José A. Mira

Fast fibrosis progression between repeated liver biopsies in patients coinfected with human immunodeficiency virus/hepatitis C virus

A few studies have assessed the observed fibrosis progression between serial liver biopsies (LB) in human immunodeficiency virus (HIV) / hepatitis C virus (HCV)‐coinfected patients. Approximately half of the patients progressed at least one fibrosis stage over a short period of time. The risk factors for this fast progression need clarification. Because of this, we evaluated the observed fibrosis progression rates of HIV/HCV‐coinfected patients and the risk factors for accelerated progression. Overall, 135 HIV‐infected patients with positive serum HCV RNA, without other possible causes of liver disease, who underwent two LB, separated at least by 1 year, were included in this retrospective cohort study. The median (Q1‐Q3) time between both LBs was 3.3 (2.0‐5.2) years. Patients showed the following changes in fibrosis stage: regression ≥1 stage: 23 (17%), no change: 52 (39%), progression 1 stage: 38 (28%), and progression ≥2 stages: 22 (16%). Seventeen (13%) patients had cirrhosis in the second biopsy. Factors independently associated with progression ≥1 stage were undetectable plasma HIV RNA during the follow‐up (relative risk [RR] [95% confidence interval, 95% CI] 0.61 [0.39‐0.93], P = 0.03), moderate‐to‐severe lobular necroinflammation (1.77 [1.16‐2.7], P = 0.009), time between biopsies (1.11 [1.08‐1.2], P = 0.01), and end of treatment response to anti‐HCV therapy (0.41 [0.19‐0.88], P = 0.02). Conclusion: Fibrosis progresses with high frequency in HIV/HCV‐coinfected patients over a period of time of 3 years. Absent‐to‐mild lobular necroinflammation at baseline, achievement of response with anti‐HCV treatment, and effective antiretroviral therapy are associated with slower fibrosis progression. (HEPATOLOGY 2009.)

Effect of antiretroviral drugs on liver fibrosis in HIV-infected patients with chronic hepatitis C: harmful impact of nevirapine.

Background: The hepatotoxicity of highly active antiretroviral therapy (HAART) could enhance liver fibrosis in HIV/Hepatitis C virus (HCV)-coinfected patients. Moreover, HAART-related immune restoration could lessen HCV-associated liver damage. The data on the effect of protease inhibitors (PI) on liver fibrosis are scant and contradictory. No information is available on the relationship between non-nucleoside analogue therapy and liver fibrosis in co-infected patients. Objective: To investigate the associations between the use of different antiretroviral drugs and the liver fibrosis in patients with HIV and HCV infections. Design: Cross-sectional study. Methods: All HIV/HCV co-infected patients with an available liver biopsy and known or estimated duration of HCV infection seen at a Infectious Diseases Unit were included in the study. The fibrosis stage and the fibrosis progression rate were evaluated. Results: The inclusion criteria were fulfilled by 152 patients. Age at HCV infection < 20 years [adjusted odds ratio (AOR), 0.39; 95% confidence interval (CI), 0.19–0.82], PI-based HAART (AOR, 0.39; 95% CI, 0.19–0.78) and nevirapine-based HAART (AOR, 2.56; 95% CI, 1.02–6.58) were associated with fibrosis stage ⩾ F3. The variables associated with fibrosis progression rate > 0.2 units/year were age at HCV infection < 20 years (AOR, 0.23; 95% CI, 0.1–0.52), CD4 cell counts ⩽ 250 × 106/l at liver biopsy (AOR, 2.8; 95% CI, 1.1–7.1), PI-based HAART (AOR, 0.39; 95% CI, 0.2–0.8) and nevirapine-based HAART (AOR, 3.82; 95% CI, 1.9–7.6). Conclusions: HAART regimens including nevirapine are associated with faster liver fibrosis progression in HIV-infected patients with chronic hepatitis C. In contrast, patients on PI as the backbone of potent antiretroviral therapy are more likely to show less liver fibrosis.

