Safety and efficacy of adefovir dipivoxil in patients co-infected with HIV-1 and lamivudine-resistant hepatitis B virus: an open-label pilot study.

BACKGROUND: Lamivudine-resistant hepatitis B virus (HBV) is found in about 15-32% of infected patients with or without co-infection with HIV-1 after 1 year of lamivudine therapy. Adefovir dipivoxil is active in vivo and in vitro against wild-type and lamivudine-resistant HBV. We assessed the safety and efficacy of a once daily dose of adefovir dipivoxil in an open-label trial for the treatment of lamivudine-resistant HBV infection in HIV-1-infected patients. METHODS: 35 HIV-1/HBV co-infected patients receiving lamivudine therapy (150 mg twice daily) as part of their current HIV-1 antiretroviral regimen were enrolled. Patients received a 10 mg once-daily dose of adefovir dipivoxil for48 weeks while maintaining their existing anti-HIV-1 therapy, including lamivudine. Patients were assessed every 4 weeks for safety and efficacy. FINDINGS: Four patients withdrew from the study (two because of adverse events), leaving 31 patients who received adefovir dipivoxil for a median of 48 weeks (range 44-48). Mean decreases in serum HBV DNA concentrations from baseline (log 8.64 copies/mL [SE log 0.08]) were 2log 3.40 copies/mL [log 0.12] at week 24 (n=31) and 2log 4.01 copies/mL [log 0.17] at week 48 (n=29; p<0.0001). Two patients underwent hepatitis B e antigen seroconversion-one at week 32 and one at week 36. Adefovir dipivoxil was generally well tolerated, but was associated with a transient increase in serum alanine aminotransferase concentrations in 15 patients. We found no significant changes in either HIV-1 RNA or CD4 cell count. INTERPRETATION: These results indicate that 48 weeks of 10 mg daily adefovir dipivoxil is well tolerated and active against lamivudine-resistant HBV in HIV-1/HBV co-infected patients.

Factors affecting liver fibrosis in human immunodeficiency virus-and hepatitis C virus-coinfected patients: impact of protease inhibitor therapy.

Hepatitis C virus (HCV)-related liver fibrosis progression is accelerated in human immunodeficiency virus (HIV)-infected patients. The effect of protease inhibitor (PI) therapy on liver fibrosis is unknown. The aim of this work was to analyze the impact of PI therapy on HCV-related liver fibrosis in HIV/HCV coinfected patients. We evaluated in a long-term follow-up retrospective cohort study the influence of antiretroviral therapy containing PI on liver fibrosis in 182 consecutive HIV/HCV coinfected patients. At liver biopsy, 63 patients had received PI and 119 patients had never been treated with PI. Relationships between liver histologic features, age, alcohol consumption, CD4 cell count, HIV-RNA load, and antiretroviral regimens were analyzed. Liver fibrosis stage was lower in patients receiving PIs by comparison with patients who had never received PIs (P =.03). The 5-, 15-, and 25-year cirrhosis rates were 2% versus 5%, 5% versus 18%, and 9% versus 27%, respectively, in patients who had received PIs compared with PI-untreated patients (P =.0006). Multivariate analysis identified 4 independent predictors of progression to cirrhosis: absence of protease inhibitor therapy (relative risk [RR] = 4.74, 95% confidence interval [CI], 1.34-16.67), heavy alcohol consumption (> or = 50 g daily) (RR = 4.71, 95% CI, 1.92-11.57), low CD4 cell count (<200/microL) (RR = 2.74, 95% CI, 1.17-6.41), and age at HCV contamination (> or = 20 years) (RR = 2.37, 95% CI, 1.04-5.38). In conclusion, protease inhibitor therapy might not accelerate progression to HCV-related cirrhosis. Furthermore, chronic use of antiretroviral therapy containing PI together with reduction of alcohol consumption and maintenance of high CD4 count could have a beneficial impact on liver fibrosis progression in HIV/HCV coinfected patients.

Safety and efficacy of interferon-ribavirin combination therapy in HCV-HIV coinfected subjects: an early report.

