR = 3.79, 95% confidence interval [CI]: 2.18 to 6.57), HIV-1 RNA level >100,000 copies/mL (HR = 1.84, 95% CI: 1.26 to 2.69), and hepatitis C virus (HCV) coinfection (HR = 2.40, 95% CI: 1.65 to 3.49), whereas a lower risk was found for those who started HAART between January 2001 and June 2004 (HR = 0.55, 95% CI: 0.30 to 0.90). When lead time and unseen events were included, we found a higher risk of progression to AIDS among patients who deferred treatment when the CD4 count reached <200 cells/microL (HR = 2.97, 95% CI: 1.91 to 4.63) and 200 to 350 cells/microL (HR = 1.85, 95% CI: 1.03 to 3.33) compared with those who started treatment with CD4 counts from 200 to 350 cells/microL and >350 cells/microL, respectively. CONCLUSIONS: Advanced HIV disease, HCV coinfection, and early HAART period were determinants of AIDS progression or death. Lead-time analysis in asymptomatic HIV-infected patients suggests that the best time to start HAART is before the CD4 count falls to lower than 350 cells/microL.

Larrousse M, Laguno M, Segarra M, De Lazzari E, Martinez E, Blanco JL, León A, Deulofeu R, Miquel R, Milinkovic A, Lonca M, Miró JM, Biglia A, Murillas J, Gatell JM, Mallolas J. · Infectious Diseases Unit, Hospital Clínic Universitari de Barcelona-IDIBAPS, University of Barcelona, Spain. · J Acquir Immune Defic Syndr. · Pubmed #18172937 No free full text.

Abstract: BACKGROUND: Several serum markers reflecting extracellular matrix status have been correlated with liver fibrosis in non-HIV-infected patients with chronic hepatitis C infection. These indexes have been less examined in HIV/HCV-coinfected individuals. OBJECTIVE: We aimed to evaluate the predictive value of serum markers for liver fibrosis in HIV-infected patients with chronic hepatitis C virus (HVC). METHODS: Serum levels of metalloproteinases 1 and 2 (MMP-1 and -2), tissue inhibitors of matrix metalloproteinases (TIMP-1), procollagen type III N-terminal peptide (PIIINP), and hyaluronic acid (HA) were measured in HIV-infected patients with chronic hepatitis C at the time of obtaining a liver biopsy and before the consideration of anti-hepatitis C therapy. RESULTS: One hundred and nineteen consecutive HIV-HVC coinfected patients were included. TIMP-1 (r = 0.6; P < 0.001), TIMP-1/MMP-1 ratio (r = 0.5; P < 0.001), TIMP-1/MMP-2 ratio (r = 0.3; P < 0.001), MMP-2 (r = 0.2; P = 0.044), PIIINP (r = 0.4; P < 0.001), and HA (r = 0.5; P < 0.001) were positively and significantly correlated with the fibrosis stage. In the multivariate analysis, TIMP-1 (odds ratio [OR] = 1.004, 95% confidence interval [CI]: 1.002 to 1.006, P = 0.001) and HA >95 microg/dL (OR = 6.041, 95% CI: 1.184 to 30.816, P = 0.031) were independently associated with liver fibrosis. The area under the curve of score to discriminate mild (F0-F1) from significant (F2-F4) fibrosis in the received-operating analysis using the variables TIMP-1 and HA was 0.84, with a sensitivity of 72.9% and a specificity of 83.1%. CONCLUSION: TIMP-1 and HA were quite sensitive and specific for predicting the degree of liver fibrosis in HIV-infected patients with chronic hepatitis C. These parameters may become a noninvasive alternative to liver biopsy when the degree of liver fibrosis needs to be estimated.

Ramos-Casals M, Forns X, Brito-Zerón P, Vargas A, Ruiz M, Laguno M, Yagüe J, Sánchez-Tapias JM, Gatell JM, Font J. · Department of Autoimmune Diseases, Institut d'Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), Hospital Clinic, Barcelona, Spain. · J Viral Hepat. · Pubmed #17875009 No free full text.

