Human Immunodeficiency Virus Hepatitis C Virus Research Articles

HIV/HCV co‐infection: histopathologic findings, natural history, fibrosis, and impact of antiretroviral treatment: a review article

Human immunodeficiency virus/hepatitis C virus (HIV/HCV) co-infection has emerged as a leading cause of liver morbidity in the last two decades. Liver failure is also frequently a cause of death in HIV/HCV co-infected patients. Highly active antiretroviral treatment (HAART) has revolutionized the HIV treatment, leading to a significantly decreased morbidity, prolonged survival, and an overall better outcome of HIV infection. Hepatotoxicity associated with antiretroviral treatment, however, has been recognized as one of the serious complications of the treatment. The effects of HIV infection on the natural history and progression of HCV-associated chronic liver disease that had been well documented in the pre-HAART treatment era have been changing, and there are now many indications that HIV/HCV co-infection should be recognized as an evolving and a challenging disease entity.

Cryoglobulinaemia associated with hepatitis C virus: influence of HCV genotypes, HCV‐RNA viraemia and HIV coinfection

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.

Impact of Hepatitis C on HIV Progression in Adults With Alcohol Problems

Coinfection of human immunodeficiency virus (HIV) and hepatitis C virus (HCV) is a substantial medical and public health concern due to its increasing prevalence and complex patient management. Alcohol use may worsen HCV-related liver disease and interfere with adherence to antiretroviral therapy (ART) and medical care. We therefore studied the association between HCV infection and markers of HIV disease progression in adults with alcohol problems. This is a longitudinal study of 396 HIV-infected persons with alcohol problems, 199 (50%) of whom were coinfected with HCV (positive HCV RNA test). CD4 cell counts and HIV RNA levels were assessed at baseline and then every 6 months for up to 42 months. Hepatitis C virus RNA status was determined at study enrollment. We examined the relationship between HCV infection and laboratory markers of HIV progression (CD4 cell count and log10 HIV RNA) by fitting multivariable longitudinal regression models for each outcome. Among subjects who were adherent to ART, the presence of HCV infection was associated with a lower CD4 cell count (adjusted mean difference -46.0 cells/microL, p=0.03). There was no association observed between HCV infection and CD4 cell count among those not adherent to ART or those not taking ART. No significant association was observed between HCV infection and HIV RNA regardless of ART status. Hepatitis C virus infection has an adverse effect on CD4 cell count in patients with alcohol problems who are adherent to ART. Addressing HCV coinfection among these patients may confer additional immunologic benefit for this patient population.

Risk factors for anaemia in human immunodeficiency virus/hepatitis C virus‐coinfected patients treated with interferon plus ribavirin

The most frequent and the most troublesome adverse effect of interferon plus ribavirin-based therapy is anaemia. The aim of this analysis was to determine the incidence and risk factors of anaemia (Hb < 10 g/dL) in human immunodeficiency virus/hepatitis C virus (HCV)-coinfected patients receiving anti-HCV therapy. We reviewed all cases of anaemia occurring among 416 patients participating in a randomized, controlled 48-week trial comparing peginterferon (peg-IFN) alpha 2b plus ribavirin with interferon alpha-2b plus ribavirin. Univariate and multivariate analyses were used to identify links with antiretroviral treatments, HCV therapy and clinical and laboratory findings. Sixty-one (15.9%) of the 383 patients who received at least one dose of anti-HCV treatment developed anaemia. In multivariate analysis the risk of anaemia was significantly associated with zidovudine (OR, 3.27 95% CI, 1.64-6.54, P = 0.0008) and peg-IFN (OR, 2.35; 95% CI, 1.16-4.57, P = 0.0179). The risk of anaemia was lower in patients with higher baseline haemoglobin levels (OR, 0.35 95% CI, 0.26-0.49, P < 0.0001) and in patients receiving protease inhibitor-based antiretroviral therapy (OR, 0.51 95% CI, 0.30-0.86, P = 0.0114). Zidovudine discontinuation could help to avoid anaemia associated with anti-HCV therapy.