Prediction of Response to Pegylated Interferon plus Ribavirin by IL28B Gene Variation in Patients Coinfected with HIV and Hepatitis C Virus

BACKGROUND Variation in the IL28B gene is associated with sustained virologic response (SVR) to pegylated interferon plus ribavirin in hepatitis C virus (HCV)-monoinfected patients with genotype 1. Data on other genotypes and on patients coinfected with human immunodeficiency virus (HIV) and HCV are more limited. We aimed to assess the predictive ability of variations in the single-nucleotide polymorphism rs12979860 for SVR in HIV/HCV-coinfected patients, regardless of HCV genotype. METHODS The rs12979860 genotype was determined by polymerase chain reaction in 154 patients who had received therapy against HCV with pegylated interferon plus ribavirin. RESULTS rs12979860 genotype was TT in 20 patients (13%), TC in 66 patients (43%), and CC in 68 patients (44%). Rates of SVR in patients with genotype CC and in those with genotype TC or TT, according to HCV genotype, were, respectively, 50% and 17% (P < .001) in patients with genotype 1, 80% and 25% (P = .027) in patients with genotype 4, and 93% and 77% (P = .115) in patients with genotype 3. The median (interquartile range) low-density lipoprotein cholesterol level in patients with rs12979860 CC was 89 mg/dL (73-120 mg/dL) versus 75 mg/dL (55-91 mg/dL) (P = .001) in those with TC or TT. Independent predictors of SVR were HCV genotype 2-3 (odds ratio [OR], 13.98; 95% confidence interval [CI], 4.87-40.1; P < .001), rs12979860 CC (OR, 5.05; 95% CI, 2.04-12.5; P < .001), baseline plasma HCV RNA load of < or =600,000 IU/mL (OR, 1.99; 95% CI, 1.18- 3.34; P = .009), and female sex (OR, 4.28; 95% CI, 1.08-16.96; P = .039). CONCLUSIONS IL28B gene variations independently predict SVR in HIV/HCV-coinfected patients with HCV genotype 1 and non-genotype 1 HCV infection. The association between rs12979860 and plasma low-density lipoprotein cholesterol suggests that the system low-density lipoprotein ligand/receptor might be involved in the effect of this genotype.

Prediction of liver fibrosis in human immunodeficiency virus/hepatitis C virus coinfected patients by simple non-invasive indexes

Background: Liver biopsy is an invasive technique with associated major complications. There is no information on the validity of five non-invasive indexes based on routinely available parameters, estimated and validated in hepatitis C virus (HCV) monoinfected patients, in human immunodeficiency virus (HIV)/HCV coinfected patients. Aim: To validate these predictive models of liver fibrosis in HIV/HCV coinfected patients. Patients: A total of 357 (90%) of 398 patients from five hospitals were investigated, who underwent liver biopsy and who had complete data to validate all of the models considered. Methods: The predictive accuracy of the indexes was tested by measuring areas under the receiver operating characteristic curves. Diagnostic accuracy was calculated by estimating sensitivity, specificity, and positive (PPV) and negative (NPV) predictive values. Results: The models performed better when liver biopsies ⩾15 mm were used as reference. In this setting, the Forns and Wai indexes, models aimed at discriminating significant fibrosis, showed PPV of 94% and 87%, respectively. Using these models, 27–34% of patients could benefit from exclusion of liver biopsy. If both models were applied sequentially, 41% of liver biopsies could be spared. The indexes aimed at predicting cirrhosis achieved NPV of up to 100%. However, they showed very low PPV. Conclusions: The diagnostic accuracy of these models was lower in HIV/HCV coinfected patients than in the validation studies performed in HCV monoinfected patients. However, simple fibrosis tests may render liver biopsy unnecessary in deciding anti-HCV treatment in over one third of patients with HIV infection and chronic hepatitis C.

Relationship between low bone mineral density and highly active antiretroviral therapy including protease inhibitors in HIV-infected patients.

Abstract Purpose: The objectives of this study were to determine the prevalence of osteopenia and the factors associated with its presence in HIV-infected patients under highly active antiretroviral therapy (HAART) and to assess the changes of bone mineral density (BMD) in a population followed prospectively. Method: BMD was assessed by dual-energy X-ray absorptiometry (DEXA) scans at the lumbar spine and at the femoral neck in 78 HIV-infected patients who had previously received HAART as the first antiretroviral regimen and in 11 antiretroviral-naive HIV-infected patients. BMD measurements were repeated in 70 treated patients who had completed 1 year of follow-up. Results: Thirty-seven (42%) patients showed osteopenia at any localization. The prevalence of osteopenia in PI-naive patients was 23% versus 49% in individuals who had received PI at any moment [p = .001; adjusted odds ratio (95% CI) = 0.11 (0.02-0.48)]. The frequency of osteopenia was significantly higher among men than among women [50% vs. 17%; p = .016; adjusted OR (95% CI) = 12.1 (2.22-66.20)]. The level of plasma albumin was independently associated with osteopenia [adjusted OR (95% CI) per each g/dL of plasma albumin decrease 2.55 (1.18-10)]. In patients in whom a second DEXA was done, no significant changes in BMD were found. Conclusion: The prevalence of osteopenia in HIV-infected patients on HAART is high. Loss of BMD is associated with PI therapy, low plasma albumin level, and male sex. Osteopenia does not progress after 1 year of continued HAART.