Abstract: To determine whether the clinical and immunological expression of patients with cryoglobulinaemia associated with chronic hepatitis C virus (HCV) infection varied according to HCV-RNA load, HCV genotype or human immunodeficiency virus (HIV) coinfection. We studied 340 HCV patients (188 women and 152 men, with a mean age of 49 years) consecutively diagnosed with cryoglobulinaemia between 1993 and 2003 in our hospital. HCV infection was confirmed by serum HCV-RNA determination in all patients. Two hundred and forty-eight (73%) patients had asymptomatic cryoglobulinaemia and 92 (27%) presented cryoglobulinaemic symptoms. Patients with genotype 1 had a higher mean age at diagnosis of cryoglobulinaemia (48.2 vs 40.2 yrs, P < 0.001) and a higher prevalence of cryoglobulinaemic symptoms (25%vs 10%, P = 0.02), especially of vasculitic features (19%vs 5%, P = 0.014). In comparison with monoinfected HCV patients, those with HIV coinfection had a lower mean age at diagnosis of cryoglobulinaemia (40.4 vs 52.8 years, P < 0.001), a lower prevalence of cryoglobulinaemic symptoms (15%vs 34%, P < 0.001), vasculitis (10%vs 28%, P < 0.001), associated systemic autoimmune disease (3%vs 14%, P = 0.001), rheumatoid factor (30%vs 70%, P = 0.001) and hypocomplementaemia (50%vs 78%, P = 0.01). In HCV-HIV patients, a high viral load was associated with a high frequency of symptomatic cryoglobulinaemia, especially in patients with a high viral load of the two viruses (50%vs 7%, P = 0.001) A higher frequency of cryoglobulinaemic symptoms (especially vasculitis) was found in patients with HCV monoinfection and in those carrying HCV genotype 1. In contrast, patients with HIV coinfection presented a threefold lower prevalence of vasculitis. Associated HIV infection significantly attenuated the clinical and immunological expression of cryoglobulinaemia, except in coinfected patients with high viral loads for the two viruses.

Castro P, Laguno M, Nomdedeu M, López A, Plana M, Fumero E, Gallart T, Mallolas J, Gatell JM, García F. · Infectious Diseases Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Spain. · AIDS Res Hum Retroviruses. · Pubmed #17678468 No free full text.

Abstract: We assess the severity and response to treatment of hepatitis C virus (HCV) infection in a cohort of long-term nonprogressors (LTNP) and analyze whether HCV infection affects the progression of HIV-1 infection. A case-control study comparing coinfected LTNP (n = 28) with coinfected normal progressors (NP) (n = 56) was performed. Signs of hepatopathy, response to HCV treatment, HIV viral load (VL), and lymphocyte T subsets were analyzed. A cohort of LTNP with (n = 28) and without HCV infection (n = 7) was compared to assess the influence of HCV on HIV-1 infection. Liver enzymes were lower in LTNP than in NP. There were no significant differences between LTNP and NP in clinical signs of chronic liver disease at physical examination, echostructure, degree of inflammation, or fibrosis score in liver biopsy. There were no differences in the response to HCV treatment between groups (57% vs. 45%, p = 0.69). LTNP presented a proportionally higher drop of CD4 during HCV treatment, which persisted 2 years after discontinuing treatment [-195, -10, and 30 cells/mm3 HCV-treated LTNP (n = 7), NP (n = 56), and non-HCV-treated LTNP (n = 21), respectively, p < 0.05]. There were no differences in any variables analyzed when coinfected and monoinfected LTNP were compared. LTNP do not seem to have a better outcome or response to HCV treatment than NP. HCV-treated LTNP could have a worse HIV progression than HIV-HCV-treated NP or untreated coinfected LTNP. HCV infection does not have a deleterious effect on the progression of LTNP.

Laguno M, Larrousse M, Murillas J, Blanco JL, León A, Milinkovic A, Loncá M, Martinez E, Sánchez-Tapias JM, de Lazzari E, Gatell JM, Costa J, Mallolas J. · Infectious Diseases Service, Hospital Clínic Universitari de Barcelona, Barcelona, Spain. · J Acquir Immune Defic Syndr. · Pubmed #17106276 No free full text.