Seroprevalence of vaccine preventable and blood transmissible viral infections (measles, mumps, rubella, polio, HBV, HCV and HIV) in medical students

In the course of clinical training medical students are in particular exposed to infectious diseases. Therefore, the present study was performed to investigate the immunity status of 223 medical students in their first clinical semester to job-related diseases. Specific serological antibody testing of hepatitis B-virus (HBV), hepatitis C-virus (HCV), human immunodeficiency virus (HIV), varicella zoster- (VZV), measles-, mumps-, rubella and polioviruses' type 1, 2 and 3 were performed. The results yielded, that 69.5% of the students had an anti-HBs-level > or =10 IU/l and 54.7% > or =100 IU/l. Neither HCV infection nor HIV infection were found, but one student showed an active HBV infection. Virus specific immunity rates were found in 91.5% for measles, 80.3% for mumps, 90.1% for rubella and 96.9% for varicella. Furthermore the medical students demonstrated neutralizing antibodies to polioviruses: 95.1% (type 1), 96.9% (type 2) and 70% (type 3). 68.2% had antibodies (titer 1:> or =10) against all three virus types. The partly significant gaps of immunity in the students need to be closed prior to the first contact with patients.

Natural History of Anemia Associated with Interferon/Ribavirin Therapy for Patients with HIV/HCV Coinfection

The natural history of anemia related to interferon/ribavirin (IFN/RBV) treatment in patients with human immunodeficiency virus/hepatitis C virus (HIV/HCV) coinfection is not completely understood. The current 8-week, multicenter, observational study characterized anemia over the course of HCV treatment in patients with HIV/HCV coinfection. Eligible HIV/HCV coinfected patients were receiving care in community-based and academic institutions and were on stable antiretroviral therapy and initiating IFN/RBV therapy. Hb, sEPO, reticulocytes, transfusions, laboratory values (e.g., total bilirubin), and IFN and RBV dosages were monitored weekly. Ninety-one patients were analyzed (mean age, 46 years; 71% on HAART) and 53 patients completed the study. Mean Hb decreased significantly (5.0 g/dl) within 1 week of initiating IFN/RBV therapy (p = 0.0002); Hb nadir occurred at a median of 37 days. Maximum Hb decreases of > or =2.0 g/dl occurred in 56 (62%) patients and > or =3.0 g/dl occurred in 45 (49%) patients. Reticulocyte count increased within the first 2 weeks and sEPO peaked at week 3. Mean increase from baseline to week 2 in reticulocyte count and sEPO, respectively, was 1.3% (n = 74) and 45.0 mIU/ml (n = 80) (p < 0.0001 for each parameter), and from baseline to week 8 was 0.9% (n = 48) and 41.0 mIU/ml (n = 52) (p < or = 0.0001 for each parameter). Adverse events (AEs) were the most common reason for study discontinuation (66% of discontinuing patients). Among the 25 patients who discontinued due to AEs, 84% discontinued due to anemia (n = 21). Significant decreases in Hb were observed in HIV/HCV-coinfected patients within 1 week of initiating IFN/RBV therapy. sEPO and reticulocyte increases were blunted in response to anemia; Hb levels did not return to baseline values and anemia was a frequent reason for discontinuing the study.

Oral complication risks after invasive and non‐invasive dental procedures in HIV‐positive patients