BACKGROUND: More severe liver disease together with a poor response rate to alpha interferon argue for the use of more potent anti-hepatitis C virus (HCV) therapies in human immunodeficiency virus (HIV)-HCV coinfected patients, but the efficacy and safety of interferon-ribavirin combination therapy in HIV infected subjects are unknown. AIM: To retrospectively evaluate the efficacy and safety of anti-HCV combination therapy in 21 HCV-HIV coinfected patients receiving antiretroviral therapy, and to access the clinical relevance of in vitro inhibition of phosphorylation by ribavirin of potent inhibitors of HIV-that is, zidovudine, stavudine, and zalcitabine. PATIENTS: Twenty one patients were treated with combined antiretroviral therapy including zidovudine (n=8) or stavudine (n=13) (in association with protease inhibitors in 12). All received ribavirin (1000 or 1200 mg/day) and alpha interferon (3 MU three times/week) for chronic hepatitis C infection. All patients had not responded (n=20) or relapsed (n=1) after a previous six month course of alpha interferon therapy. METHODS: HIV viral load (Monitor test) and CD4 cells count were measured at the beginning and every three months during and after ribavirin plus alpha interferon therapy over a mean period of 11 (1) months. Clinical and biological adverse effects were recorded. RESULTS: There was no significant variation in HIV viral load or CD4 cell counts after three or six months of ribavirin therapy compared with baseline values. Of the 21 subjects, three (14%) had an increase in HIV viral load of more than 0.5 log leading to discontinuation of ribavirin in one. Eleven of 21 (52.4%) had initial negative HCV viraemia at three (n=10) or six (n=1) months but only six were polymerase chain reaction negative at the end of therapy, leading to rates for primary response and breakthrough of 23.8% and 28.5%, respectively. Six months after completion of therapy, three patients relapsed (14. 3%) and three (14.3%) had sustained virological response. Median haemoglobin concentration decreased significantly after three and six months of ribavirin therapy (p= 0.0002 and p=0.0003, respectively) leading to withdrawal of therapy in one patient. CONCLUSIONS: These preliminary results show that: (1) despite in vitro interactions between ribavirin, zidovudine, and stavudine, significant variation in HIV replication does not usually occur in HCV-HIV coinfected patients receiving ribavirin and different antiretroviral regimens, including zidovudine and stavudine; (2) alpha interferon and ribavirin combination therapy induced primary and sustained virological responses in 28.5% and 14.3% of treated subjects (who were previous non-responders to interferon therapy), respectively; (3) anaemia is a frequent adverse event. Such results should be confirmed in larger prospective trials.

Long-term incidence of hepatitis B virus resistance to lamivudine in human immunodeficiency virus-infected patients.

Hepatitis B virus (HBV) resistance to lamivudine has not been extensively documented in human immunodeficiency virus (HIV)-infected patients. We studied the long-term incidence of HBV resistance to lamivudine in HIV-positive patients. Sixty-six HIV-HBV-coinfected patients were studied while receiving lamivudine (150 mg twice daily) as a part of antiretroviral therapy. All these patients had a detectable serum HBV DNA at the beginning of lamivudine therapy. Serum HBV DNA was quantified by molecular hybridization. Sequence analysis of the HBV polymerase was performed in patients who became resistant to lamivudine. After 2 months of lamivudine, HBV DNA became undetectable in 57 patients (86.4%, 95% CI: 75.7%-93.6%). After 2 years of lamivudine, 47% +/- 18.6% of the patients, had sustained HBV-DNA suppression. All the 22 tested patients with HBV resistance developed mutation at position 550 in the YMDD motif of the DNA polymerase. None of the following variables were associated with an increased risk of lamivudine resistance: age, associated protease inhibitor therapy, Center for Disease Control (CDC) stage C, known HIV-infection duration, serum HBV-DNA level at baseline, CD4 cell count and serum alanine transaminase levels at baseline and at HBV-replication suppression (2 months of lamivudine). Lamivudine (300 mg/d) is effective for the inhibition of HBV replication in HIV-infected patients. However, emergence of lamivudine-resistant HBV may occur in 20% of patients per year.

Liver fibrosis progression in human immunodeficiency virus and hepatitis C virus coinfected patients. The Multivirc Group.

The natural history of hepatitis C virus (HCV) infection in human immunodeficiency virus (HIV)-infected patients has never been studied according to the concept of liver fibrosis progression. The aim of this work was to assess the fibrosis progression rate in HIV-HCV coinfected patients and in patients infected by HCV only. A cohort of 122 HIV-HCV coinfected patients was compared with a control group of 122 HIV-negative HCV-infected patients. Groups were matched according to age, sex, daily alcohol consumption, age at HCV infection, and duration and route of HCV infection. The fibrosis progression rate was defined as the ratio between fibrosis stage (METAVIR scoring system) and the HCV duration. The prevalence of extensive liver fibrosis (METAVIR fibrosis scores 2, 3, and 4) and moderate or severe activity were higher in HIV-infected patients (60% and 54%, respectively) than in control patients (47% and 30%, respectively; P <.05 and P <.001, respectively). The median fibrosis progression rate in coinfected patients and in control patients was 0.153 (95% confidence interval [CI], 0.117-0.181) and 0.106 (95% CI, 0.084-0.125) fibrosis units per year, respectively (P <.0001). HIV seropositivity (P <.0001), alcohol consumption (>50 g/d, P =.0002), age at HCV infection (<25 years old, P <.0001), and severe immunosuppression (CD4 count 50 g/d), CD4 count (

Hepatitis B virus (HBV) mutations associated with resistance to lamivudine in patients coinfected with HBV and human immunodeficiency virus.

