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Liver Fibrosis Found in HIV/HCV-Coinfected Patients With Normal ALT
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NEW YORK (Reuters Health) Feb 10 - One quarter of individuals infected with both HIV and hepatitis C virus (HCV) with persistently normal alanine aminotransferase (ALT) levels have liver fibrosis in need of treatment, report Italian investigators from the San Raffaele Scientific Institute in Milan.
"Little is known" about liver disease in the subpopulation of HIV/HCV-coinfected patients with persistently normal ALT values, Dr. Caterina Uberti-Foppa and colleagues explain in the January 1st issue of the Journal of Acquired Immune Deficiency Syndromes.
To "better define liver disease" in HIV/HCV-coinfected patients with persistently normal ALT levels, they reviewed liver biopsies from 326 coinfected patients of similar age, gender, and risk factors, who had persistently normal (n = 24) or elevated (n = 302) ALT values for 12 months before liver biopsy.
Analysis of liver biopsies revealed some degree of liver fibrosis in 70% of patients with persistently normal ALT values. Twenty-five percent of these patients required treatment.
Although overall histologic abnormalities in patients with persistently normal ALT levels were milder than those observed in patients with elevated ALT levels, roughly 12% of patients with consistently normal ALT readings had "incomplete and frank cirrhosis."
In these subjects, older age and CD4+ T-cell count less than 500 cells per microliter were independently associated with a stage of liver fibrosis fulfilling histologic criteria for anti-HCV treatment. "These parameters may help to select difficult-to-treat persistently normal ALT patients eligible for liver biopsy," the investigators suggest.
They also point out patients with normal ALT levels showed a "heterogeneous progression of HCV-related liver disease, ranging from high stable clinical status for 5 years after liver biopsy to fast progression and even lethal evolution during the same interval."
These observations "highlight the threat hidden by persistently normal ALT levels, which are too often considered a sign of well-balanced liver status in HIV-positive subjects with chronic HCV infection," Dr. Uberti-Foppa and colleagues conclude.
J Acquir Immune Defic Syndr 2006;41:63-67.
Liver Fibrosis in HIV-Positive Patients With Hepatitis C Virus: Role of Persistently Normal Alanine Aminotransferase Levels
Uberti-Foppa, Caterina MD; De Bona, Anna MD; Galli, Laura MSc; Sitia, Giovanni MD; Gallotta, Giulia MD; Sagnelli, Caterina MD; Paties, Carlo MD; Lazzarin, Adriano MD
From Clinic of Infectious Diseases, Vita-Salute University, San Raffaele Scientific Institute, Milan, Italy.
Abstract
Background: Liver fibrosis requiring treatment in HIV/hepatitis C virus (HCV)-coinfected patients with persistently normal alanine aminotransferase (ALT) values (PNAL) is currently not well defined; in this study clinical and histologic features of PNAL were compared with those of subjects with elevated ALT (EAL).
Methods: A total of 326 liver biopsies of HIV/HCV-coinfected patients, performed from 1997-2003, were retrospectively identified. Subjects with at least 3 consecutive normal ALT determinations during a prebiopsy follow-up of 12 months were grouped as PNAL (24 patients) and compared with EAL subjects (302 patients). Liver biopsy was classified with the modified Ishak score.
Results: Age, HCV viral load, and genotype, CD4 T-cell count, and antiretroviral drugs did not show a statistical difference between the 2 groups. Statistical significance was found when comparing mean grading (1.4 ± 1.8 vs. 7.2 ± 2.6, P < 0.0001) and staging (1.4 ± 1.79 vs. 2.5 ± 1.7, P < 0.0003) between PNAL and EAL subjects. The proportion of PNAL patients fulfilling histologic criteria for anti-HCV treatment (25% with stage 2-6) was also significantly different from EAL subjects (69%; P = 0.0001). At multivariate analysis, only age, CD4 count (>500 vs. ≦500 cells/mL), and patient's group (EAL vs. PNAL) were found to be independently associated with a fibrosis score of ≥2.