Limited published scientific evidence is available to provide guidance to clinicians on possible increased risks of invasive oral procedures associated with the human immunodeficiency virus (HIV) status of the patient. The aim of this study was to assess post-procedural complications in patients infected with HIV. This was a retrospective cross-sectional study of the records of 101 consecutive HIV patients treated at the School of Dentistry of Madrid Complutense University and Sandoval STD Clinic in Madrid between January 2003 and February 2005. Data were gathered by an experienced dental practitioner using a structured epidemiological questionnaire for information on gender, age, HIV transmission category, medical history, hepatitis B virus (HBV) or hepatitis C virus (HCV) coinfection and other diseases, TCD4+ and TCD8+ count, HIV viral load (VL), platelet count, neutrophil count, international normalized ratio and haemoglobin level; tobacco and alcohol intake, highly active antiretroviral treatment and presence of oral lesions. Information was also collected on complications related to dental treatment (invasive or non-invasive) during the previous 6 months. Chi-squared test and Fisher's exact test were used to establish statistical significance. Data were gathered on 314 dental procedures in 101 patients. The overall complication rate was 2.2% (7/314); in 147 invasive procedures, seven complications (4.8%) were documented (one persistent pain, two prolonged bleeding, three infections, one bone sequestrum) including extractions, periodontal scaling, endodontic treatment and biopsy. No differences were found in TCD4+, TCD8+, platelet count, HBV or HCV co-infections or HIV VL between patients with and/or without complications. Patients with complications were mainly in B stage of HIV disease (P=0.020). Oral lesions and smoking habit>20 cig day-1 were documented in 83.3% (P=0.086) and 50% (P=0.060), respectively, of patients with complications. The complication rate was 2.2% overall and 4.8% after invasive dental procedures. Presence of oral lesions, smoking habit or HIV clinical stage B may be predictive factors for oral complications in HIV patients. No relationship was found between complications and virological, immunological or other laboratory values. Studies with wider samples and negative control group are warranted to confirm the absence of an association between HIV positivity and higher risk of oral complications.

Zidovudine use but not weight‐based ribavirin dosing impacts anaemia during HCV treatment in HIV‐infected persons

Anaemia during peginterferon (PEG-IFN) and ribavirin (RBV) therapy is common in human immunodeficiency virus/hepatitis C virus (HIV/HCV)-coinfected patients despite the use of lower doses of RBV than are recommended for HIV-seronegative persons. In addition, concurrent zidovudine (ZDV) may exacerbate the anaemia caused by PEG-IFN and RBV. We retrospectively analysed the incidence of anaemia, RBV dose reduction and epoetin-alpha (EPO) use among coinfected patients treated with PEG-IFN and weight-based RBV (800-1400 mg/day) who enrolled in two clinical trials and had haemoglobin (Hb) levels assessed at baseline and after 4 and/or 12 weeks of HCV treatment. Overall, 217 patients were included; pre-treatment Hb levels (mean 14.7 g/dL) were similar in all patients, including ZDV users (29% of patients). After 4 weeks of therapy, the mean Hb decline was greater among ZDV recipients (3.13 g/dL) compared with those on other anti-retroviral treatment (ART) (2.13 g/dL) or on no ART (1.47 g/dL) (P < 0.0001). RBV dose reduction and EPO use were more common in patients taking ZDV compared with those not taking ZDV (P < 0.0001). RBV dose was not associated with Hb reduction, RBV dose reduction or EPO use. Virologic response after 12 weeks of therapy and the treatment discontinuation rate did not differ by ZDV use. The use of ZDV but not weight-based RBV dosing was associated with an increased risk of anaemia, RBV dose reduction or EPO use in coinfected patients treated with PEG-IFN/RBV. However, ZDV use was not associated with higher rates of treatment discontinuation or lower early virologic response rates. HIV and hepatitis C care providers should be cognizant of these data.

Face‐to‐face interviewing in predonation screening: lack of effect on detected human immunodeficiency virus and hepatitis C virus infections

Predonation screening has become more elaborate over the years, while human immunodeficiency virus (HIV)- and hepatitis C virus (HCV)-positive donations have declined. The impact of face-to-face interviewing and of the format of the Donor Health Assessment Questionnaire (DHAQ) have not been evaluated. Canadian Blood Services DHAQ records between 1990 and 2004 were examined, and changes in them were tracked. The proportion of first-time donors permanently deferred for HIV or HCV risk, and the HIV and HCV rates per 100,000 donations, were calculated annually. Time-series analysis was used to determine whether major predonation screening changes had any effect on the HIV or HCV rates or permanent deferrals. In 1992, receiving money or drugs for sex was added to the DHAQ; otherwise, the content of high-risk questions changed little between 1990 and 2004. In 1997, the method of administration of the DHAQ changed from donor-completed to face-to-face interviewing for high-risk questions. Permanent deferrals for HIV or HCV risk factors and HIV and HCV rates in first-time donors decreased over this period. The HIV rates were close to 0 before 1997, whereas HCV rates decreased steadily through 2004. There was no interruption in rates in 1997 when the method of administration changed. Face-to-face interviewing for high-risk questions had no effect on HIV or HCV rates in first-time donations over 15 years of observation (during the latter 8 of which face-to-face interviewing was in place), and it did not increase permanent deferrals for HIV or HCV risk factors.

