Sagnelli, Caterina PhD*†; Uberti-Foppa, Caterina MD*; Pasquale, Giuseppe MD†; Coppola, Nicola MD†; Albarello, Luca MD‡; Masiello, Addolorata MD†; Doglioni, Carlo MD‡; Lazzarin, Adriano MD*; Sagnelli, Evangelista MD†
To the Editors:
Information on liver histology of patients coinfected with HIV and hepatitis C virus who have persistently normal alanine aminotransferases (PNAL) is limited, and the data on the comparison of the liver histology between HIV/HCV-coinfected patients and HCV-monoinfected patients with PNAL come from a study involving only few cases.1
We describe a comparative investigation of 34 consecutive HIV/HCV-coinfected patients with PNAL (group HIV/HCV) and 30 HCV-monoinfected patients with PNAL (group HCV) who underwent liver biopsy (LB). The criteria used to define PNAL are those established in a previous study: normal alanine aminotransferase (ALT) serum levels in at least 3 consecutive determinations over a 1-year observation period before LB.2 Patients were enrolled at the time of the percutaneous LB from 1995 to 2005 at the Clinic of Infectious Diseases of San Raffaele University in Milan or at the Department of Infectious Diseases of the Second University of Naples. These 2 centers had been using the same laboratory and clinical approach for years and had cooperated in several investigations. Before LB, each patient signed an informed consent as established by the local ethics committee. For patients in group HIV/HCV, the epidemiological, clinical, and immunovirological data recorded at the baseline included risk factors for acquiring HIV and HCV infection, liver function tests, CD4+ and CD8+ cell counts, HCV genotype, HIV and HCV viral load, and routine tests. For patients in group HCV, the same data were recorded excluding those pertaining to HIV infection. The median duration of HCV infection in group HIV/HCV was 10.5 years (interquartile range: 5.8-14.04); it was impossible to calculate this parameter in group HCV because the time of infection was uncertain in most cases. Excluded from the study were patients treated with α-interferon (INF) or Peg-INF, alone or in combination with ribavirin (RBV), before LB was performed; those with an alcohol intake >40 g/daily for males and >30 g for females in the 6 months preceding LB; those circulating HBsAg or autoantibodies associated to autoimmune hepatitis; patients with genetic disorders inducing liver disease; and those who in the 6 months preceding enrollment had taken drugs known to potentially induce liver damage.
Patients in group HIV/HCV were more frequently males (P < 0.02) and significantly younger than those in group HCV (P < 0.0001); more frequently they had HCV genotype 3 (38.2% vs 0%, P < 0.0001) or HCV genotype 4 (29.4% vs 0%, P < 0.0001); and more frequently stated a history of intravenous drug abuse (82.9% vs. 0%; P < 0.0001); conversely, HCV genotype 1 predominated in patients in group HCV (73.3% vs 32.2%, P < 0.0001) (Table 1). Patients in group HIV/HCV showed a good immunological status (CD4 = 564 ± 314), but a nadir of CD4 ≤200 cells per microliter was recorded in 52.9% of cases. Of the 34 patients in group HIV/HCV, 27 (79.4%) were under effective highly active antiretroviral therapy at the time of LB, whereas 7 with a good immunovirological condition had been left untreated (Table 1). Patients in group HIV/HCV, compared with those in group HCV, showed a higher score of fibrosis (Ishak score) (2.1 ± 1.5 vs 1.4 ± 0.6, P < 0.05) and a higher prevalence of patients with fibrosis score 3-6 (23.5% vs 6.6%, P < 0.05) (see Figure, Supplemental Digital Content 1, http://links.lww.com/QAI/A34). A necroinflammation score <7 (Ishak score) was found in the majority of cases in both groups. Liver steatosis was graded as follows: score 1 = 1%-10% of hepatocytes with fatty deposition; score 2 = 11%-30%; score 3 = 31%-60%; score 4 ≥60%. The higher degrees of steatosis (scores 2-4) were more frequent in group HIV/HCV than in group HCV (32.4% vs 3.4%, P < 0.005). We also analyzed other histological liver lesions: lipogranulomas, portal eosinophils, portal neutrophils, portal plasma cells, parenchymal granulomas, hemosiderosis, mega mitochondria, Mallory bodies, germinal centers, multinucleated giant hepatocytes, hepatocytic dysplasia, sanded nuclei, ground-glass hepatocytes, glycogen nuclei, ballooning, sinusoidal lymphocytosis, acidophilic rhomboid-shaped hepatocytes, Kupffer cell hyperplasia, acidophil bodies, bile duct wall lesions, bile duct proliferation, pericellular fibrosis, perivenular fibrosis, and focal intralobular necrosis. These lesions were graded as absent, mild, moderate, or severe and named “overlapping liver lesions”, according to Klatskin and Conn.3 A severe or more extensive expression of some overlapping liver lesions was more frequently observed in patients in group HIV/HCV than those in group HCV (Table 1): the differences were statistically significant for sinusoidal lymphocytosis (P = 0.031) and for acidophilic rhomboid-shaped hepatocytes (P = 0.0007) but not significant for acidophilic bodies, glycogen nuclei, ballooning, Kupffer cell hyperplasia, bile duct wall lesions, or bile duct proliferation (Table 1). The other overlapping liver lesions investigated were never or rarely observed.
HCV viral load was not associated to adverse liver histology or to a particular HCV genotype or other parameters explored.