High prevalence of hepatitis C virus infection among noninjecting drug users: association with sharing the inhalation implements of crack

Background: Most of the prevalent cases of hepatitis C virus (HCV) infection are attributable to intravenous drug using. However, a substantial number of individuals, particularly noninjecting drug users (NIDU), report no identifiable source of HCV exposure. This may be interpreted as inaccurate reporting of past intravenous exposure or as the presence of an unidentified source of HCV infection. Because of this, we evaluated the prevalence of and factors associated with HCV infection among NIDU.

Benefits From Sustained Virologic Response to Pegylated Interferon Plus Ribavirin in HIV/Hepatitis C Virus–Coinfected Patients With Compensated Cirrhosis

BACKGROUND The objective of this study was to determine the impact of sustained virologic response (SVR) to pegylated interferon (peg-IFN) plus ribavirin (RBV) on the incidence of liver-related complications and overall mortality in human immunodeficiency virus (HIV)-infected patients with compensated hepatitis C virus (HCV)-related cirrhosis. METHODS We included in this prospective cohort study 166 coinfected patients with compensated cirrhosis, who received peg-IFN plus RBV, to assess the time from the starting date of HCV therapy to the first hepatic decompensation and death due to any cause. RESULTS SVR was observed in 43 (25%) individuals. Two (4.6%) patients with SVR developed liver decompensation vs 33 (26.8%) individuals without SVR (P = .002). The incidence of liver-related complications was 0.89 cases per 100 person-years (95% confidence interval [CI], .11-3.1) in SVR patients and 6.4 cases per 100 person-years (95% CI, 4.5-8.9) in non-SVR patients. Factors independently associated with liver decompensation were non-SVR (hazard ratio [HR], 8.1; 95% CI, 1.08-61.5; P = .042) and MELD score ≥9 at baseline (HR, 2.9; 95% CI, 1.2-7.2; P = .016). Two (4.6%) patients with SVR died due to any cause compared with 22 (17.9%) individuals without SVR (P = .02). MELD score ≥9 (HR, 3.1; 95% CI, 1.3-7.7; P = .011) and non-SVR (HR, 8.0; 95% CI, 1.07-61; P = .043) were independently associated with overall mortality. CONCLUSIONS The achievement of SVR following peg-IFN plus RBV markedly reduces the incidence of liver-related decompensation and the overall mortality in HIV/HCV-coinfected patients with compensated cirrhosis.

Incidence of and Risk Factors for Symptomatic Visceral Leishmaniasis among Human Immunodeficiency Virus Type 1-Infected Patients from Spain in the Era of Highly Active Antiretroviral Therapy

ABSTRACT The way in which the extensive use of highly active antiretroviral therapy (HAART) has influenced the incidence of visceral leishmaniasis (VL) among human immunodeficiency type 1 (HIV-1)-infected patients is not yet understood. The present study assessed whether the incidence of symptomatic VL in HIV-infected patients has decreased since the introduction of HAART. Likewise, the role of other potential risk factors for VL was also analyzed. Therefore, 479 HIV-1-infected patients receiving antiretroviral treatment, according to the available drugs at each moment, were prospectively followed from April 1989 to June 2000 in two university hospitals in southern Spain. A bone marrow aspiration was performed when patients showed symptoms suggestive of kala-azar. A diagnosis of VL was made when Leishmania amastigotes were seen in Giemsa-stained samples or promastigotes were cultured in specific media. The median follow-up time was 1,380 [8 to 4,536] days. Twenty-one patients were diagnosed with symptomatic VL. The density of incidence of VL has decreased 64.8% as of January 1997, when HAART began to be used extensively in our area. The use of HAART was the main independent factor associated with VL; this therapy was a protective factor (adjusted hazard ratio [HR], 0.05; 95% confidence interval [CI], 0.02 to 0.15). CDC clinical category C at entry in the cohort (HR, 4.08; 95% CI, 1.46 to 11.35) and CD4+ cell counts below 300 cells/mm3 during the follow-up (HR, 3.96; 95% CI, 1.56 to 10.01) were also independently associated with kala-azar. A VL diagnosis prior to follow-up and low compliance with antiretroviral therapy were not independently associated with symptomatic VL, although statistical significance was almost reached (P = 0.1 and P = 0.08, respectively). In summary, the use of HAART has led to a fall in the incidence of symptomatic VL in HIV-infected patients. The main risk factor associated with kala-azar emergence in patients infected with HIV is deep immunosuppression.