Pretreatment assessment and predictors of hepatitis C virus treatment in US veterans coinfected with HIV and hepatitis C virus

The US Department of Veterans Affairs (VA) cares for many human immunodeficiency virus/hepatitis C virus (HIV/HCV)-coinfected patients. VA treatment recommendations indicate that all HIV/HCV-coinfected patients undergo evaluation for HCV treatment and list pretreatment assessment tests. We compared clinical practice with these recommendations. We identified 377 HIV/HCV-coinfected veterans who began HCV therapy with pegylated interferon and ribavirin and 4135 HIV/HCV-coinfected veterans who did not but were in VA care at the same facilities during the same period. We compared laboratory and clinical characteristics of the two groups and estimated multivariate logistic regression models of receipt of HCV treatment. Overall, patients had high rates of receipt of tests necessary for HCV pretreatment assessment. Patients starting HCV treatment had higher alanine aminotransferase (ALT), lower creatinine, higher CD4 counts and lower HIV viral loads than patients not starting HCV treatment. In the multivariate model, positive predictors of starting HCV treatment included being non-Hispanic whites, having higher ALTs, lower creatinines, higher HCV viral loads, higher CD4 counts, undetectable HIV viral loads and receiving HIV antiretrovirals. A history of chronic mental illness and a history of hard drug use were negative predictors. Most HIV/HCV-coinfected patients received the necessary HCV pretreatment assessments, although rates of screening for hepatitis A and B immunity can be improved. Having well-controlled HIV disease is by far the most important modifiable factor affecting the receipt of HCV treatment. More research is needed to determine if the observed racial differences in starting HCV treatment reflect biological differences, provider behaviour or patient preference.

HIV, HBV, HCV, and syphilis co-infections among patients attending the STD clinics of district hospitals in Northern India

The objective of the study was to assess the risk of co-infections with human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), and syphilis among patients attending sexually transmitted disease (STD) clinics, antenatal clinics (ANC) and Ob-Gyn outpatients department (OPD) clinics which were part of the sentinel surveillance program. A serological screening was carried out during the period August-November 2002 to assess the risk of infection with HIV-1/2, and co-infection with HBV, HCV, and syphilis among the outpatients attending STD clinics, Ob-Gyn OPD clinics, and ANC of three district hospitals (Agra, Etawah, and Farrukhabad) of Uttar Pradesh state in Northern India. Unlinked and coded serum samples received from 863 patients (635 females and 228 males) were screened by laboratory tests commonly used for laboratory diagnosis of HIV, HBV, HCV, and syphilis. Among the 863 samples serological reactivity was detected for HIV-1/2 in 21 (2.4%), HBV in 25 (2.9%), HCV in nine (1.0%), and syphilis in 47 (5.4%). The incidence of HBV was higher among males than females, i.e. 10/228 (4.4%) versus 15/635 (2.4%). Co-infection was observed for HIV-HBV in two (0.2%), HBV-HCV in one (0.1%), and HIV-syphilis in one (0.1%). None were found to have co-infection with HIV-HCV, HBV-syphilis, and HCV-syphilis. Age, sex, literacy level, occupation, locality, migration, and presence of different sexually transmitted infections did not significantly influence the rate of HIV positives. A substantial percentage of the outpatients seen in the clinics of the district hospital in Uttar Pradesh harbor HIV and viral hepatitis infections, which otherwise would remain undiagnosed without serological screening.

