Carmen Quereda

Sustained virological response to interferon plus ribavirin reduces liver‐related complications and mortality in patients coinfected with human immunodeficiency virus and hepatitis C virus

Human immunodeficiency virus (HIV) infection modifies the natural history of chronic hepatitis C, thus promoting more rapid progression to cirrhosis and end‐stage liver disease. The objective of our study was to determine whether hepatitis C virus (HCV) clearance is associated with improved clinical outcomes in patients positive for HIV and HCV. It was an ambispective cohort study carried out in 11 HIV units in Spain and involved 711 consecutive patients positive for HIV/HCV who started interferon plus ribavirin therapy between 2000 and 2005. We measured sustained virologic response (SVR), i.e., undetectable HCV RNA at 24 weeks after the end of treatment, and clinical outcomes, defined as death (liver‐related or non–liver‐related), liver decompensation, hepatocellular carcinoma, and liver transplantation. Of 711 patients who were positive for HIV/HCV, 31% had SVR. During a mean follow‐up of 20.8 months (interquartile range: 12.2‐38.7), the incidence rates per 100 person‐years of overall mortality, liver‐related mortality, and liver decompensation were 0.46, 0.23, and 0.23 among patients with SVR and 3.12, 1.65, and 4.33 among those without SVR (P = 0.003, 0.028, and <0.001 by the log‐rank test), respectively. Cox regression analysis adjusted for fibrosis, HCV genotype, HCV RNA viral load, Centers for Disease Control and Prevention clinical category, and nadir CD4+ cell count showed that the adjusted hazard ratio of liver‐related events was 8.92 (95% confidence interval, 1.20; 66.11, P = 0.032) for nonresponders in comparison with responders and 4.96 (95% confidence interval, 2.27; 10.85, P < 0.001) for patients with fibrosis grade of F3‐F4 versus those with F0‐F2.Because this was not a prospective study, selection and survival biases may influence estimates of effect. Conclusion: Our results suggest that the achievement of an SVR after interferon‐ribavirin therapy in patients coinfected with HIV/HCV reduces liver‐related complications and mortality. (HEPATOLOGY 2009.)

Incidence and Predictors of Severe Liver Fibrosis in Human Immunodeficiency Virus—Infected Patients with Chronic Hepatitis C: A European Collaborative Study

A study was performed in 10 European health care centers in which 914 patients coinfected with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) who had elevated serum alanine aminotransferase (ALT) levels underwent liver biopsy during the period of 1992 through 2002. Overall, the METAVIR liver fibrosis stage was F0 in 10% of patients, F1 in 33%, F2 in 22%, F3 in 22%, and F4 in 13%. Predictors of severe liver fibrosis (METAVIR stage, F3 or F4) in multivariate analysis were age of >35 years (odds ratio [OR], 2.95; 95% confidence interval [CI], 2.08-4.18), alcohol consumption of >50 g/day (OR, 1.61; 95% CI, 1.1-2.35), and CD4+ T cell count of <500 cells/mm3 (OR, 1.43; 95% CI, 1.03-1.98). Forty-six percent of patients aged >40 years had severe liver fibrosis, compared with 15% of subjects aged <30 years. The use of antiretroviral therapy was not associated with the severity of liver fibrosis. In summary, severe liver fibrosis is frequently found in HCV-HIV-coinfected patients with elevated serum ALT levels, and its severity increases significantly with age. The rate of complications due to end-stage liver disease will inevitably increase in this population, for whom anti-HCV therapy should be considered a priority.

Colonization and Infection With Methicillin-Resistant Staphylococcus aureus: Associated Factors and Eradication