Mutations associated with hepatitis B virus (HBV) resistance to lamivudine have not been extensively addressed in human immunodeficiency virus (HIV)-HBV coinfection. We have studied the HBV polymerase sequences from nine coinfected patients who experienced HBV recurrence while under lamivudine treatment. In seven of these nine patients, Met(550), belonging to the highly conserved YMDD motif, was mutated to Val and was associated with a substitution of Met for Leu(526) in each case. In the two remaining patients, we found a Met(550)-to-Ile change that was associated in only one case with a Leu(526)-to-Met mutation. No mutation was observed in three control patients not receiving lamivudine. This study demonstrates the emergence of particular genetic profiles in HBV-HIV-coinfected patients experiencing a loss of control of HBV infection despite high doses of lamivudine.

[Nephrotoxicity of ritonavir]. / Néphrotoxicité du ritonavir.

A RECOGNIZED COMPLICATION: Ritonavir is an antiprotease used in the treatment of HIV-positive patients. Among the known side effects, nephrotoxicity can be severe. We have observed acute renal failure in 8 patients. CIRCUMSTANCES: Renal failure occurs early after introducing ritonavir (3-21 days). It is often severe with major creatinine elevation. One patient was dialyzed for 16 days. In these patients, saquinavir was usually associated with ritonavir. RITONAVIR ALONE: We retrospectively analyzed creatinine levels in 87 patients treated with ritonavir without saquinavir. Twelve of these 87 patients (13.7%) developed renal failure. Creatinine clearance (Cockcroft) was reduced 116 to 71 ml/min in 12 patients. Finally, it was demonstrated in 6 patients that ritonavir can reduce creatinine clearance by 25% after only 3 days of treatment. VIGILANCE: Ritonavir has a known nephrotoxic potential. Acute renal failure may be severe and can occur with ritonavir alone or in combination with saquinavir. The pathogenic mechanism has not been demonstrated from renal biopsies or experimental studies. Renal function should be followed in these patients and risk factors controlled.

Mycobacterium avium complex common-source or cross-infection in AIDS patients attending the same day-care facility.

To delineate the epidemiology of Mycobacterium avium complex (MAC) infection in acquired immunodeficiency syndrome patients, we studied 32 case patients with disseminated MAC infection who attended the same daycare facility during a period of 13 months. Pulsed-field gel electrophoresis analysis showed very low similarity between MAC strains, suggesting that, despite close contacts between the patients, nosocomial cross-transmission or exposure to a common source of MAC did not occur.

Clostridium difficile-associated diarrhea in HIV-infected patients: epidemiology and risk factors.

A retrospective analysis of all the cases of Clostridium difficile-associated diarrhea (CDAD) in hospitalized patients infected with HIV was performed over a 52-month period to assess the incidence, epidemiology, and risk factors of CDAD. A case of CDAD was defined as a patient with diarrhea and a positive stool cytotoxin B assay. Sixty-seven cases of CDAD were recorded in HIV-infected patients between January 1991 and April 1995. The annual incidence of CDAD ranged from 1.7 to 6.4 per 100 HIV-infected patients discharged from hospital. The 67 CDAD cases included 48 (72%) first episodes and 19 (28%) relapses. Serogroup C accounted for 69% of strains from initial episodes of CDAD. To identify risk factors for CDAD, 34 HIV-infected patients with a first episode were compared with 66 HIV-infected controls matched for the length of hospital stay. Three independent factors remained significantly associated with CDAD among HIV-infected patients: CD4+ cell counts <50/mm3 (OR = 5.2; 95% CI = 1.4-19.3; p = 0.01), clindamycin use (OR = 5.0; 95% CI = 1.3-18.3; p = 0.02) and penicillin use (OR = 4.6; 95% CI = 1.1-18.8; p = 0.03). C. difficile is a common enteric pathogen responsible for nosocomial diarrhea in HIV-infected patients. Clinicians should keep this pathogen in mind when searching for the cause of diarrhea in these patients, especially those who are severely immunocompromised or have received clindamycin or penicillin.

[Prospective study of pathogenic agents isolated from feces of patients with HIV infections]. / Etude prospective des agents pathogènes isolés dans les selles de patients infectés par le VIH.

OBJECTIVE: Determine the frequency of enteropathogenic agents isolated in diarrheic feces of patients with HIV infection and to compare findings with a control group (HIV + without diarrhea) in order to identify risk factors. PATIENTS AND METHODS: All HIV seropositive inpatients and outpatients seropositive for HIV, with or without diarrhea, seen between 1 November 1994 and 30 April 1995 were included. Samples of feces were obtained for culture, virology examination, parasite examination and search for Clostridium difficile. The same samples were obtained in case of diarrhea during the course of hospitalization. RESULTS: There were 113 samples. Analyses demonstrated a pathogenic agent in 73.6% of the samples in patients with diarrhea and in 31.6% of those without diarrhea. Clostridium difficile and parasites were the most frequently identified agents. An infectious agent was identified in one-fourth of the patients without clinical signs of diarrhea, and in one-fourth of those with diarrhea no pathogen could be demonstrated. No factor of risk for finding a particular microorganism in feces of patients with diarrhea could be identified. DISCUSSION: The exact pathogenic roles of Pseudomonas aeuriginosa, yeast, and adenovirus remain to be determined. It is hypothesized that the HIV has a direct effect on the host digestive tract.