Conclusion: Liver fibrosis requiring treatment was found in 25% of HIV/HCV-coinfected subjects with PNAL values.
The mutual relationship between hepatitis C virus (HCV) and HIV is not well understood, although it has been observed that progression rate of HCV infection is faster in HIV-positive patients.1,2 Liver biopsy is the gold standard for assessing liver damage, and nearly half of HCV/HIV-coinfected patients with high serum alanine aminotransferase (ALT) levels shows unexpected cirrhosis or precirrhosis.3 Few data are presently available on liver disease of HIV/HCV-positive patients with persistently normal ALT values.4 About 30% of HIV-negative patients with chronic hepatitis C infection have persistently normal ALT levels defined on the basis of at least 3 consecutive normal ALT values over a 6-month period.5 Although formerly defined as healthy HCV carriers, some of these subjects carry histologic liver damage despite their normal liver biochemistry. Controversies exist regarding the natural history, the role of liver biopsy, and the management of chronic hepatitis C in these subjects.5,6 A biopsy in this situation can help to make a more informed decision on whether to start or defer treatment, particularly in difficult-to-treat genotypes 1 and 4. The current retrospective study was undertaken to better define liver disease in HIV/HCV-coinfected patients with persistently normal ALT (PNAL) levels compared with patients showing elevated ALT (EAL) values.
Eligibility and Study Design
All outpatients with HIV/HCV coinfection, presented to the Clinic of Infectious Diseases, Vita-Salute University, San Raffaele Scientific Institute of Milano, between 1997-2003 were retrospectively identified. Patients who had a liver biopsy performed were eligible in the study. Exclusion criteria were other possible causes of chronic liver disease, including hepatitis B virus infection, autoimmune liver disease, hemochromatosis, and heavy alcohol consumption (defined as average daily consumption >50 grams/d for ≥2 years. No patients had received prior antiviral treatment of HCV infection. Data for this study were available for 326 subjects. The patient cohort was divided into 2 groups, according to ALT values: the PNAL group comprised subjects presenting 3 consecutive PNAL values (≦55 IU/L for male and ≦50 for female according to our laboratory normal values) during the 12-month follow-up prior to liver biopsies; and the EAL group comprised subjects showing elevated ALT values during the same period of observation. Because in most patients, the date of HCV acute infection was unknown, we analyzed the duration of this disease addressing the distribution of staging in relation to age and to the date of initiation of intravenous drug use (IVDU) (drug users are likely to acquire HCV during the 1st year of drug use). Signed consent for the study was obtained from all eligible patients.
DISCUSSION
Published data on HIV/HCV-coinfected subjects pertain mostly to patients with EAL values, and little is known about the subpopulation showing PNAL values. In our retrospective study, 2 groups of HIV/HCV-coinfected patients similar in terms of gender, age, and risk factors presenting persistently normal or elevated values of ALT for 12 months before liver biopsy were compared to assess how ALT values are related to severity of histopathologic liver damage. The rationale was to select a population that is presently considered not eligible for liver biopsy, as also indirectly shown by the relatively small number of PNAL patients referred by primary HIV care providers. A bias of the present study may be the unreported true duration of HCV disease, which may have influenced either the ALT values or histology. In the absence of HIV and HCV seroconversion dates for each patient, we decided to address this point analyzing the relationship between staging and age in each group or staging and IVDU initiation date. The grouping of the median age in the same 5-year range of time suggests a comparable duration of HCV disease as also shown by the similar mean duration of coinfection in the 2 subgroups of previous or active IVDU. Analysis of liver biopsies showed that 70% of PNAL patients presented some degree