Influence of hepatitis C virus genotypes and HIV infection on histological severity of chronic hepatitis C. The Hepatitis/HIV Spanish Study Group

OBJECTIVES: The factors influencing the histological severity of chronic hepatitis C (CHC) have not been well established. We therefore investigated the effect of hepatitis C virus (HCV) genotypes and human immunodeficiency virus (HIV) infection on histological liver damage in a cohort of intravenous drug users with CHC. METHODS: We analyzed the histological activity score and the HCV genotypes in 59 HCV-RNA-positive patients with biopsy-proven CHC. Forty-eight (81%) of them had concomitant HIV infection with a CD4+ cell count above 200 x 10(6) cells/L and an absence of AIDS-defining conditions. Multivariate analysis was performed to determine the features associated with the histological severity. RESULTS: Minimal/mild hepatitis was found in 16 patients (27%), moderate chronic hepatitis in 29 (49%), and severe chronic hepatitis in 14 (24%). Patients with HCV subtype 1b had a higher histological score than others (8.7 +/- 3.3 vs. 6.5 +/- 3.2, p = 0.012), either as single or mixed infections. In multivariate analysis, HIV-infected individuals had a higher score of piecemeal necrosis (OR = 21.7, p = 0.002) and a higher stage of fibrosis (OR = 17.9, p = 0.004) than patients without HIV infection. HIV infection and HCV genotype 1b were found to be independent factors of histological severity. CONCLUSIONS: Liver damage in patients with CHC seems to be directly influenced by HCV subtypes. Infection by HCV subtype 1b is closely associated with more severe forms of liver pathology. Furthermore, the presence of HIV infection is an independent factor associated with more aggressive histological damage. In these patients, higher degrees of piecemeal necrosis and fibrosis are commonly seen.     

Effect of immunosuppression on composition of quasispecies population of hepatitis C virus in patients with chronic hepatitis C coinfected with human immunodeficiency virus

BACKGROUND/AIMS: To study the effects of the immunosuppression caused by the reduction of CD4 activity on the composition of hepatitis C virus (HCV) populations, we analyzed the number of HCV quasispecies clones and the nucleotide diversity of the hypervariable region 1 (HVR1) of HCV in 37 patients with hemophilia with persistent HCV infection, with or without human immunodeficiency virus (HIV). METHODS: The numbers of HCV quasispecies clones were measured by fluorescence single-strand conformation polymorphism analysis. Direct sequencing was used to analyze the degree of diversity of HVR1. We compared these values according to coinfection with HIV, and CD4 counts of patients. RESULTS: There were no differences in either the number of HCV clones or the diversity between patients with and without HIV coinfection. In HIV coinfected patients the diversity decreased in association with the decrease in CD4 count while the number of HCV clones did not. The diversity of HVR1 was 3.64 +/- 5.03% in patients with a CD4 count < 50/microliters and 14.92 +/- 6.03% in patients with a CD4 count > or = 50/microliters; it was significantly lower in the former (p = 0.0002). CONCLUSIONS: A severe reduction in the CD4 count, which is considered to cause a decline in the activity of helper T-lymphocytes, induced changes in the composition of HCV populations; one or a few quasispecies clones are predominant in the HCV population in the serum of individual patients.     

Immunosuppression may lead to progression of hepatitis C virus-associated liver disease in hemophiliacs coinfected with HIV

