Snapshot on drug-resistance rate and profiles in patients with chronic hepatitis B receiving nucleos(t)ide analogues in clinical practice.

While the selection of complex HBV drug-resistance patterns on therapeutic failure can compromise the efficacy of anti-HBV therapies, recent data show that patients failing treatment without drug-resistance have a rate of virological success close to drug-naive patients. The goal of this study is defining, in clinical practice, the burden of drug-resistance mutations in a cohort of patients treated with anti-HBV drugs. Prevalence and patterns of drug-resistance were analyzed by RT-sequencing in 204 patients infected chronically: 148 experiencing virological rebound (defined as an increase in serum HBV-DNA > 20 IU/ml after achieving virological success [HBV-DNA < 20 IU/ml]), and 56 null/partial responders (always detectable serum HBV-DNA [>20 IU/ml] within 48 weeks of therapy). The highest rate of drug-resistance was observed in patients experiencing virological rebound (prevalence, 79.1%). Conversely, almost half (46.4%) null/partial responders have no evidence of drug-resistance. The rate of drug-resistance was higher in patients treated with lamivudine (76.8% [109/142]) and telbivudine (83.3% [5/6]), followed by adefovir (62.5% [15/24]), and entecavir (52.2% [12/23]). Complex mutational patterns characterized by the co-presence of rtM204V/I-rtA181T/V (impairing the efficacy of all anti-HBV drugs) were detected in four patients (2.7%) with virological rebound. Drug-resistance is the main cause of failure to therapy in patients experiencing virological rebound, supporting the need of rapid switch to anti-HBV drugs with higher genetic barrier and potency (entecavir/tenofovir). Conversely, nearly half of null/partial responders shows no evidence of drug-resistance mutations, maintaining high chance of achieving therapeutic success with the same class of drug. In this setting, genotypic resistance may help in selecting patients still carrying wild-type viruses, that may take major benefits from antiviral treatment.

Eligibility and feasibility of the treatment of chronic hepatitis C in a Cohort of Italian HIV-positive patients at a single HIV reference center.

Chronic hepatitis C is frequent and aggressive among HIV-positive patients; evaluation for anti-hepatitis C virus (HCV)-specific therapy is mandatory, but it has many limitations, due to efficacy, tolerability but also applicability. The objective of our retrospective analysis was to evaluate the eligibility and feasibility of anti-HCV therapy in HIV/HCV-coinfected patients followed at the II Department of Infectious Diseases, L. Sacco Hospital, Milan, Italy, from 2000 to March 2010. In our database, 545 HIV/HCV-coinfected patients were present, representing 40% of our whole HIV population, and 421 included in the analysis. One hundred twenty-four patients were excluded because of loss to follow-up (81) or deceased (43). Forty-eight patients spontaneously cleared HCV during follow-up (11%). Ninety-nine patients received anti-HCV therapy (26%), while the majority was excluded for several reasons (mainly concomitant diseases and low CD4(+) cell count). Globally, we found that in at least one third of untreated patients modifiable barriers to treatment were present. The access to therapy was significantly associated with the absence of history of intravenous drug use (p=0.01), a higher CD4(+) cells count at nadir (p=0.01), the presence of more than 6 HAART regimens (p=0.04), higher alanine aminotransferase (ALT) levels (p<0.0001), HCV genotype 2 or 3 (p=0.005). In a multivariate analysis, the same factors remained significantly associated with anti-HCV therapy. In conclusion, the feasibility of anti-HCV therapy in HIV/HCV-coinfected patients, in our highly specialized center, is approximately 26%. Relative contraindications, such as substance abuses, mild and controlled concomitant conditions, and low compliance are common and modifiable in order to reconsider patients as suitable for therapy.

Predictability of sustained virological response to pegylated interferon alpha-2b Plus ribavirin therapy by week-8 viral response in HIV-positive patients with chronic hepatitis C virus infection.