of liver fibrosis (1-6) and that 1 of 4 required adequate treatment (2-6). Although overall histologic abnormalities found in patients with PNAL levels were milder than those found in EAL patients, incomplete and frank cirrhosis (staging ≥5) were found in PNAL subjects (12.5%) as also described for HIV-seronegative HCV-infected patients.5,6 Our proportions of significant fibrosis and also of histologic cirrhosis differ from those recently described by Fonquernie et al.4 These authors did not observe cirrhosis in the coinfected PNAL subjects. This discordance may be explained by the different definition used to select the PNAL population in the French study compared with ours (3 years of prebiopsy follow-up vs. our 1 year of follow-up). It is possible that longer observation periods would allow a more strict selection of PNAL patients. However, our findings clearly show the threat hidden by PNAL in patients who have had 1 year of follow-up. Although mean CD4 T-cell counts were similar in both groups of patients, this parameter was shown to be inversely related to the patient's staging, as also observed in other cohorts.8 Notably, older age and CD4+ T-cell count <500 cell/mL were independently associated with a stage of liver fibrosis fulfilling histologic criteria for anti-HCV treatment in patients with PNAL. These parameters may help to select difficult-to-treat PNAL patients eligible for liver biopsy. In HCV-monoinfected PNAL subjects, 18%-50% of patients developed intermittent or persistent elevation of ALT levels during a 6-month to 7-years follow-up, a percentage comparable to that observed in our study (37.5% during 5 years of follow-up).9,10 The follow-up of our PNAL patients showed a heterogeneous progression of HCV-related liver disease, ranging from high stable clinical status for 5 years after liver biopsy to fast progression and even lethal evolution during the same interval. In conclusion, these findings highlights the threat hidden by persistently normal ALT levels, which are too often considered a sign of well-balanced liver status in HIV-positive subjects with chronic HCV infection.
RESULTS
Comparison of Demographic and Immunovirologic Status of HIV/HCV-Coinfected Patients With Persistently Normal ALT and Elevated ALT
PNAL and EAL subjects, comprising 326 HIV/HCV-coinfected patients, did not present statistically significant differences in term of gender, age, and behavioral risk factors as summarized in Table 1. Median age was in the majority of each group distribution in the same 5-year range of time (EAL = 41 years, interquartile range 39-44; PNAL = 40 years, interquartile range 39-42). The average interval since diagnosis of HIV infection was >10 years in both groups; the duration from diagnosis of HCV infection was shorter probably owing to a delay in managing HCV infection. For previous or active IVDU, the estimated mean duration of coinfection, using the date of IVDU initiation, was similar in the 2 groups (14 years). HCV genotype 3 was the most judgement genotype in the overall sample (44%), followed by genotype 1 (40%), genotype 4 (13%), and genotype 2 (3%). Genotype distribution analysis showed a higher proportion, not statistically significant, of genotype 1 in PNAL (61%, 11 cases) compared with EAL (38%, 97 cases; P = 0.08), followed by genotype 3 (22%, 4 cases vs. 46%, 116 cases) and genotype 4 (17%, 3 cases vs. 13%, 32 cases). No genotype 2 was found in the PNAL group vs. 3% of EAL (9 cases). HCV RNA levels in plasma did not significantly differ in PNAL and EAL subjects; high-level HCV viremia (HCV RNA ≥2 ~ 106 copies/mL) generally associated with a reduced response to treatment was also homogeneously distributed. The mean CD4+ T-cell count did not differ significantly. Among patients receiving antiretroviral therapy, 46% were on protease inhibitor-based highly active antiretroviral therapy (HAART) and 17% were receiving nonnucleoside reverse transcriptase inhibitor (NNRTI)-based HAART. Three nucleoside reverse transcriptase inhibitors (NRTIs) were administered in 10% of subjects and 2 NRTIs in 27%. Statistical analysis did not show any difference in the antiretroviral therapy distribution between PNAL and EAL patients (data not shown).