OBJECTIVE: The aim of this study was to examine the interaction between HIV and hepatitis C virus (HCV) in hemophiliacs coinfected with the viruses and to investigate the possible relationship between immunosuppression and liver failure. METHODS: To identify risk factors for impending liver failure in hemophiliacs coinfected with HIV and HCV, we analyzed clinical and laboratory parameters, including CD4 count, aminotransferases (ALT, AST), cholinesterase, alkaline phosphatase, bilirubin, and gamma-glutamyltransferase, during 3 yr of follow-up (1990-1993) in four groups of patients: hemophiliacs with progressive immunodeficiency who were coinfected with HCV and HIV (group A, n = 49); hemophiliacs with stable immune function who were seropositive for HIV and HCV (group B, n = 95); hemophiliacs who were infected with HCV but not HIV (group C, n = 72); and homosexuals with progressive immunodeficiency who were infected with HIV but not HCV (group D, n = 24). RESULTS: Univariate analysis of data for group A showed a significant rise in gamma-glutamyltransferase and alkaline phosphatase (p < 0.01) that was not seen in groups B, C, and D. In a multivariate Cox regression analysis, age (odds ratio, 1.054 per yr; 95% confidence interval, 1.014-1.096 per yr), decline in CD4 count (odds ratio, 1.063 per cell/microl; 95% confidence interval, 1.037-1.091 per cell/microl), and alkaline phosphatase level (odds ratio, 1.012 per U/L; 95% confidence interval, 1.002-1.021 per U/L) emerged as independent determinants of death. CONCLUSIONS: Our data suggest that progressive immune dysfunction in hemophiliacs coinfected with HIV and HCV may influence progression of liver failure. In these patients cholestasis is an additional prognostic marker for survival that may reflect both exhausted immunity and impaired liver function.     

Usefulness of BTA Stat test (Bard) in the diagnosis of bladder cancer. Preliminary results and comparison with cytology and cystoscopy]

Risk factors associated with surgical infections are related to many events that modulate the immune system and affect the surgical procedure. The aim of this study was to determine the influence of low CD4+ lymphocyte counts in 24 patients with human immunodeficiency virus (HIV) undergoing abdominal surgery. Blood samples were obtained, and the lymphocyte population was evaluated perioperatively, as was the nutritional status of the patient. All the patients received selective antibiotic prophylaxis depending on the surgical procedure performed: (1) clean surgery: splenectomies (n = 8); (2) clean-contaminated: cholecystectomy and biliary tract surgery (n = 8); and (3) contaminated: appendectomy (n = 8). Depending on their CD4 count, two groups were formed: one with 200 to 500 cells/ml (n = 11) and the other with < 200 cells/ml (n = 13). When surgical infection was suspected, surgical drainage and microbiologic cultures were undertaken. For statistical evaluation of the groups ANOVA and the chi-square test were used; p < 0.05 was considered significant. Altogether 14 patients (58.3%) had a wound infection, and the mean (+/- SD) CD4 count in those patients was decreased (221.7 +/- 75.1) compared with that of the 10 patients in the uneventful group (386 +/- 81.2). Surgical infection rates were 50% for clean procedures, 62.5% for clean-contaminated procedures, and 62.5% for contaminated surgery. The group of patients with CD4 counts of < 200 cell/ml had an increased incidence of surgical infection, regardless of the type of surgery (p = 0.002). Thus the surgical infection rates with HIV patients undergoing abdominal surgery are dramatically increased. The CD4 and subsequently depressed neutrophil populations increase the risk of surgical infection during major procedures regardless of the type of surgery performed.     

Preventing wading pool suction-drain injuries

Clinical records of 14, CD4 cell counts > 400/mm3, mild symptoms or asymptomatic, HIV infected patients and with chronic active hepatitis (identified by hepatic biopsy) were under review. Four of them were infected with HBV, 8 with HCV, 1 with HDV and other one with HBV + HCV + HDV. They were treated with alpha interferon for 6 months. Effectiveness was evaluated. It was found that in 4 (50%) of HCV infected patients transaminases raised normal value two of them remained with normal values at the end of review (22 and 48 months of follow-up). All HBV infected patients (4) normalized transaminases. Three of them lost HBeAg, that persisted through 38 months of follow-up. It was found too, whose did not improved with 6 months treatment did not benefit with a longer treatment. Therefore, HIV infected patients uncompromised (CD4+ > 400/mm3) and with chronic active hepatitis were benefited by interferon treatment (57%). Reversal of HBeAg was remarkable.     