Abstract: BACKGROUND: As a result of adverse events, a moderate rate of virologic response, and high costs associated with hepatitis C virus (HCV) therapy, finding early markers of sustained treatment response is a clinical priority. In the HCV-monoinfected population, a reduction >or=2 log in plasma HCV RNA at week 12 of therapy (early virologic response [EVR]) predicts a sustained virologic response (SVR). Few data are available in HIV/HCV-coinfected patients, however. METHODS: A subanalysis of data from HIV/HCV-coinfected patients treated with pegylated interferon-alpha-2b (PEG, 100-150 mug/wk) or interferon-alpha-2b (IFN, 3 MIU 3 times per week) plus ribavirin (RBV, 800-1200 mg/d) was conducted in a randomized single-center clinical trial. The duration of treatment was 48 weeks (only 24 weeks for HCV genotype 2 or 3 with a baseline HCV RNA level <800,000 IU/mL). RESULTS: Ninety-five patients were randomized (43 assigned to IFN + RBV and 52 assigned to PEG + RBV). Eighty patients completed at least 12 weeks on therapy and were included in the EVR analysis. Thirty-five (43%) of them attained an SVR (56% and 30% of patients treated with PEG and IFN, respectively; P = 0.026). An EVR occurred in 55 (69%; 80% of PEG + RBV group and 56% of IFN + RBV group). Overall, 35 of 55 patients with an EVR were sustained responders, yielding a positive predictive value of 64% (70% in PEG + RBV arm and 55% in IFN + RBV arm). None of the patients who demonstrated an HCV RNA decline of <2 logs at week 12 reached an SVR (negative predictive value of 100%). CONCLUSION: Our results confirm the utility of an EVR to predict the chance of the lack of an SVR in HIV/HCV-coinfected patients, particularly those treated with PEG.

Soriano A, Lozano F, Oliva H, García F, Nomdedéu M, De Lazzari E, Rodríguez C, Barrasa A, Lorenzo JI, Del Romero J, Plana M, Miró JM, Gatell JM, Vives J, Gallart T. · Service of Infectious Diseases and AIDS Unit, Hospital Clínic de Barcelona, Villarroel, 170, 08036, Barcelona, Spain. · Immunogenetics. · Pubmed #16189667 No free full text.

Abstract: Interleukin (IL) 4 is a key T helper-2 cytokine that downregulates and upregulates CCR5 and CXCR4, respectively, the main coreceptors for HIV. Our objective is to investigate whether single-nucleotide polymorphisms (SNPs) in the IL-4 receptor alpha chain gene (IL4RA) affect HIV infection and its progression to AIDS. The I50V SNP in exon 5 and the haplotypes of six SNPs in exon 12 (E375A, C406R, S411L, S478P, Q551R, and V554I) were studied by polymerase chain reaction and sequencing in 30 HIV+ long-term nonprogressors (LTNP), 36 HIV+ typical progressors (TP), 55 highly exposed but uninfected individuals (EU), 25 EU-sexuals (EU-Sex; mostly women) and 30 EU-hemophiliacs (EU-Hem; hepatitis C virus+), and 97 healthy controls (HC), all Caucasians and lacking CCR5Delta32 homozygosity. V50 homozygosity was increased in LTNP (44%) compared with the other groups [p = 0.005; relative risk ratio = 3.4, 95% confidence interval (CI) = 1.12-10.6, p = 0.03]. The most common (C) exon 12 haplotype, ECSSQV, predominated in all groups, but uncommon (U) haplotypes were increased in HIV+ individuals (n = 64), especially in those (51 of 64) infected via parenteral exposure (35.3%) compared with HC (20.4%) and EU-Hem (18.4%) [p = 0.01; odds ratio (OR) = 2.14, 95% CI = 1.25-3.67, p = 0.01]. EU-Sex also had an increased frequency of U-haplotypes (34.8%) (OR = 2.10, 95% CI = 1.03-4.21, p = 0.01) as well as an increased frequency of CU + UU genotypes (60.9%) compared with HC (38.2%) and EU-Hem (26.6%) (p = 0.043). Distributions of genotypes fitted Hardy-Weinberg equilibrium. Data suggest that V50 homozygosity associates with slow progression and that exon 12 U-haplotypes might be associated with both susceptibility to infection via parenteral route and resistance to infection via sexual exposure. Further studies are required to confirm these findings.