Chronic hepatitis C is frequent and aggressive in HIV-positive patients. Identification of early predictors of response to anti-HCV therapy is needed for a lower rate of response and higher discontinuations, compared to HCV mono-infected subjects. The aim of our study was to evaluate the predictive value of virological response (VR) at week 4-8-12 of Pegylated interferon alpha-2b (PEG-IFN) plus ribavirin (RBV) on sustained virological response (SVR) in HIV-HCV co-infected patients. 100 patients were treated with PEG-IFN (1.5 mcg/Kg/w) plus RBV (> or =10.6 mg/kg/d) and randomized for 24-48 or 48-72 weeks, respectively for genotype 2-3 and 1-4, in case of response (HCV-RNA PCR negativity) at the end of standard therapy (24 weeks for genotype 2-3, 48 weeks for genotype 1-4). Transcription-Mediated Amplification (TMA) assay for HCV-RNA was also applied. 27 patients reached end-of-treatment response (9 genotype 1-4, 18 genotype 2-3), 21 achieved SVR (8 genotype 1-4, 13 genotype 2-3). 35 patients dropped, 15 due to side-effects. SVR was statistically related to lower baseline HCV-RNA and to VR at week 4-8-12, with PPV 64%, 53% and 58%, and NPV 81%, 96% and 88%, respectively. In 27 patients, TMA was performed and confirmed standard PCR, except in two cases of relapse, who were PCR negative but TMA positive at week-12. In conclusion, VR at week 8 showed the highest NPV on SVR (96%). The study of viral kinetics requires further investigations in HIV-positive patients to guarantee a cost-effective therapy and to guide individually the duration of treatment. In this setting, TMA might be useful.

Antiretroviral treatment and age-related comorbidities in a cohort of older HIV-infected patients.

BACKGROUND: The availability of several therapeutic regimens has transformed HIV infection from a life-threatening disease into a chronic condition. Older patients (>50 years old) with HIV infection constitute a new treatment challenge in terms of the cumulative effects of ageing and antiretroviral therapy (ART). METHODS: The immunovirological effects and metabolic interactions of 48 weeks of ART in older patients followed up in three Infectious Diseases Units in Milan, Italy since 1994 were compared with those in younger controls aged 25-35 years. RESULTS: The 159 older patients and 118 controls enrolled in the study were comparable for HIV stage, baseline CD4 cell count and viral load but differed for mode of HIV transmission, comorbid conditions and related chronic treatments. Mean viral load decreased after 48 weeks of treatment by 2.6 log(10) HIV RNA copies/mL and CD4 count increased by 137.5 cells/microL in older patients, and similar values for immunovirological effects were obtained in the young controls. The relative risk (RR) of an abnormal test in older patients was 7.33 [95% confidence interval (CI) 4.36-12.36] for glucose, 1.73 (95% CI 1.45-2.07) for total cholesterol, 1.56 (95% CI 1.22-2.0) for high-density lipoprotein cholesterol, 1.26 (95% CI 1.02-1.56) for triglycerides, 6.48 (95% CI 4.36-9.66) for serum creatinine, and 0.45 (95% CI 0.35-0.58) for ALT. Moderate/severe liver and renal toxicities were recorded in the older patients but not in the controls. The tolerability of ART did not differ between the older patients and the controls. Thirty-nine new cardiovascular, endocrine-metabolic and neuralgic disorders (24.52 per 100 person-years) were diagnosed in the older patients and four (3.39 per 100 person-years) in the controls (P<0.0001). CONCLUSIONS: Diseases induced by, or related to, the toxic effects of antiretrovirals interact with age-specific health profiles, raising new questions and challenges. Comparative epidemiological studies, research studies addressing specific questions and surveillance are needed to answer the questions that arise in clinical monitoring.

Risk factors for fibrosis progression in HIV/HCV coinfected patients from a retrospective analysis of liver biopsies in 1985-2002.