Agrobacterium-mediated transformation of élite indica and japonica rice cultivars

Human immunodeficiency virus (HIV) infection is increasingly an urban disease in the United States, and Medicaid is the principal payer of the health care costs of patients with HIV. We wished to determine the costs to Medicaid of patients in Maryland infected with HIV as immunosuppression progresses, and to determine how costs varied by demographic characteristics of the patient. We analyzed combined economic and clinical data in patients from the Johns Hopkins HIV Service, the provider of primary and specialty care for a majority of HIV-infected patients in the Baltimore metropolitan region. All patients were enrolled in Medicaid and received care longitudinally in Maryland from July 1992 to June 1995. Monthly Medicaid payments were calculated for all inpatient and outpatient services by sex, race, age, use of injecting drugs, CD4+ count (>500, 201-500, 51-200, < or =50 cells/mm3), several opportunistic diseases, and death. Lifetime costs were also calculated by use of a Markov simulation. During 13,174 person-months of follow-up in 606 patients, a total of $18,223,700 in Medicaid payments was made. Mean monthly payments ranged from $2,436 (SE $171) for patients with CD4+ counts < or =50 cells/mm3 to $1,015 (SE $177) for patients with CD4+ counts >500 cells/mm3. Mean monthly inpatient costs ranged from $1,355 (SE $131) for CD4+ counts < or =50 cells/mm3 and $617 (SE $164) for CD4- counts >500 cells/mm3. For those with CD4+ counts < or =50 cells/mm3, outpatient pharmacy costs averaged $515 (SE $57) monthly, second only to inpatient costs. In bivariate analysis, costs were significantly higher (p = .013) in men (mean $1696; SE $126) than in women (mean $1,208; SE $101), though the difference was not significant with multivariate adjustment. Cytomegalovirus retinitis was the most costly opportunistic disease, with mean monthly costs of $7,825 (SE $1,141) within the 6 mo after diagnosis. Within 6 mo of death, mean monthly costs are $4,600 (SE $424). Lifetime costs for treating an HIV-infected patient who presents with a CD4+ count >500 cells/mm3 are $133,500 over 8.3 years of life. We concluded that in the clinic where the analysis was done, average costs to Medicaid of treating patients increase more than two-fold as the CD4+ count declines from >500 cells/mm3 to < or =50 cells/mm3. Interventions that decrease hospitalization, opportunistic disease, and the costs of terminal care may be most likely to decrease overall costs. Demographic patient characteristics do not affect costs significantly when access to care is comparable.     

The chemosensitivity of strains of Vibrio cholerae group O1 isolated in Romania between 1977-1995

A retrospective series of 25 patients with AIDS and tuberculosis is presented. Their clinical presentation, absolute lymphocyte count, CD4+ and CD8+ lymphocyte counts, treatment details and outcome are detailed. Commonest method of acquiring HIV infection was through heterosexual contact (10 of the 25; 40%) and blood transfusion (10 of the 25; 40%). More than 50% of the patients (14 of the 25) had extrapulmonary tuberculosis. Eighteen of the 19 patients for whom values were available had CD4+ lymphocyte count < 200/mm3. Four of the 18 patients for whom follow-up details were available died.     

Effect of human immunodeficiency virus on hepatitis C virus infection among injecting drug users

To assess the effect of human immunodeficiency virus (HIV) immunosuppression on ongoing hepatitis C virus (HCV) infection, CD4 lymphocyte counts and serum concentrations of HCV RNA, HIV RNA, and alanine aminotransferase (ALT) were evaluated among members of a cohort of injecting drug users (IDUs). With 100 participants randomly selected at various stages of HIV-related immunosuppression, serum HCV RNA concentrations increased with age (P = .007) and were higher in HIV-positive IDUs with 201-500 (P = .026) and 51-200 (P = .004) CD4 cells/mL than in HIV-negative participants. Among 27 HCV-infected IDUs who acquired HIV infection, serum HCV RNA concentrations varied between semiannual visits by a mean of 0.45 logs, increasing by 0.60 logs after HIV seroconversion (P < .0001), by 0.12 logs each subsequent year (P = .006), and by 0.36 logs per log increase in CD4 cells (P = .01). Serum ALT levels were similar between HIV-positive (40.1 IU/mL) and HIV-negative (45.4 IU/mL) patients (P > .10). While HIV infection and possibly HIV progression are associated with increased HCV RNA levels, other factors appear to affect biochemical and virologic markers of HCV infection in some dually infected persons.     