Laguno M, Milinkovic A, de Lazzari E, Murillas J, Martínez E, Blanco JL, Loncá M, Biglia A, Leon A, García M, Larrousse M, García F, Miró JM, Gatell JM, Mallolas J. · Infectious Diseases Unit, Hospital Clinic Barcelona, Barcelona, Spain. · Antivir Ther. · Pubmed #15918333 No free full text.

Abstract: BACKGROUND: Coinfection with hepatitis C virus (HCV) and HIV is not uncommon and therapies for both infections are currently available. A major drawback, however, could be a potentially higher risk for mitochondrial toxicity (MT), defined as the elevation of pancreatic enzymes or lactate levels due to the nucleoside analogue reverse transcriptase inhibitors contained in both therapies. METHODS: Prospective analyses of clinical and laboratory data, including plasma lactate levels and pancreatic enzymes, of 113 consecutive HIV/HCV-coinfected patients were assigned to receive ribavirin (RBV) plus interferon (IFN)-alpha. RESULTS: Fourteen patients (12%) showed increased levels of amylase/lipase and/or hyperlactataemia. No patient developed clinical pancreatitis. Four patients with hyperlactataemia had clinical symptoms of lactic acidosis and recovered uneventfully by 2 weeks after treatment withdrawal. The variables significantly associated with MT in the univariate analysis were: therapy with didanosine (ddl), ddl plus stavudine (d4T), previous history of diabetes and the baseline lactate level. However, ddl use was the only independent risk factor for MT identified in the multivariate analysis. MT was not associated with gender, age, alcohol consumption, type of IFN, degree of steatosis and fibrosis in liver biopsy, presence of lipodystrophy, CD4+ cell count, HCV or HIV viral load, mitochondrial DNA and COXII-expression in liver tissue, or antiretroviral therapy containing d4T or protease inhibitors. CONCLUSIONS: 12% of HIV/HCV-coinfected patients receiving IFN plus RBV concomitantly with highly active antiretroviral therapy developed laboratory markers of MT. Although most of cases were asymptomatic, our study suggests that concomitant use of RBV plus ddl should be avoided, and that routine monitoring of lactate and pancreatic enzymes may be recommended.

Bäuerle J, Laguno M, Mauss S, Mallolas J, Murillas J, Miquel R, Schmutz G, Setzer B, Gatell JM, Walker UA. · Department of Clinical Immunology, Medizinische Universitätsklinik, Freiburg, Germany. · HIV Med. · Pubmed #15807720 No free full text.

Abstract: OBJECTIVES: It has been suggested that chronic hepatitis C virus (HCV) infection depletes mitochondrial DNA (mtDNA) in the liver. Because decreased mtDNA levels were also found in humans infected with HIV, we investigated whether HIV may have aggravated hepatic mtDNA depletion in individuals with HCV infection. METHODS: In this cross-sectional study, liver biopsies were performed in a total of 40 individuals prior to any antiviral therapy. The individuals were recruited from the Hospital Clinic, Barcelona and the HIV Centre, Dusseldorf. Seventeen patients were negative for HIV and HCV and were biopsied for liver enzyme elevation of unknown cause (controls), 14 individuals had chronic HCV but no HIV infection, and nine subjects were coinfected with both viruses. mtDNA and liver histology were centrally assessed. RESULTS: The groups did not differ with respect to age, gender, liver function tests and HCV viral load, where applicable. mtDNA levels were decreased by 19% in the HCV-monoinfected group (P=0.03) and by 27% in the HIV/HCV-coinfected subjects (P=0.02) compared to controls. The mtDNA content, however, did not differ between individuals with HCV monoinfection and HCV/HIV coinfection (P=0.75). The degrees of liver fibrosis, inflammatory activity or steatosis did not correlate with mtDNA content. CONCLUSIONS: Liver mtDNA content is reduced in both HCV-monoinfected and HIV/HCV-coinfected patients. Under the limitations of our study, we could demonstrate only a slight trend towards more pronounced mtDNA depletion in HIV/HCV-coinfected subjects.