OBJECTIVES To identify characteristics associated with methicillin-resistant Staphylococcus aureus (MRSA) colonization and infection, and to evaluate the efficacy of systemic and topical antimicrobials in the eradication of MRSA carriage among hospitalized patients. DESIGN A case-control study was done to identify associations. Odds ratios were estimated by unconditional multiple logistic regression. Cohort study was done to evaluate MRSA decolonization efficacy by an oral regimen. Patients infected or colonized with MRSA received a 5-day course of oral (160 mg/800 mg) trimethoprim-sulfametroxazole twice daily and 600 mg of rifampin once daily as decolonization treatment. The proportion of MRSA-free patients after decolonization treatment was determined. Persistence of clearing was estimated by the Kaplan-Meier method. SETTING Ramón y Cajal Hospital, a 1,249-bed, tertiary-care teaching hospital in Madrid, Spain. PATIENTS One hundred ninety-two patients with hospital-acquired MRSA infection/colonization and 195 MRSA-free random controls. RESULTS Six factors were associated independently with MRSA infection/colonization: age (every 10 years of age, odds ratio [OR] = 1.3); ward (surgical, OR = 1; medical, OR = 3.1; intensive care unit, OR = 60); previous hospitalization (OR = 6.9); coma (OR = 25.3); invasive procedures (each, OR = 1.7); 3 or more weeks of hospitalization (OR = 3.8). We failed to show antibiotic therapy to be an independent risk factor for MRSA hospital infection/colonization. Overall, MRSA eradication was 64.2% by day 2 to 9 after completion of treatment. Kaplan-Meier product limit survival analysis showed that the probability of remaining MRSA-free was 65.3% (SE = 0.09) at 32 days after completion of treatment. CONCLUSIONS The results offer a rationale for reduction of MRSA infection/colonization in the hospital by interventions aimed at early identification of patients at higher risk, at prompt discharge of patients, and at preventing dissemination while performing invasive procedures. They also provide estimates of antibiotic treatment efficacy to reduce the reservoir of MRSA in the hospital.

Influence of Liver Fibrosis on Highly Active Antiretroviral Therapy—Associated Hepatotoxicity in Patients with HIV and Hepatitis C Virus Coinfection

BACKGROUND Coinfection with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) is a known risk factor for hepatotoxicity in patients receiving highly active antiretroviral therapy (HAART). The aim of this study was to evaluate the role of HCV-related liver fibrosis in HAART-associated hepatotoxicity. METHODS In a prospective study involving 107 patients who underwent liver biopsy, fibrosis was graded according 5 stages, from F0 (no fibrosis) to F4 (cirrhosis). Hepatotoxicity was defined as an increase in levels of aspartate aminotransferase and alanine aminotransferase to >5 times the upper limit of normal, or a >3.5-fold increase if baseline levels were abnormal. The incidence of hepatotoxicity was compared with liver fibrosis stage and with time and composition of HAART. RESULTS Overall, 27 patients (25%) had hepatotoxic events (5.1 events/100 person-years of therapy). The incidence was greater for patients with stage F3 or F4 fibrosis (38%) than for those with stage F1 or F2 fibrosis (15%; 7.6 vs. 3 events/100 person-years; relative risk, 2.75; 95% confidence interval, 1.08-6.97; P=.013). Duration of HCV infection, duration of HAART, diagnosis of acquired immunodeficiency syndrome, HCV load, HCV genotype, and nadir CD4(+) cell count did not affect the risk of hepatotoxicity. Of the 86 patients who received nonnucleoside reverse-transcriptase inhibitors (NNRTIs), 11 (13%) developed liver toxicity. In these patients, fibrosis stages F1 and F2 were associated with similar rates of toxicity (3 events/100 person-years for patients who received nevirapine, 3.3 events/100 person-years for those who received efavirenz, and 3.4 events/100 person-years for those who received non-NNRTIs). There was a greater incidence among patients with F3 or F4 fibrosis who received NNRTIs (11.7 events/100 person-years for patients who received nevirapine, and 8.6 events/100 person-years for those who received efavirenz), compared with those who received non-NNRTIs (4 events/100 person-years). CONCLUSIONS HAART-associated hepatotoxicity correlates with liver histological stage in patients coinfected with HIV and HCV. There was no difference in hepatotoxicity risk for different antiretroviral therapies in patients with mild-to-moderate fibrosis.

Predictors of long-term response to protease inhibitor therapy in a cohort of HIV-infected patients