Spectrum of liver diseases in HIV infection

BACKGROUND: Most earlier reports on the spectrum of liver diseases in HIV-infected individuals originated from the West. OBJECTIVE: To study the spectrum of liver diseases in HIV-infected individuals. METHODS: Seventy four consecutive HIV-positive patients (57 men; age range 23-75 years, mean 34) were studied prospectively with clinical evaluation, liver function tests, ultrasonography, radioisotope liver scan, markers of hepatitis B (HBV) and C (HCV) viruses, and liver histology whenever necessary. RESULTS: Thirty four patients (45%) were chronic alcoholics. Mean (SD) absolute lymphocyte count was 2521 (1271)/mm3; count < 2000/ mm3 was present in 20 patients. Serum bilirubin, transaminases and alkaline phosphatase levels were elevated in 13%, 13% and 24% of patients, respectively. Ultrasonography detected an abscess in two patients (tuberculous-1, amebic-1). Evidence of exposure to HBV was present in 81% (HBsAg-12, hepatitis B core and/or surface antibody-48); anti-HCV antibody was positive in 29.7%. Five patients with liver tuberculosis (granuloma-4, abscess-1) had AFB either in liver tissue or lymph nodes. CONCLUSION: Chronic alcoholism, HBV and HCV infection, hepatic tuberculosis, and evidence of other liver disease were common in patients with HIV infection.     

Cytomegalovirus viremia: risk factor for allograft cirrhosis after liver transplantation for hepatitis C

BACKGROUND: Despite recent advances in diagnosis and treatment, cytomegalovirus (CMV) infection continues to be a common cause of morbidity in liver transplant (LT) recipients. Because CMV infection suppresses cell-mediated immunity, which seems to be important in neutralizing hepatitis C virus (HCV) infection, we assessed the impact of CMV infection on histopathological HCV recurrence after LT. METHODS: The study group was comprised of 43 consecutive LT recipients with at least 6 months of histologic follow-up. Group 1 consisted of the 8 patients who developed CMV viremia after LT; group 2 comprised the 35 patients without CMV viremia. There was no significant difference with regard to age, initial immunosuppression, incidence of rejection, distribution of HCV genotypes, or mean follow-up between the groups. Semiquantitative histopathologic assessment of allograft hepatitis was performed using the Knodell's score. RESULTS: The mean total Knodell score of the final allograft biopsy was significantly greater in group 1 patients (P=0.016), with most of the difference due to periportal/bridging necrosis (P=0.009) and lobular activity subitem (P=0.01) scores. Half of the CMV viremic patients eventually developed allograft cirrhosis as compared with 11% of the CMV-negative patients (P=0.027). Accordingly, the cirrhosis-free actuarial survival by Kaplan-Meier estimates was significantly diminished in the CMV viremic patients. Glycoprotein B genotype analysis of CMV isolates revealed no significant differences between patients who did and those who did not develop allograft cirrhosis. CONCLUSIONS: After LT for chronic HCV, patients who develop CMV viremia incur a significantly greater risk of severe HCV recurrence.     

Abnormal expression of a 170-kilodalton P-glycoprotein encoded by MDR1 gene, a metabolically active efflux pump, in CD4+ and CD8+ T cells from patients with human immunodeficiency virus type 1 infection

Peripheral blood CD4+ and CD8+ T cells from 16 patients with HIV-1 infection, 8 each with CD4+ T cell counts of > 200/mm3 (group I) and with CD4+ T cell counts of < 200/mm3 (group II), and 8 age- and sex-matched controls, were examined for the expression of P-glycoprotein (P-gp), a 170-kDa phosphoglycoprotein encoded by the MDR1 gene, using dual-color flow cytometric analysis. The function of P-glycoprotein was assessed by the accumulation of rhodamine-123 (Rh123) dye in the presence or absence of cyclosporin A (which inhibits Rh123 efflux). A significantly increased proportion of CD4+ T cells from patients with HIV-1 infection expressed P-glycoprotein as compared to controls, resulting in a significantly increased ratio of the proportions of CD4+P-gp+/CD8+P-gp+ cells. The ratio of CD4+P-gp+/CD8+P-gp+ in group II patients was significantly higher (p = 0.02) than in group I patients, suggesting a progressive increase in P-gp expression with the advancement of HIV-1 infection. The proportions of CD4+P-gp+ and CD8+P-gp+ T cells did not differ significantly between those who received AZT and those who were not treated with AZT. Contrary to expectation, both CD4+ and CD8+ T cells from patients accumulated significantly more Rh123 as compared to controls. Furthermore, cyclosporin A failed to increase intracellular accumulation of Rh123 in CD4+ and CD8+ T cells from patients. These data suggest a functionally defective P-gp expression in HIV-1 infection that appears to increase with the progression of HIV-1 infection. A study of a large number of patients with HIV-1 infection is needed to determine the effects of opportunistic infection and antiretroviral therapy on the expression of P-gp and to determine whether the expression of P-gp could serve as another surrogate marker for the progression of HIV-1 infection.     