Incidence of and risk factors for severe hepatotoxicity of nelfinavir-containing regimens among HIV-infected patients with chronic hepatitis C

To determine the incidence of and risk factors for severe hepatotoxicity of nelfinavir-containing regimens among human immunodeficiency virus/hepatitis C virus (HIV/HCV)-coinfected patients with known stage of liver fibrosis. All HIV/HCV-coinfected patients were monitored for a period of 12 months after starting nelfinavir-containing regimens and, with an available liver biopsy, were included in a retrospective study. A total of 82 patients were included in the study. Nine (10.9%) HIV/HCV-coinfected patients showed an episode of severe hepatotoxicity during the study period. Eight (9.8%) individuals showed grade 3 or 4 change in levels of serum alanine aminotransferase and one subject presented with an event of decompensated liver cirrhosis. Six (18.2%) of 33 patients with advanced liver fibrosis and three (6%) of 49 individuals without advanced liver fibrosis showed an episode of severe hepatotoxicity (P = 0.1). In the multivariate analysis, only nevirapine use during nelfinavir therapy [adjusted odds ratio (AOR) 8.9; 95% confidence interval (CI), 1.4-54.1; P = 0.01] was independently associated with risk of development of severe liver toxicity. The incidence of severe hepatotoxicity of nelfinavir-containing regimens is low among HIV/HCV-coinfected patients with known stage of liver fibrosis. In addition, our findings show that concomitant nevirapine use is associated with an increased risk of severe hepatotoxicity in these subjects. Likewise, the proportion of severe liver toxicity tended to be higher in individuals with advanced liver fibrosis.

Progression to Cirrhosis in Latinos With Chronic Hepatitis C: Differences in Puerto Ricans With and Without Human Immunodeficiency Virus Coinfection and Along Gender

Hepatitis C virus (HCV) infection is prevalent in Latinos. There is some evidence that progression to cirrhosis is more rapid. To calculate time of cirrhosis from time of HCV infection in a large Latino population. Other end points were to assess variables that predict cirrhosis and the effect of gender, alcohol, and human immunodeficiency virus (HIV) infection status on time to cirrhosis. Four hundred sixty-nine Latino patients evaluated at a referral center in Puerto Rico were included. Several demographic parameters, such as risk factors, estimated duration of HCV infection, alcohol use, HIV status, and findings from the usual HCV and HIV laboratory tests were noted. All patients had liver biopsy specimens assessed by Ishak score. Monoinfected and coinfected latinos have a median cumulative risk/hazard for cirrhosis of 42.0 vs. 32.0 years after infection (P = 0.0016). The median age of cirrhotic patients is 53.0 years in monoinfections and 42.0 years in coinfection. Among coinfected patients there is no gender-associated difference in time to onset of cirrhosis (P = 0.785). Among monoinfected patients, males have a shorter median risk/hazard to cirrhosis than females (11.0-year difference; P = 0.05) and have a shorter time until onset of cirrhosis by fibrosis progression rate (FPR) (33.33 vs. 41.66 years; P = 0.021). There is no difference between male patients with regard to HIV status (P = 0.199). Alcohol use is significant in monoinfected males (59.2 g/day) vs. females (11.4 g/day; P = 0.001). Variables that predict cirrhosis are male sex, age, and Ishak grade in monoinfected patients and alanine aminotransferase value in coinfected patients. Puerto Ricans with HCV have a median risk/hazard time to cirrhosis at younger age than other populations. Males who are HIV/HCV-coinfected have the same median risk/hazard and time to cirrhosis than those monoinfected with HCV. Special attention for early diagnosis and treatment is mandatory.

Effect of Ribavirin on Intracellular and Plasma Pharmacokinetics of Nucleoside Reverse Transcriptase Inhibitors in Patients with Human Immunodeficiency Virus-Hepatitis C Virus Coinfection: Results of a Randomized Clinical Study