Laguno M, Blanch J, Murillas J, Blanco JL, León A, Lonca M, Larrousse M, Biglia A, Martinez E, García F, Miró JM, de Pablo J, Gatell JM, Mallolas J. · Infectious Diseases Unit, Hospital Clinic Universitari de Barcelona, Barcelona, Spain. · Antivir Ther. · Pubmed #15651749 No free full text.

Abstract: BACKGROUND: Interferon alpha (IFN-alpha) therapy for chronic hepatitis C (CHC) infection is commonly associated with neuropsychiatric side effects including depressive symptomatology. In this study, we evaluated the incidence and management of depressive symptoms during IFN-alpha therapy in HIV-infected patients with CHC. METHODS: HIV-infected patients with CHC who began IFN-alpha and ribavirin therapy during the recruitment period April 2001 to April 2003 were included in the study. Patients with a history of major depressive disorder were excluded. RESULTS: Of 113 co-infected patients who started IFN-alpha therapy during the recruitment period, 45 (40%) developed symptoms of depression (sadness, tiredness and apathy). Twenty of them (44%) were treated with citalopram, a selective serotonin re-uptake inhibitor, resulting in a significant improvement in their symptoms. Most of the patients (60%) showed depressive side effects in the first 3 months after initiation of IFN-alpha. In addition, during the study, three patients developed psychotic symptoms and one committed suicide. CONCLUSIONS: The incidence of depressive symptoms in patients with HIV/HCV co-infection treated with IFN-alpha is high. Most of the depressive symptoms were not severe and improved with antidepressant therapy, without reduction or cessation of IFN-alpha therapy. During the first weeks after initiating IFN-alpha therapy for HIV/HCV co-infection, close assessment of psychiatric symptoms is recommended. Early treatment of these side effects with antidepressants would help avoid early dropouts from interferon therapy.

Biglia A, Blanco JL, Martínez E, Domingo P, Casamitjana R, Sambeat M, Milinkovic A, Garcia M, Laguno M, Leon A, Larrousse M, Lonca M, Mallolas J, Gatell JM. · Infectious Diseases Unit, Hospital Clinic-Institut d'Investigaciones Biomediques August Pi i Sunyer, University of Barcelona, Barcelona, Spain. · Clin Infect Dis. · Pubmed #15546089 No free full text.

Abstract: BACKGROUND: The prevalence, risk factors, and potential hormonal abnormalities associated with gynecomastia in a cohort of HIV-infected men are poorly understood. METHODS: Breast enlargement was assessed in consecutively evaluated HIV-infected men, and gynecomastia was subsequently confirmed with sonography. For each patient with breast enlargement, a randomly selected control subject without breast enlargement was studied. Clinical data were obtained, including age, body mass index, clinically evident lipodystrophy, prior symptomatic hyperlactatemia, current antiretroviral therapy and duration of exposure to each antiretroviral drug, history of injection drug use, and serological status regarding hepatitis B and hepatitis C. Laboratory parameters, including plasma HIV-1 RNA load, CD4 cell count, free testosterone index, and levels of fasting triglycerides, cholesterol, prolactin, total testosterone, sex hormone-binding globulin, 17-beta-estradiol, follicle-stimulating hormone, luteinizing hormone, and thyroid-stimulating hormone, were measured. RESULTS: There were 44 of 2275 patients with breast enlargement, of whom 40 (1.8%) had gynecomastia. The mean free testosterone index (+/-SD) was significantly lower among the 40 patients with gynecomastia (42.6%+/-24.0%) than among the 44 control subjects (58.0%+/-25.3%) (P=.006). Although the proportion of patients who were receiving treatment with zidovudine, stavudine, and/or efavirenz at the time of the present study was significantly different between case patients and control subjects, the duration of exposure to each individual antiretroviral drug was not. Lipoatrophy (adjusted odds ratio [OR], 5.6; 95% confidence interval [CI], 1.7-18.6; P=.005), hepatitis C (adjusted OR, 6.1; 95% CI, 1.8-20.6; P=.003), and hypogonadism (adjusted OR, 7.6; 95% CI, 1.8-32.2; P=.003) were independent factors associated with gynecomastia. CONCLUSIONS: The data suggest that gynecomastia among HIV-infected patients is related to hypogonadism, rather than to an adverse effect of antiretroviral drugs.