Objective:To assess the rate of long-term effectiveness and factors associated with response to protease inhibitor therapy in a cohort of HIV-infected patients. Design and setting:Prospective, non-randomized study in a tertiary care centre. Patients:A total of 400 HIV-infected patients who started on protease inhibitor therapy (saquinavir, 28%; ritonavir, 26%; indinavir, 46%) from March 1996 to March 1997. Main outcomes measures:Long-term virological and immunological effectiveness were defined as HIV RNA levels below 200 copies/ml and CD4+ cell count increase greater than 100 × 106/l, respectively, after 12 months of therapy. Results:Fifty-seven per cent of patients had a prior AIDS-defining illness, and 91% had received nucleoside analogues for a median time of 28 months. Median CD4+ count was 86 × 106 cells/l and HIV RNA level was 4.46 log10 copies/ml. The global rate of virological and immunological effectiveness at 1 year was 45 and 59%, respectively. In a logistic regression analysis, treatment failure was associated with higher baseline HIV load [relative risk (RR), 2.10; P < 0.01], prior antiretroviral therapy (RR, 2.07; P < 0.01), and use of saquinavir (RR, 1.55; P = 0.03), whereas a reduction of more than 1 log10 in HIV load within the first 3 months on therapy was strongly associated with response (RR, 0.65; P < 0.01). There was no strict correlation between virological and immunological effectiveness (r = −0.35; P = 0.01). Conclusions:Nearly half of the patients maintain undetectable HIV load after 1 year of therapy, although important immunological benefit can be obtained in a greater proportion of patients. These data suggest the use of the most potent antiretroviral therapy in pretreated patients with high HIV load, and the capacity of initial virological decline to predict the long-term outcome.

Nosocomial transmission of Mycobacterium bovis resistant to 11 drugs in people with advanced HIV-1 infection

BACKGROUND Since 1990, several nosocomial outbreaks of multidrug-resistant (MDR) tuberculosis have occurred, none of which have involved Mycobacterium bovis. We describe an epidemic of nosocomial and primary MDR M bovis tuberculosis from December, 1993, to February, 1995, among HIV-1-infected patients in a district of Madrid. METHODS We undertook genetic characterisation of the M bovis strain and investigated its presence in a tuberculosis epidemic in a Madrid hospital in a case-controlled study. We assessed 19 cases diagnosed with MDR tuberculosis due to M bovis during the study period. For the control group, we randomly selected 33 patients with HIV-1 infection and isolation of a strain of M tuberculosis susceptible to isoniazid, rifampicin, or both, who were treated in Ramón y Cajal Hospital. Infection-control policies and practices were implemented. FINDINGS We detected 19 cases in HIV-1-infected patients of primary MDR tuberculosis produced by M bovis resistant to 11 antituberculosis drugs. We found phenotypic and genotypic similarities in the strains of M bovis. In the case group, the index case and two other cases had had previous contact with another hospital that had had an MDR tuberculosis outbreak. All patients died after a mean of 44 days (range 2-116), despite multidrug treatment with first-line and second-line antituberculosis drugs. The cases with M bovis MDR tuberculosis were significantly more likely than controls to have been admitted to a hospital ward at the same time as patients already infected with MDR tuberculosis during the 10 months before their diagnosis (adjusted odds ratio 94.6 [95% CI 9.4-956.3], p < 0.0001). Advanced HIV-1 immunosuppression was associated with the development of MDR tuberculosis. Implementation of control measures stopped the epidemic. INTERPRETATION An M bovis primary MDR tuberculosis epidemic that cannot be treated effectively and with high mortality has emerged in Europe and has been transmitted between hospitals.

Consensus conference on chronic viral hepatitis and HIV infection: updated Spanish recommendations

Summary.  Chronic hepatitis B and C represent a leading cause of morbidity and mortality among human immunodeficiency virus (HIV)‐infected patients worldwide. New treatment options against both hepatitis B (HBV) and C (HCV) viruses have prompted us to update previous recommendations for the management of coinfected individuals. Fifteen topics (nine related to HCV, five to HBV and one to both viruses) were selected for this purpose. A panel of Spanish experts in the field was invited to review these areas and propose specific recommendations, which were scored according to the Infectious Disease Society of America (IDSA) grading system. These guidelines represent a comprehensive and updated overview on the management of hepatitis B and C in HIV‐infected patients.

Increased Risk of Serious Non-AIDS-Related Events in HIV-Infected Subjects on Antiretroviral Therapy Associated with a Low CD4/CD8 Ratio