Comparison of Liver Histologic Features in PNAL and EAL Patients: Correlation With Immunovirologic Status and Antiretroviral Therapy
One third of all patients presented an absent or minimal liver fibrosis; in PNAL and EAL subjects stage 0-1 was shown in 75% and 31% of cases, respectively (Table 1). Mild to moderate fibrosis was more frequent in PNAL with respect to EAL patients, despite the presence of some cases of advanced fibrosis in the first group (1 patient in stage 5 precirrhosis and 2 patients in stage 6 cirrhosis). Stage 0 was described in 31 subjects (10%) (PNAL 7 patients, EAL 24); stage 1 in 81 subjects (25%) (PNAL 11 patients, EAL 70); stage 2 in 81 subjects (25%) (PNAL 2 patients, EAL 79); stage 3 in 53 subjects (16%) (PNAL 1 patient, EAL 52); stage 4 in 26 subjects (8%) (PNAL 0 patients; EAL 26); stage 5 in 21 subjects (6%) (PNAL 1 patient, EAL 20); and stage 6 in 33 subjects (10%) (PNAL 2 patients, EAL 31). The necroinflammatory status was found to be minimal or moderate (≦7) in more than half of patients. The analysis of CD4 count and liver fibrosis showed a significant inverse association (P = 0.0036) between immune status and staging: staging 0-1 was detected in 46 subjects (42%) and 63 (58%), respectively, for CD4 count <500 cells/mL and ≥500 cells/mL, whereas higher stage ≥2-6 was evaluated in 127 (61%) and 81 (39%) of the same CD4 categories with available CD4 count at the time of biopsy. A multivariate analysis was done, aimed at evaluating factors possibly related to liver fibrosis ≥2. Three variables were found, independently associated with mild to severe liver fibrosis: higher age (for 1-unit increment: odds ratio [OR] = 1.09, 95% CI: 1.03 to 1.18, P = 0.01); CD4+ T-cell count at the time of liver biopsy (<500 vs. ≥500: OR = 1.98, 95% CI: 1.07 to 3.7; P = 0.03); and patient's group (EAL vs. PNAL: OR = 3.83, 95% CI: 1.23 to 14.28; P = 0.02). Neither the HCV genotype (1 vs. other than 1), nor high HCV RNA (<2,000,000 vs. ≥2,000,000 copies/mL), log HIV RNA (for 1-unit increment), and antiretroviral therapy (no vs. yes) were found to be associated to staging score ≥2.
Clinical Follow-Up of PNAL Patients
Because HIV has a deleterious impact on chronic HCV infection and no data are available on the course of liver disease in HIV/HCV-coinfected patients with PNAL, we performed a post-biopsy clinical follow-up of 2-8 years (mean duration: 5.13 years ± 1.9 SD) as summarized in Figure 1. More than half the patients in the PNAL group (n = 14, 58%) had a follow-up duration of ≥5 years, 3 of whom (12%) were followed for 9 years. Considering HIV-related clinical follow-up, a consistent number of patients (n = 22, 91%) had stable clinical conditions at the end of follow-up (December 2003; 8 patients of this number, accounting for >1/3 of the whole PNAL group, remained naive for antiretroviral therapy during the whole period). Conversely, HCV-related clinical follow-up showed that progression rate of liver disease in this population was heterogeneous (Fig. 1). The patients displayed a range of HCV-related conditions from clinical and biochemical steady state of liver function, with PNAL for 14 subjects with different fibrosis stage at baseline (58%), to 10 with progressive disease who presented elevated ALT at last observation (42%). Of the 10 with progressive disease, 1 died from cirrhosis (5 years after stage 0 at biopsy; liver specimen was 1.5 cm long, 1.4 mm wide, and contained 8 portal tracts) and 1 developed clinical decompensated cirrhosis (3 years after stage 6 at liver histology).We emphasize that at biopsy no clinical or biochemical signs of advanced liver disease (spider angiomata, palmar erythema, splenomegaly, ascites, platelets lower than the upper limit of normal, abnormal PT, aspartate > alanine aminotransferase) were present in patients 1, 7, and 12 (Fig. 1). All of the 6 patients treated for chronic active hepatitis remained clinically stable for HCV-related conditions independently from the therapy outcome.
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