Mocroft A, Monforte A, Kirk O, Johnson MA, Friis-Moller N, Banhegyi D, Blaxhult A, Mulcahy F, Gatell JM, Lundgren JD, Anonymous00327. · Royal Free Centre for HIV Medicine, Royal Free and University College Medical School, London, UK. · HIV Med. · Pubmed #15544697 No free full text.

Abstract: OBJECTIVES: To describe changes in the proportions of patients admitted to hospital and the duration of admission during the month of March between 1995 and 2003 and to describe the factors related to admission for 9802 patients from EuroSIDA, a pan-European, observational cohort study. METHODS: Generalized estimating equations were used to determine changes over time in the proportion of patients admitted and the median duration of admission. Logistic regression was used to determine factors related to admission in March 1995, March 1998 and March 2001. RESULTS: The proportion of patients admitted during March declined from 7.4% in 1995 to 2.6% in 2003. After adjustment, the estimated reduction in the proportion of patients admitted was 5.5% per year [95% confidence interval (CI) 2.5-8.5%; P=0.0004], a 26% reduction. The median duration of hospital admission declined by 58% from 12 days in 1995 [interquartile range (IQR) 5-19 days] to 5 days in 2003 (IQR 3-12 days), a significant decline of 0.7 days per year after adjustment (95% CI 0.5-0.9 days; P=0.031). Patients with a lower CD4 lymphocyte count, and with an AIDS diagnosis made within the 3 months prior to March, all had increased odds of admission during March 1995, 1998 or 2001. In March 2001, patients whose treatment regimen was changed as a consequence of toxicities had increased odds of admission [odds ratio (OR) 2.34; 95% CI 1.26-4.37; P=0.0074]. In addition, patients who were hepatitis C virus-positive during March 2001 (OR 1.66; 95% CI 1.02-2.68; P=0.041) had increased odds of admission. CONCLUSIONS: There has been a considerable decline in both the proportion of patients admitted to hospital and the median duration of the stay. Patients with hepatitis C had increased odds of admission, but there was little evidence of an increase in admissions among patients taking highly active antiretroviral therapy (HAART) associated with serious adverse events, although longer follow up is required.

Walker UA, Bäuerle J, Laguno M, Murillas J, Mauss S, Schmutz G, Setzer B, Miquel R, Gatell JM, Mallolas J. · Medizinische Universitätsklinik, Department of Clinical Immunology, Freiburg, Germany. · Hepatology. · Pubmed #14767983 No free full text.

Abstract: The "D drug" HIV reverse-transcriptase inhibitors zalcitabine, didanosine, and stavudine are relatively strong inhibitors of polymerase-gamma compared with the "non-D drugs" zidovudine, lamivudine, and abacavir. D drugs deplete mitochondrial DNA (mtDNA) in cultured hepatocytes. This mtDNA depletion is associated with an increased in vitro production of lactate. To investigate the origin of hyperlactatemia in HIV-infected patients and the effects of antiretroviral therapy on liver mtDNA, we biopsied liver tissue from 94 individuals with chronic hepatitis C virus (HCV) infection. Eighty subjects were coinfected with HIV. Serum lactate was measured at the time of biopsy. Hepatic mtDNA and liver histology were centrally assessed. Liver mtDNA content of HIV-infected patients receiving D drugs at the time of biopsy (n = 34) was decreased by 47% (P<.0001) compared with those without D drugs (n = 35). Aside from a possible association between HCV genotype I status and mtDNA depletion in multivariate analysis, there were no other virologic, immunologic, histologic, demographic or treatment-related variables that could explain the mtDNA depletion. Lactate was above the upper limit of normal in only three patients, all of whom were treated with D drugs. The mtDNA in each of them was lower than in any non-D drug patient and significantly (P =.017) depleted compared with D drug patients with normal lactate. In conclusion, D drug treatment is associated with decreased hepatic mtDNA in HIV-infected patients with chronic HCV infection. Moderate mtDNA depletion in liver does not necessarily lead to hyperlactatemia, but more pronounced decreases in hepatic mtDNA may be an important contributor to lactate elevation.