Background A low CD4/CD8 ratio has been identified in the general population as a hallmark of inmmunosenescence and a surrogate of all-cause mortality. We aimed to investigate in treated HIV-infected individuals the relationship between the CD4/CD8 ratio and serious non-AIDS events. Methods Case-control study within a prospective hospital-based cohort of HIV-infected subjects during at least one year of ART-mediated viral suppression. Cases were patients with serious non-AIDS events (non-AIDS malignancies, cardiovascular disease, and end-stage kidney disease), and controls individuals who did not developed non-AIDS events during follow-up. Data were analyzed using ROC analysis and multivariate logistic regression. Conditional logistic regression was performed in 200 cases/controls matched by age, sex, nadir CD4 and proximal CD4 counts. Results We analyzed 407 subjects (109 cases, 298 controls). The CD4/CD8 ratio was lower in cases (0.44 vs. 0.70, P<0.0001), with higher discriminatory ability for the detection of non-AIDS events than the CD4 count, CD8 count and nadir CD4. Multivariate analyses (adjusted for age, sex, nadir CD4, proximal CD4 count, year of ART initiation and ART duration) confirmed the independent association of a low CD4/CD8 ratio with the risk of non-AIDS morbidity (per CD4/CD8 ratio quartile decrease, OR, 2.9; 95% CI, 1.3–6.2) and non-AIDS mortality (OR, 2.8; 95% CI, 1.5–5.3). Conclusions The CD4/CD8 ratio provides additional information to the CD4 counts and nadir CD4 in treated HIV-infected individuals, since it is independently associated with the risk of non-AIDS-related morbidity and mortality. This association is robust and maintained within different subgroups of patients.

Candidal Meningitis in HIV-Infected Patients: Analysis of 14 Cases

Five cases of candidal meningitis in human immunodeficiency virus (HIV)-infected patients have been diagnosed in our hospital. This article describes these cases and reviews another nine previously reported in the literature. Most patients (71%) had at least one well-known predisposing factor for candidiasis. Median CD4 cell count was 135/mm3. Headache and fever, in the absence of focal neurologic signs, were the predominant clinical features. The CSF analysis revealed mild pleocytosis and hypoglycorrachia, indistinguishable from those seen in tuberculous or cryptococcal meningitis. Twelve patients (92%) received amphotericin B for a median of 51 days, in combination with flucytosine in five cases. The overall mortality among treated patients was 31%. Although the risk of relapse of candidal meningitis is unknown, maintenance antifungal therapy was given to seven patients (63%), usually with fluconazole. Candida species must be kept in mind as a cause of chronic meningitis in HIV-infected patients who have a known predisposing factor.

Estudio multicéntrico sobre prevalencia de las coinfecciones por virus de hepatitis, indicaciÓn de tratamiento de hepatitis crÓnica C y necesidad de trasplante hepático en pacientes infectados por el VIH en España.Estudio GESIDA 29/02-FIPSE 12185/01

Introduccion Los objetivos del estudio son estimar la prevalencia de las coinfecciones por virus de la hepatitis en la poblacion espanola infectada por el VIH y determinar el porcentaje de pacientes candidatos a tratamiento de la hepatitis C cronica (HCC) y a trasplante hepatico dentro de esta poblacion. Metodos Estudio transversal de dos poblaciones de pacientes infectados por el VIH realizado en el ano 2002: 1.260 pacientes de la poblacion de 39 centros de toda la geografia espanola (P1) y 1.560 pacientes de la de tres hospitales de tercer nivel de Madrid (P2). Resultados La prevalencia serica de virus de las hepatitis A (VHA), B (VHB) y HCC encontrada respectivamente en P1 y P2. IgG anti-VHA+: 74% y 78%. HBsAg+: 4,9 y 4,8%. HBsAg−, anti-HBc+, anti-HBs+: 39 y 39%. HBsAg−, anti-HBc+, anti-HBs− : 25 y 31%. HBsAg−, anti-HBc−, anti-HBs+: 7 y 8%. HBsAg−, anti-HBc−, anti-HBs− : 22 y 16%. Anti-VHC+: 61 y 65%. Entre estos 88,8 y 84,6% tenian una PCR VHC+. Coinfeccion multiple por virus de la hepatitis 3,2 y 2,8% y de estos, 70 y 78% con coinfeccion por el VHB, el VHC y el VHD. Cirrosis hepatica el 5,8 y 9,6% de los pacientes coinfectados por el VIH y el VHC, con indicacion de considerar trasplante hepatico aproximadamente en uno de cada seis. El 43 y 37% de los coinfectados por el VHC eran buenos candidatos a tratamiento de HCC, pero solo el 14 y el 15% lo habian iniciado. Conclusiones Un elevado porcentaje de pacientes infectados por el VIH en Espana estan coinfectados por virus de hepatitis, especialmente por el tipo C (VHC). El numero de posibles candidatos a trasplante hepatico es elevado y puede aumentar en los proximos anos. En el futuro sera necesario un mayor esfuerzo de tratamiento en los pacientes coinfectados por el VIH y virus de hepatitis.