Cytomegalovirus (CMV) viremia and the CD4+ lymphocyte count as predictors of CMV disease in patients infected with human immunodeficiency virus

We screened 192 patients infected with human immunodeficiency virus (HIV) to examine the relation between CD4+ lymphocyte counts and cytomegalovirus (CMV) viremia and the occurrence of CMV disease and subsequent duration of survival. When we stratified the viremic patients by CD4+ lymphocyte counts, the proportions were as follows: <50/mm3, 20 (25%) of 80 patients; 50-100/mm3, 2 (5.5%) of 36; 101-150/mm3, none of 14; and >150/mm3, 1 (1.5%) of 62. After a mean follow-up period of 8.5 months, 21 (11%) of 192 patients developed CMV disease. The probability of developing CMV disease at 6 months was 13% when the CD4+ lymphocyte count was <50/mm3, 3% when the CD4+ lymphocyte count was 50-100/mm3, and 0 when the CD4+ lymphocyte count was >100/mm3; this probability was 46% for viremic patients and 1% for nonviremic patients. In a multivariate analysis, CMV viremia was independently prognostic of CMV disease (relative risk, 22.03; 95% confidence interval, 6.49-78.97; P < .001), whereas a CD4+ lymphocyte count of <50/mm3 was not (P = .26). These results support the value of CMV viremia for predicting which HIV-infected patients are at risk of developing CMV disease and should therefore receive primary prophylaxis.     

Immunological differentiation between tickborne encephalitis with and without concomitant neuroborreliosis

Cerebrospinal fluid lymphocyte subsets in patients with tickborne encephalitis (TBE) and in patients with TBE with concomitant neuroborreliosis (double infection) were analysed by flow cytometry. In the TBE group, higher percentages of CD4+DR+ T cells (p = 0.02) and CD25+ T cells (p = 0.0002) were observed, while in the group with double infection, higher percentages of CD19+ cells (p = 0.007), CD8+DR- T cells (p = 0.04), and CD3+CD71 + T cells (p = 0.0002) were found. It was concluded that several differences in immune cell parameters are present between the two groups of patients. Three variables (CD19+ cells, CD3+CD25+ T cells, CD3+CD71+ T cells) were included in the logistic regression model for calculation of probability for double infection. Flow cytometric characterisation of lymphocyte subsets in CSF can further substantiate the diagnosis of concomitant neuroborreliosis in patients with TBE.     

Interferon alpha treatment of chronic hepatitis C in HIV-infected patients receiving zidovudine: efficacy, tolerance and response related factors

BACKGROUND/AIMS: In our area most of the human immunodeficiency virus (HIV) infected patients are intravenous drug users; HIV and hepatitis C virus infections often coexist in these patients. Due to the repercussions of both infections, we designed a trial to evaluate the efficacy, response-related factors and tolerance during an eight-month regime of recombinant interferon alpha-2b on hepatitis C virus infection. METHODOLOGY: We included 79 patients in an open, prospective and multicentric trial with zidovudine and interferon alpha-2b. Response to interferon treatment was evaluated by biochemical and histopathological criteria. RESULTS: A complete response (alanine aminotransferase normalization) was obtained in 57.4% of patients. The significant response-related factors were: degree of histopathological activity, CD4+ cell number and initial leukocyte number. CONCLUSIONS: Recombinant interferon therapy seems to be effective for chronic hepatitis C in HIV infected patients; the best response was in those with active chronic hepatitis and CD4+ cell counts > or = 200/mm3. General tolerance was variable, although side effects were not different from those seen in non-HIV patients. The most common side effect was flu-like syndrome (constitutional manifestations), with no interference on treatment continuity; however, hematological toxicity prevents the indiscriminate use of interferon.     