OBJECTIVES: To identify predictive factors for moderate/severe liver fibrosis and to analyse fibrosis progression in paired liver biopsies from HIV-positive patients with chronic hepatitis C virus (HCV) infection. METHODS: HIV/HCV coinfected patients followed at the 2nd Department of Infectious Diseases of L. Sacco Hospital in Milan, Italy, with at least one liver biopsy specimen were retrospectively evaluated. RESULTS: A total of 110 patients were enrolled in the study. In a univariate analysis, predictive factors of Ishak-Knodell stage > or =3 were a history of alcohol abuse [odds ratio (OR) 3.6, P=0.004], alanine aminotransferase level >100 IU/L at biopsy (OR 2.4, P=0.05), necro-inflammatory grade > or =9 (OR 37.14, P<0.0001) and CD4 count <350 cells/microL at nadir (OR 5.3, P=0.05). In a multivariate analysis, age >35 years (OR 3.19, P=0.04) and alcohol abuse (OR 4.36, P=0.002) remained independently associated with Ishak-Knodell stage. Paired liver biopsies were available in 36 patients; 18 showed an increase of at least one stage in the subsequent liver biopsy. Either in a univariate or in a multivariate analysis, a decrease of CD4 cell count of more than 10% between two biopsies (OR 6.85, P=0.002) was significantly associated with liver fibrosis progression. CONCLUSION: Our findings highlight the relevance of encouraging a withdrawal of alcohol consumption in people with chronic HCV infection and of carrying out close follow-up of patients, especially if they are more than 35 years old. It is therefore mandatory to evaluate HIV/HCV coinfected patients for anti-HCV treatment and to increase CD4 cell count through antiretroviral therapy in order to reduce the risk of fibrosis progression and to slow the evolution of liver disease.

Intramuscular beta interferon for chronic hepatitis C: is it worth trying?

BACKGROUND AND AIMS: The intramuscular use of beta interferon has been tested in the treatment of chronic hepatitis C, but it did not prove effective when the schedule was 3 million units three times a week for six months. Since the lack of effectiveness of this treatment might be due to the low bioavailability of beta interferon when administered intramuscularly, we tested a higher dosage of the drug: 6 million units three times a week for twelve months. PATIENTS AND METHODS: Ninety-two patients were randomized to receive, intramuscularly, either 3 or 6 million units of natural human fibroblast beta interferon three times a week for 12 months. RESULTS: The short-term biochemical response was significantly more frequent in the group of patients who received the higher dosage of beta interferon: 21% vs 4.5% (p < 0.05). Nevertheless, a sustained biochemical response was obtained in only one patient (2%), who received the higher dosage of beta interferon. CONCLUSIONS: Since the better short-term response rate was obtained with the higher dosage of beta interferon, a further increase in the dosage might improve the short-term and, possibly, the long-term response to treatment. However, due to the high cost of beta interferon, this high-dose schedule would probably not be cost-effective in the treatment of chronic hepatitis C.

Hepatic histology of patients with HIV infection and chronic hepatitis C treated with interferon.

AIMS: To evaluate the histological changes seen in liver biopsies after interferon (IFN) treatment in patients with chronic hepatitis C and human immunodeficiency virus (HIV) infection. METHODS: Twenty four intravenous drug users with chronic hepatitis C were investigated histologically before beginning a 12 month course of IFN treatment and 18 months later. Twelve were HIV positive, without opportunistic or other viral infections (group A), and 12 were HIV negative (group B). RESULTS: According to alanine amino-transferase concentrations, four sustained responders and eight non-responders were found in group A; six sustained responders, five relapsers, and one non-responder were found in group B. HCV RNA became negative in one sustained responder of group A and in the six sustained responders of group B. When histological findings of biopsies performed before therapy and 18 months later were compared, no significant changes in the mean value of Knodell's index and subindices were found in group A, whereas in group B Knodell's index, piecemeal necrosis, and focal hepatocellular necrosis decreased significantly. CONCLUSIONS: In chronic hepatitis C, coinfection with HIV showed a tendency towards a lower response to IFN, although this did not reach statistical significance; however, none of the HIV positive patients developed cirrhosis during the follow up and this should be considered in clinical management of such patients.

Diagnosis of PCP by ITSs nested PCR on notinvasive oropharingeal samples.