The present study is, to our knowledge, the first performed on a substantial number of patients that compared the clinical presentation and liver histology of HIV/HCV-coinfected patients with PNAL with that of HCV-monoinfected patients with PNAL, and the only one investigating possible differences in the so-called “overlapping liver lesions” between these 2 groups. Of the previous studies, the study by Dr Gonzalez et al1 is the only one in which HIV/HCV-coinfected patients with PNAL were compared with HCV-monoinfected patients with PNAL, but the number of patients investigated was small, and the criterion to define the PNAL levels was different: the mean ALT level of 3 single determinations within the normal range over the 12 months before LB.
The data from the present study show that the percentage of patients with moderate or severe fibrosis is significantly higher in the coinfected patients and, therefore, the extent of fibrosis is significantly greater than in group HCV. The HIV viral load and levels of CD4+ cell count may be crucial in modulating the progression of fibrosis in HIV/HCV-coinfected patients, as suggested by the association of an increased rate of fibrous septa with severe CD4+ cell depletion, which, by inducing changes in the intrahepatic cytokine pattern and a predominance of a Th2 pattern, may activate hepatic stellate cells and lead to collagen deposition.4
Considering the low fibrosis scores found in HCV-monoinfected patients with PNAL in the present study, there is no indication for anti-HCV therapy for most of them, particularly for those with HCV genotype 1 for whom a low efficacy of treatment is expected; however, anti-HCV treatment should be considered for the quarter of HIV/HCV-coinfected patients with PNAL showing moderate or severe fibrosis.
Several investigations have shown that in most HCV-monoinfected patients with PNAL, liver fibrosis is mild or absent and that this lesion infrequently progresses to its more severe stages.5 However, 2 studies on HCV-monoinfected patients have recently attracted the attention of clinicians, the first demonstrating that patients with initially mild chronic HCV infection may develop moderate or severe fibrosis,6 and the second showing a good response to Peg-IFN plus RBV in HCV-monoinfected patients with PNAL.7 In the latter study a sustained virological response (SVR) was obtained in nearly 40% of cases with HCV genotype 1, in 93% of those with HCV genotype 2, and in 79% of those with genotype 3.7 Considering that a SVR after PEG-INF + RBV treatment indicates the eradication of HCV infection, we conclude on this point that each patient with HCV infection, whether HIV/HCVcoinfected or HCV monoinfected, should be individually assessed for treatment regardless of the ALT serum levels.
Patients with fatty deposition in more than 10% of hepatocytes were significantly more frequent in group HIV/HCV than in group HCV; most of the patients in group HIV/HCV, however, were under highly active antiretroviral therapy at the time of LB and more than one third of them circulated HCV genotype 3, 2 factors possibly associated with fatty deposition in the hepatocytes.
In the present study, HCV genotype 4 was detected in nearly 30% of cases in group HIV/HCV, a very high prevalence for our geographical area; none of the 10 patients with HCV genotype 4 in the present study showed an HAI >4, but a comparison with patients with other genotypes is not possible due to the small subgroups established on the basis of HCV genotype.
Although the role of the overlapping liver lesions in HIV/HCV-coinfected patients with PNAL is still obscure, some significant differences with HCV-monoinfected patients with PNAL were found. Of interest is that a more frequent and greater expression of sinusoidal lymphocytosis and acidophilic rhomboid-shaped hepatocytes were associated to HIV infection. This association, however, requires confirmation in further studies.
Caterina Sagnelli, PhD*†
Caterina Uberti-Foppa, MD*
Giuseppe Pasquale, MD†
Nicola Coppola, MD†
Luca Albarello, MD‡
Addolorata Masiello, MD†
Carlo Doglioni, MD‡
Adriano Lazzarin, MD*
Evangelista Sagnelli, MD†
*Clinic of Infectious Diseases, Vita-Salute University, San Raffaele Scientific Institute, Milan, Italy
†Department of Public Medicine, Section of Infectious Diseases, Second University of Naples, Naples, Italy
‡Department of Pathology, San Raffaele Scientific Institute, Milan, Italy
1. Gonzalez SA, Liu RC, Edlin BR, et al. HIV/hepatitis C virus in coinfected patients with normal alanine aminotransferase levels. J Acquir Immune Defic Syndr. 2006;41:582-589.
2. Uberti-Foppa C, De Bona A, Galli L, et al. Liver fibrosis in HIV-positive patients with hepatitis C virus: role of persistently normal alanine aminotransferase levels. J Acquir Immune Defic Syndr. 2006;41:63-67.
3. Klatskin G, Conn HO. Abnormalities on the hepatic parenchyma. Abnormalities of the portal track. In: Klatskin G, Conn HO, eds. Histology of the Liver. Vol 1. Oxford University Press; New York:1993:19-52; 59-76.
4. Puoti M, Bonacini M, Spinetti A, et al. Liver fibrosis progression is related to CD4 cell depletion in patients coinfected with hepatitis C virus and human immunodeficiency virus. J Infect Dis. 2001;183:134-137.
5. Persico M, Perrotta S, Persico E, et al. Hepatitis C virus carriers with persistently normal ALT levels: biological peculiarities and update of the natural history of liver disease at 10 years. J Viral Hepat. 2006;13:290-296.
6. Boccato S, Pistis R, Noventa F, et al. Fibrosis progression in initially mild chronic hepatitis C. J Viral Hepat. 2006;13:297-302.
7. Zeuzem S, Diago M, Gane E, et al. Peg-INF alfa-2a (40 kilodaltons) and RBV in patients with chronic hepatitis C and normal aminotransferase levels. Gastroenterology. 2004;127:1724-1732.
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