The intracellular triphosphorylation and plasma pharmacokinetics of lamivudine (3TC), stavudine (d4T), and zidovudine (ZDV) were assessed in a pharmacokinetic substudy, in 56 human immunodeficiency virus-hepatitis C virus (HIV-HCV) coinfected patients receiving peginterferon alfa-2a (40KD) 180 microg/week plus either placebo or ribavirin (RBV) 800 mg/day in the AIDS PEGASYS Ribavirin International Coinfection Trial. There were no significant differences between patients treated with RBV and placebo in plasma pharmacokinetics parameters for the nucleoside reverse transcriptase inhibitors (NRTIs) at steady state (weeks 8 to 12): ratios of least squares mean of area under the plasma concentration-time curve (AUC(0-12 h)) were 1.17 (95% confidence interval, 0.91 to 1.51) for 3TC, 1.44 (95% confidence interval, 0.58 to 3.60) for d4T and 0.85 (95% confidence interval, 0.50 to 1.45) for ZDV, and ratios of least squares mean plasma C(max) were 1.33 (95% confidence interval, 0.99 to 1.78), 1.06 (95% confidence interval, 0.68 to 1.65), and 0.84 (95% confidence interval, 0.46 to 1.53), respectively. Concentrations of NRTI triphosphate (TP) metabolites in relation to those of the triphosphates of endogenous deoxythymidine-triphosphate (dTTP) and deoxcytidine-triphosphate (dCTP) were similar in the RBV and placebo groups. Differences (RBV to placebo) in least squares mean ratios of AUC(0-12 h) at steady state were 0.274 (95% confidence interval, -0.37 to 0.91) for 3TC-TP:dCTP, 0.009 (95% confidence interval, -0.06 to 0.08) for d4T-TP:dTTP, and -0.081 (95% confidence interval, -0.40 to 0.24) for ZDV-TP:dTTP. RBV did not adversely affect HIV-1 replication. In summary, RBV 800 mg/day administered in combination with peginterferon alfa-2a (40KD) does not significantly affect the intracellular phosphorylation or plasma pharmacokinetics of 3TC, d4T, and ZDV in HIV-HCV-coinfected patients.

Molecular Mechanism of Hepatic Injury in Coinfection with Hepatitis C Virus and HIV

We have previously shown that hepatocytes exposed to hepatitis C virus (HCV) and human immunodeficiency virus (HIV) envelope proteins undergo apoptosis. In this article, we further elucidate the signaling mechanisms that mediate this effect. We found that, in human hepatocellular carcinoma (HepG2) cells, HCV E2 protein and HIV glycoprotein (gp) 120 significantly up-regulated the Fas ligand (FasL) and enhanced the formation of the Fas death-inducing signaling complex downstream of Fas receptor activation. Moreover, after stimulation with HCV E2 and HIV gp120, enhanced expression of caspases 2 and 7 and increased caspase 3 activity were observed. In addition, we showed up-regulation of the proapoptotic molecule Bid and its association with caspase 8 after treatment with these envelope proteins. We also found that HCV E2 and HIV gp120 induced a partial translocation of Bid to the mitochondria, which resulted in the release of cytochrome C and the apoptosis-inducing factor. Thus, the results of this study suggest that FasL and Bid play an important role in HCV and HIV envelope protein-induced apoptosis.

Predictive factors of lopinavir/ritonavir discontinuation for drug-related toxicity: results from a cohort of 416 multi-experienced HIV-infected individuals