Pneumocystis carinii pneumonia is an opportunistic disease usually affecting immunocompromised hosts. Diagnosis is based on the microscopical detection of microrganism on BAL, an invasive sample which requires pt compliance for collection and skilled health care personnel for examination. In order to verify the possible diagnostic utility of noninvasive specimens collected in the upper respiratory tract we examined by the Internal Transcribed Spacers (ITSs) nested PCR, 39 oropharingeal samples (garglings) collected from 20 HIVAb positive pts and from 15 healthy controls.

Post transfusion hepatitis: comparison between homologous and autologous blood transfusion.

OBJECTIVES: To assess whether the use of autologous blood transfusion may affect the incidence of post-transfusion hepatitis in transfused patients who undergo cardiac surgery. METHODS: One thousand one hundred and twelve polytransfused patients having undergone cardiac surgery were studied from October 1982 through September 1990. Patients were transfused with homologous blood from selected volunteer donors; autologous blood collection or blood saving were introduced in September 1986. Routine laboratory tests were carried out upon hospitalization and monthly for a six-month period. Patients with hepatitis were followed for at least 24 months and liver biopsy was performed in those with chronic hepatitis. RESULTS: Ninety-four (9.8%) of the 959 polytransfused patients developed non-A, non-B post-transfusion hepatitis; anti-hepatitis C virus antibodies were present in 52 out of the 72 patients tested. The mean incubation period for post-transfusion hepatitis was 70 days; hospitalization was required in 47.9% of the patients. The mean number of transfused units was 12.9 in patients who developed post-transfusion hepatitis and 6.96 in the those who did not. Hepatitis was chronic in 42% of the 94 patients; in the others alanine aminotransferase levels normalized in a mean period of 10.3 months. None of the 237 patients who received autologous blood had hepatitis. CONCLUSION: In our study the role of surgical teams in preventing post-transfusion hepatitis was shown to be essential. The high percentage of chronicity and symptom-free hepatitis observed is a further reason to reduce homologous blood transfusions and instore careful follow-up of polytransfused patients.

Prevalence of hepatitis C virus antibodies in hemodialysis patients in the area of Milan.

We studied the seroprevalence of antibodies to hepatitis C virus (HCV Ab) in a cohort of 229 chronic hemodialysis patients followed by 6 Dialysis Units in the Milan area. HCV Ab was present in 51 (22.3%) of 229 examined patients. Previous blood transfusions and surgery did not clearly influence HCV seroconversion, whereas duration of dialysis treatment seems to be strictly related to HCV Ab positivity.

European experience with itraconazole in systemic mycoses.

Since January 1985 more than 100 patients with deep fungal infections have been treated with itraconazole (200 to 400 mg/day) in Northern Italy. Evaluation of the drug efficacy and tolerance was possible in one patient with sporotrichosis, in 34 with aspergillosis, and in 36 with cryptococcosis (mainly patients positive for human immunodeficiency virus). Response to itraconazole alone was obtained in the case of sporotrichosis and in 24 of 34 patients with different forms of aspergillosis (of the 18 patients with invasive pulmonary aspergillosis, 15 were cured). Patients with cryptococcosis received itraconazole for active infection and/or for prevention of relapse. Active infection was treated successfully with itraconazole alone in 9 of 12 patients and with itraconazole plus flucytosine in 8 of 10 patients. Of the 31 patients who received itraconazole maintenance therapy for up to 27 months, 4 (13%) had relapses; 14 (45%) did not have relapses, and decline of serum antigen was detected in 12 of them; and 13 (42%) were completely cured (serum antigen titer dropped to zero). With the exception of hypokalemia in one patient, itraconazole was well tolerated even in patients who received the drug for several months or years.

Histological and immunohistochemical features in chronic delta hepatitis.

Forty-six liver biopsies from HBsAg Delta/anti-Delta serum positive patients with chronic hepatitis were compared with liver specimens from HBsAg positive Delta/antiDelta negative patients. The results indicate more severe histologic damage and inflammation among subjects who are serum-positive to the Delta system. Specific virus antigen was found in liver cell nuclei of almost all the Delta IR patients (93.5%). The rate of diffusion was directly proportional to the severity of histological lesions, which is in linea with the direct cytopathic effect of the Delta virus as ascertained in various other studies.