Efficacy of pegylated interferon plus ribavirin treatment in HIV/hepatitis C virus co-infected patients receiving abacavir plus lamivudine or tenofovir plus either lamivudine or emtricitabine as nucleoside analogue backbone

OBJECTIVES To compare the response to hepatitis C virus (HCV) therapy among human immunodeficiency virus (HIV)/HCV co-infected patients receiving a nucleos(t)ide reverse transcriptase inhibitor [N(t)RTI] backbone consisting of abacavir plus lamivudine with that observed in subjects who receive tenofovir plus lamivudine or emtricitabine. METHODS A total of 256 subjects, enrolled in a cohort of 948 HIV-infected patients who received pegylated interferon and ribavirin from October 2001 to January 2006, were included in this study. All patients were taking one protease inhibitor or one non-nucleoside reverse transcriptase inhibitor and abacavir plus lamivudine or tenofovir plus lamivudine or emtricitabine as N(t)RTI backbone during HCV therapy. Sustained virological response (SVR) rates in both backbone groups were compared. RESULTS In an intention-to-treat analysis, 20 out of 70 (29%) individuals under abacavir and 83 out of 186 (45%) under tenofovir showed SVR (P = 0.02). N(t)RTI backbone containing tenofovir was an independent predictor of SVR in the multivariate analysis [adjusted odds ratio (95% CI), 2.6 (1.05-6.9); P = 0.03]. The association between abacavir use and lower SVR was chiefly seen in patients with plasma HCV-RNA load higher than 600 000 IU/mL and genotype 1 or 4. Among patients treated with ribavirin dose <13.2 mg/kg/day, 3 (20%) of those under abacavir versus 22 (52%) under tenofovir reached SVR (P = 0.03), whereas the rates were 31% and 38% (P = 0.4), respectively, in those receiving >/=13.2 mg/kg/day. CONCLUSIONS HIV-infected patients who receive abacavir plus lamivudine respond worse to pegylated interferon plus ribavirin than those who are given tenofovir plus lamivudine or emtricitabine as N(t)RTI backbone, especially in those receiving lower ribavirin doses.

Prevalence and risk factors for abnormal liver stiffness in HIV-infected patients without viral hepatitis coinfection: role of didanosine.

BACKGROUND Unexpected cases of severe liver disease in HIV-infected patients have been reported and an association with didanosine (ddI) has been suggested. Transient elastography (TE) might detect patients harbouring such a condition. Our objective was to search for the presence of abnormal liver stiffness (LS) in a cohort of HIV-infected patients without HBV or HCV coinfection and to assess the related factors. METHODS A cross-sectional prospective study was conducted. LS was assessed by TE in 258 HIV-infected patients without HBV or HCV coinfection and with no evidence of acute hepatotoxicity or other origins of liver disease. LS values > or =7.2 kPa were considered abnormal. Multivariate analyses were performed to identify factors associated with abnormal LS. RESULTS Abnormal LS was observed in 29 (11.2%) patients. A total of 18 (16.4%) patients previously treated with ddI and 11 (7.4%) of those who never received ddI had LS values > or =7.2 kPa (P=0.02). The prevalence of abnormal LS was higher in patients previously treated with abacavir than in those who had never received abacavir (15 [21.7%] versus 14 [7.4%]; P=0.001). After multivariate analyses, age (adjusted odds ratio [AOR] 1.05, 95% confidence interval [CI] 1.002-1.1; P=0.004) alcohol intake >50 g/day (AOR 7.2, 95% CI 2.6-19.7; P<0.0001), CD4(+) T-cell count <200 cells/ml (AOR 3.4, 95% CI 1.06-11.007; P=0.03), time on ddI treatment (AOR 1.31, 95% CI 1.12-1.52; P=0.001) and previous abacavir exposure (AOR 3.01, 95% CI 1.18-7.67; P=0.02) were independently associated with abnormal LS. CONCLUSIONS The prevalence of abnormal LS in HIV-infected patients without HBV or HCV coinfection is substantial. Long-term exposure to ddI is a major cause of liver damage in these patients.