Soriano A, Martínez C, García F, Plana M, Palou E, Lejeune M, Aróstegui JI, De Lazzari E, Rodriguez C, Barrasa A, Lorenzo JI, Alcamí J, del Romero J, Miró JM, Gatell JM, Gallart T. · Institut Clínic d'Infeccions i Immunologia, Hospital Clínic Universitari, Barcelona, Spain. · J Infect Dis. · Pubmed #12232832 No free full text.

Abstract: Plasma stromal cell-derived factor (SDF)-1 levels, SDF1-3'A polymorphism, and CXCR4(+) T lymphocytes in relation to resistance to human immunodeficiency virus (HIV)-1 infection and its progression were investigated in a study of HIV-positive patients, exposed but uninfected (EU) subjects, and healthy control subjects, all lacking CCR5 Delta 32 homozygosity. SDF1-3'A homozygosity was associated with low plasma SDF-1 levels in uninfected persons and was not related to long-term nonprogression. HIV-1 infection involved increased plasma SDF-1 levels, which were not attributable to any kind of chronic viral infection, because all EU hemophiliacs were hepatitis C virus-positive but had normal SDF-1 levels. High plasma SDF-1 levels and low CXCR4 expression on T lymphocytes was associated with long-term nonprogression, whereas in advancing disease expression of CXCR4 increased, accompanied by a decrease in plasma SDF-1 during the more advanced stages of HIV-1 infection. EU subjects with sexual exposure to HIV-1, but not EU hemophiliacs, showed an underpresentation of SDF1-3'A allele frequency, which was coupled with high plasma SDF-1 levels and low CXCR4 expression.

Martínez E, Blanco JL, Arnaiz JA, Pérez-Cuevas JB, Mocroft A, Cruceta A, Marcos MA, Milinkovic A, García-Viejo MA, Mallolas J, Carné X, Phillips A, Gatell JM. · Unit of Infectious Diseases, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic Universitari, Barcelona, Spain. · AIDS. · Pubmed #11426070 No free full text.

Abstract: OBJECTIVES: To assess the incidence and risk factors for hepatotoxicity associated with nevirapine. DESIGN: A prospective cohort study in a teaching and referral hospital involving all consecutive patients who were prescribed a nevirapine-containing antiretroviral regimen between September 1997 and May 2000. METHOD: Cutaneous and hepatic adverse reactions and clinical hepatitis were assessed. Blood analysis including plasma HIV-1 RNA CD4 cell counts, liver chemistry tests, and serology for hepatitis B and C viruses. Hepatotoxicity was defined as an increase of at least threefold in serum alanine aminotransferase or aspartate aminotransferase levels compared with baseline values. RESULTS: Of a total of 610 patients, 82 (13.4%) were antiretroviral naive when commencing nevirapine, and 46.2 and 8.9% were coinfected with hepatitis C and B viruses, respectively. Median duration of exposure to nevirapine was 8.7 months (interquartile range 3.4--14.3). Hepatotoxicity developed in 76 (12.5%), an incidence of 13.1/100 person-years. Kaplan--Meier estimated incidence of hepatotoxicity at 3, 6 and 12 months was 3.7, 9.7 and 20.1%, respectively. In seven (1.1%) patients, hepatotoxicity was associated with clinical hepatitis, which was reversible upon discontinuation of therapy. Multivariate analysis identified the duration of prior exposure to antiretroviral drugs, hepatitis C virus, and higher baseline levels of alanine aminotransferase as independent risk factors for hepatotoxicity. CONCLUSIONS: Hepatotoxicity but not clinical hepatitis was common in HIV-1-infected patients receiving nevirapine-containing regimens and the incidence steadily increased over time. Prolonged exposure to any antiretroviral therapy, coinfection with hepatitis C virus and abnormal baseline levels of alanine aminotransferase identified patients at a higher risk.