The natural history of chronic hepatitis C in haemophiliacs

Most haemophiliacs treated with non-virally-inactivated clotting factor concentrates have been infected with hepatitis C virus (HCV). We have studied the natural history of chronic HCV infection by following all 138 HCV-positive patients from our centre for periods of up to 28 years. As well as the clinical and biochemical characteristics, we studied 116 liver samples from 63 patients obtained at elective biopsy (n = 103) or autopsy (n = 13). 36 (26%) of the patients were HIV positive, and three were chronic carriers of hepatitis B. Evidence of previous exposure to hepatitis A and B was found in 37.2% and 48.1% respectively. Raised transaminase levels were found in 82.6% of patients. 11 of 15 patients with normal transaminases tested by PCR for HCV RNA were positive, indicating that most patients, even in this group, have chronic hepatitis C infection. Cirrhosis was diagnosed by liver histology in 19 patients, and nine patients developed liver failure. The incidence of cirrhosis rose rapidly 15 years after HCV infection to 15.6 per 1000 person-years. Multivariate analysis showed that HIV status, length of time since HCV infection and age at HCV infection were independently associated with both the development of cirrhosis and liver failure. Two patients developed hepatocellular carcinoma: one of these was exposed only to a single batch of FVIII concentrate 11 years earlier. Chronic hepatitis C is increasingly recognized as a major cause for morbidity and mortality in haemophiliacs, especially those who are HIV positive and who were infected at an older age.     

ABV方案化疗对艾滋病相关晚期卡波氏肉瘤外周血CD4淋巴细胞的影响

Objective: The combination of highly active antiretroviral therapy (HAART) and chemotherapy with ABV regimen (doxorubicin, bleomycln and vincristine) is a promising approach for the treatment of advanced HIV-related Kaposi's sarcoma (KS). Here we analyzed the relationship between the CD4 lymphocyte cell count and the clinical response to chemotherapy.Methods: The 176 HIV infected patients with advanced KS who failed to respond to prior HAART were selected. All these patients were then preceded to chemotherapy with ABV regimen which was administered at 3 weekly intervals for 6 cycles.For each patient CD4 cell count was done before starting chemotherapy and after finishing 6 cycles of chemotherapy. The difference of CD4 cell counts pre chemotherapy and post chemotherapy was compared with the clinical progress of the patients after 6 cycles of chemotherapy. Results: The overall clinical remission was shown in 93.7% patients. Progressive disease (PD) and no change in clinical condition (NC) was shown in 6.3% patients. The increase in CD4 cell count post chemotherapy was found in 89.8% patients and the decrease in CD4 cell count was seen in 10.2% patients. The difference of the mean CD4call counts for patients in group CR + PR (complete relief + partial relief) before and after chemotherapy was highly significant.The difference of the mean CD4 cell counts for patients in group NC + PD before and after chemotherapy was not significant.The difference in CD4 cell counts in CR + PR and NC + PD groups before and after chemotherapy was highly significant.Conclusion: The HIV related KS patients on HAART benefit from the chemotherapy as it increases the CD4 cell count and it has positive impact on clinical remission of KS.     

An evaluation of the degree of the morphological activity and the stage of the process in patients with chronic liver diseases caused by coinfection with the hepatitis B, C and/or D viruses

In order to determine the differences in histological grade of activity and the stage of fibrosis in patients with chronic liver diseases due to multiple hepatitis virus infection and single infection of HBV and HCV we assessed the 68 liver biopsies samples according to Knodell and Scheuer scoring systems. Retrospectively, 216 liver biopsies reports from consecutive patients with chronic viral hepatitis were analysed. Histological activity index (HAI) in HBV/HCV coinfection was higher than in a single HCV infection; it did not differ in groups of HBV/HBC and HBV. The difference was due to the interface hepatitis; lobular activity and portal inflammation were the same. In HDV superinfection HAI was high due to both portal-periportal and lobular hepatitis. HAI depended mainly upon the presence of HBV replication; in patients with chronic hepatitis C with HBV-DNA HAI was also higher than in single HCV group. No difference in HAI between triple and dual hepatitis virus infection was found. In patients with HBV/HCV coinfection and especially with HDV superinfection the advanced stages occurred more than often than in patients with single infections.