The objective of this study was to find predictive factors of lopinavir/ritonavir (LPV/r) discontinuation for drug-related toxicities in highly pre-treated human immunodeficiency virus (HIV)-infected subjects. The study was an observational study of HIV patients starting LPV/r with HIV RNA >3 log 10 copies/mL and a follow-up ≥6 months. Parameters studied were HIV RNA, CD4+ cell counts, metabolic parameters and drug-related adverse events. Acquired immune deficiency syndrome (AIDS) events and deaths were recorded. The Kaplan–Meier (KM) model was used to estimate time-dependent probability, and the multivariable Cox model to identify predictors of LPV/r discontinuation for adverse events. The study evaluated 416 HIV-infected patients. Seventy-seven patients (18.5%) discontinued LPV/r for toxicities. Adverse events leading to LPV/r discontinuation were gastrointestinal symptoms in 40 cases, hyperlipidaemia in 27 and increase of aspartate aminotransferase (AST)/alanine aminotransferase (ALT) in 10 patients. Nineteen patients (4.6%) developed an AIDS event during observation and 15 (3.6%) died. The KM probability of LPV/r discontinuation for toxicities was 5.3% (range 3.1–7.5%) at month 12 and 15.7% (range 12.1–19.3%) at month 24. Subjects with hepatitis C virus (HCV)–HIV co-infection (odds ratio (OR) 7.40; 95% confidence interval (CI) 3.73–14.66 versus HCV-negative; P = 0.001) and receiving LPV/r plus nucleoside reverse transcriptase inhibitors (NRTIs) and protease inhibitor (PI)/non-nucleoside reverse transcriptase inhibitor (NNRTI) (OR 1.74; 95% CI 1.04–2.91 versus LPV/r plus only NRTIs; P = 0.04) showed a higher risk of LPV/r discontinuation by a Cox analysis, whereas non-intravenous drug abusers (IVDUs) (OR 0.40; 95% CI 0.24–0.67 versus IVDUs; P = 0.001) had a lower risk. The rate of discontinuation for toxicity decreased by 17% for each additional month of LPV/r exposure (OR 0.83; 95% CI 0.80–0.86 for each additional month; P < 0.001). LPV/r was substantially well tolerated. Diarrhoea was the most frequent adverse event leading to discontinuation. HCV–HIV co-infected patients and patients with a short exposure to LPV/r have a higher risk of discontinuing LPV/r and should be strictly monitored.

Liver histopathology in human immunodeficiency virus–hepatitis C virus co‐infected patients with fatal liver disease

Liver failure is an increasing cause of death in human immunodeficiency virus-hepatitis C virus (HIV-HCV) co-infected patients. Here, histopathological features of fatal liver disease in HIV-HCV co-infected patients were comparatively assessed. Liver biopsies of seven HIV-HCV co-infected patients with clinically imminent liver death and advanced immune deficiency were studied. Biopsies of seven asymptomatic patients with stable hepatic and immune functions, who were matched according to their documented duration of HIV-HCV co-infection, served as controls. Inflammatory and fibrotic changes as well as hepatocellular steatosis and cholestasis were assessed semiquantitatively by established scores. All patients with fatal liver disease had severe immunodeficiency and jaundice, while biliary ducts were patent. Unexpectedly, the extent of hepatic steatosis, inflammatory activity and fibrosis was strikingly similar in both study groups. Importantly, liver failure was observed even in the absence of marked fibrosis. Lobular bilirubinostasis was the only feature that significantly distinguished patients with advanced immunodeficiency and fatal liver disease from the control group. Thus, rapid deterioration of liver function and death can occur in HIV-HCV co-infected patients with advanced immunodeficiency even when liver histology does not reveal markers of end-stage liver disease. Jaundice and marked bilirubinostasis in the absence of biliary tract obstruction seem to herald this complication of chronic hepatitis C in HIV infection.

HCV and HIV Envelope Proteins Co-Operatively Induce Fas-Mediated Apoptosis Via a Novel Stat1 Signaling Pathway.

Hepatitis C virus (HCV) co-infects approximately 40% of patients with human immunodeficiency virus (HIV). HCV/HIV co-infected patients often have progressive liver disease that can lead to cirrhosis and death. We observed that hepatocytes exposed to HCV and HIV envelope proteins undergo apoptosis via an ‘innocent bystander' mechanism due to cell surface binding of viral proteins independent of direct viral infection. HCV envelope protein E2 (1.5 nM) and HIV envelope protein gp120 (0.8 nM) derived from M-tropic and T-tropic viruses induce significant apoptosis in both hepatocytic cell lines and primary hepatocytes, while either of these viral proteins alone does not. Now, we have elucidated the signaling mechanisms that mediate this effect. HCV-E2 and HIV-gp120 were found to significantly upregulate Fas ligand (FasL). We then examined the Stat family of proteins known to participate in FasL and apoptotic pathways. We observed an increased DNA binding activity of Stat1 upon HCV-E2 and HIV-gp120 stimulation. Furthermore, overexpression of wild type Stat1αincreased apoptosis and FasL expression in HepG2 cells, whereas a C-terminal domain deleted mutant, Stat1β, decreased HCV-E2 and HIV-gp120 mediated apoptosis and FasL upregulation. Overexpression of Stat1αand Stat1β in primary hepatocytes confirmed that Stat1αenhanced apoptosis upon HCV-E2 and HIV-gp120 treatment. We observed a tyrosine dependent activation of Stat1 and a subsequent serine phosphorylation of Stat1. TYK2, lyn kinase, RAFTK and MAP kinases were activated upstream of Stat1. In addition, Stat1 associated with the death domain-containing adapter protein TRADD. TRADD is known to induce inflammatory signaling through the NFκB pathway. Here, the association of Stat1 with TRADD would reduce the availability of TRADD to induce NFκB. Thus, Stat1 sequestration of downstream apoptotic signaling molecules would block the host inflammatory response. Further characterization of Fas-mediated apoptosis revealed that caspase 3 and caspase 7 were activated following HCV-E2 and HIV-gp120 stimulation. However, we were not able to detect significant activity of either caspase 8 or caspase 9. We also found a loss in mitochondrial membrane potential upon HCV-E2 and HIV-gp120 stimulation, which leads to the release of cytochrome C and AIF into the cytosol. Taken together, these studies indicate that the viral proteins of HCV and HIV co-operate in causing the apoptosis of hepatocytes, independent of direct infection, by induction of novel Stat1 downstream signaling pathways at the expense of a normal host inflammatory response.

High prevalence of hepatitis C virus type 5 in central France evidenced by a prospective study from 1996 to 2002.

From 1996 to 2002, hepatitis C virus (HCV) typing was prospectively performed for 1,281 unselected HCV-infected and viremic patients, irrespective of their clinical status. Eighty-three patients (6.5%) were coinfected with human immunodeficiency virus (HIV) and HCV. A total of 1,195 strains were identified by a serotype screening (Murex HCV Serotyping 1-6 assay) and/or genotyping (Inno-LiPA HCV II) test. The distribution of HCV types showed an unusually high rate of type 5 (14.2%) that was stable over time and was the third most frequent type, after type 1 (59.1%) and type 3 (15.1%). HCV type 5 was more frequent in patients who were older than 50 (P = 10(-6)), but its frequency did not differ significantly by gender (P = 0.21). Serotyping was performed for 1,160 strains but failed for 30.2% of them. The efficiency depended on HIV status (for HCV-HIV-coinfected patients, half of the strains were untypeable) and HCV type. Genotyping was performed for 428 samples, with an overall efficiency of 99.3%. It failed in three cases, which were subsequently identified as HCV type 2. Serotyping and genotyping results for 39 patients showed discrepancies between the two methods for 4 patients, who had HCV type 2, type 6, or mixed infections. Thus, HCV type 5 may also be encountered frequently in Western countries. Its apparent confinement to a restricted area raises the question of how it emerged and underscores the need for further studies of HCV type prevalence, routes of transmission, pathogenicity, and responses to treatment.

Hepatitis C and human immunodeficiency virus envelope proteins cooperatively induce hepatocytic apoptosis via an innocent bystander mechanism.

We hypothesized that hepatocytes exposed to hepatitis C virus (HCV) and human immunodeficiency virus (HIV) might be injured via an "innocent bystander" mechanism due to cell-surface binding of viral proteins. To assess this, we studied the effects of HCV envelope protein E2 and T-tropic HIV envelope glycoprotein gp120 on hepatocytes and saw potent apoptosis. Either viral protein alone did not induce this effect. HCV E2 and M-tropic HIV gp120 also induced significant apoptosis. Blocking the CXCR4 receptor led to a reduction in apoptosis. HCV E2 and HIV gp120 acted collaboratively to trigger a specific set of downstream signaling events, including up-regulation of the Fas ligand and dephosphorylation of the anti-apoptotic molecule AKT. These results suggest that hepatic injury may occur in HCV/HIV coinfection through the induction of novel downstream signaling pathways and provide a rationale for therapeutic interventions that interfere with specific receptors and signaling molecules.