Luis F. López-Cortés

Fast fibrosis progression between repeated liver biopsies in patients coinfected with human immunodeficiency virus/hepatitis C virus

A few studies have assessed the observed fibrosis progression between serial liver biopsies (LB) in human immunodeficiency virus (HIV) / hepatitis C virus (HCV)‐coinfected patients. Approximately half of the patients progressed at least one fibrosis stage over a short period of time. The risk factors for this fast progression need clarification. Because of this, we evaluated the observed fibrosis progression rates of HIV/HCV‐coinfected patients and the risk factors for accelerated progression. Overall, 135 HIV‐infected patients with positive serum HCV RNA, without other possible causes of liver disease, who underwent two LB, separated at least by 1 year, were included in this retrospective cohort study. The median (Q1‐Q3) time between both LBs was 3.3 (2.0‐5.2) years. Patients showed the following changes in fibrosis stage: regression ≥1 stage: 23 (17%), no change: 52 (39%), progression 1 stage: 38 (28%), and progression ≥2 stages: 22 (16%). Seventeen (13%) patients had cirrhosis in the second biopsy. Factors independently associated with progression ≥1 stage were undetectable plasma HIV RNA during the follow‐up (relative risk [RR] [95% confidence interval, 95% CI] 0.61 [0.39‐0.93], P = 0.03), moderate‐to‐severe lobular necroinflammation (1.77 [1.16‐2.7], P = 0.009), time between biopsies (1.11 [1.08‐1.2], P = 0.01), and end of treatment response to anti‐HCV therapy (0.41 [0.19‐0.88], P = 0.02). Conclusion: Fibrosis progresses with high frequency in HIV/HCV‐coinfected patients over a period of time of 3 years. Absent‐to‐mild lobular necroinflammation at baseline, achievement of response with anti‐HCV treatment, and effective antiretroviral therapy are associated with slower fibrosis progression. (HEPATOLOGY 2009.)

Pharmacokinetic Interactions Between Efavirenz and Rifampicin in HIV-Infected Patients with Tuberculosis

ObjectiveTo evaluate the pharmacokinetic interactions between efavirenz and rifampicin (rifampin) in patients with HIV infection and tuberculosis.DesignNonblind, randomised, pharmacokinetic study.Patients24 patients (21 male, 3 female; mean age 37 years) with HIV infection and tuberculosis.InterventionsPatients were randomised to one of the following treatments: group A (n = 16) received antituberculosis drugs without rifampicin, plus highly active antiretroviral therapy (HAART) including efavirenz 600mg once daily, on days 1 to 7. Patients were then switched to rifampicin in bodyweight-adjusted fixed-dose combination plus HAART including efavirenz 600mg once daily (group A-1; n = 8) or efavirenz 800mg once daily (group A-2; n = 8). Group B (n = 8) received rifampicin in bodyweight-adjusted fixed-dose combination on days 1 to 7; on day 8, HAART including efavirenz 800mg once daily was added. Blood samples were obtained on days 7 and 14.MethodsPlasma concentrations of efavirenz and rifampicin were quantified by using validated high performance liquid chromatography assays, and pharmacokinetic parameter values were determined by noncompartmental methods. The differences between pharmacokinetic parameters on days 7 and 14 were used to assess interactions.ResultsThere was a correlation between the pharmacokinetic parameters of efavirenz and the dose/kg administered. For efavirenz, mean (median) peak concentration, trough concentration and area under the concentration-time curve over the administration interval decreased 24% (24%), 25% (18%) and 22% (10%), respectively, in the presence of rifampicin. Large interpatient variability was observed, suggesting that plasma concentration monitoring of efavirenz may be advisable. Overall, the pharmacokinetics of efavirenz 800mg plus rifampicin were similar to those of efavirenz 600mg without rifampicin. The pharmacokinetics of rifampicin did not change substantially in the presence of efavirenz. Differences in patients’ bodyweight appeared to cause further differences in exposure to efavirenz. Plasma concentrations of efavirenz in patients weighing <50kg were similar to those previously described in HIV-infected patients without concomitant tuberculosis. However, plasma concentrations in patients weighing >50kg were almost halved compared with those in patients weighing <50kg.ConclusionsAlthough the minimal effective efavirenz plasma concentration that assures virological success is not currently known, it may be advisable to increase the dosage of efavirenz to 800mg once daily when it is coadministered with rifampicin. Rifampicin can be used with efavirenz without dosage modification.

The Use of Transient Elastometry for Assessing Liver Fibrosis in Patients with HIV and Hepatitis C Virus Coinfection

BACKGROUND Transient elastometry (TE) is accurate for detecting significant liver fibrosis and cirrhosis in hepatitis C virus (HCV)-monoinfected patients. However, this procedure has been insufficiently validated in patients with human immunodeficiency virus (HIV) and HCV coinfection. The purpose of this study was to validate reported cutoff values of TE that discriminate significant liver fibrosis and cirrhosis in HIV-HCV-coinfected subjects. METHODS Liver stiffness measurements were obtained for 169 HIV-HCV-coinfected adult patients who had undergone a liver biopsy or who had received a nonhistologic diagnosis of cirrhosis within 12 months before or after a liver stiffness measurement. Patients had received no prior therapy for HCV infection. RESULTS TE measurements ranged from 3.6 kPa to 75 kPa. The area under the receiver operating characteristic curve was 0.87 (95% confidence interval, 0.84-0.93) for significant liver fibrosis and 0.95 (95% confidence interval, 0.92-0.99) for cirrhosis. To diagnose significant liver fibrosis, a cutoff value of 7.2 kPa was associated with a positive predictive value of 88% and a negative predictive value of 75%. Thirty-four patients (20%) were misclassified when this cutoff value was used. Thirteen (24%) of 54 patients with liver stiffness values <7.2 kPa had significant liver fibrosis detected by liver biopsy. To diagnose cirrhosis, a cutoff value of 14.6 kPa was associated with a positive predictive value of 86% and a negative predictive value of 94%. Thus, 13 patients (10%) had disease that was misclassified using this cutoff value. CONCLUSIONS We found that the diagnostic accuracy of TE was high for detecting cirrhosis and good for diagnosis of significant liver fibrosis. However, the performance of TE was low for discriminating mild fibrosis from significant liver fibrosis, which might limit the applicability of this technique in clinical practice.

Benefits From Sustained Virologic Response to Pegylated Interferon Plus Ribavirin in HIV/Hepatitis C Virus–Coinfected Patients With Compensated Cirrhosis

BACKGROUND The objective of this study was to determine the impact of sustained virologic response (SVR) to pegylated interferon (peg-IFN) plus ribavirin (RBV) on the incidence of liver-related complications and overall mortality in human immunodeficiency virus (HIV)-infected patients with compensated hepatitis C virus (HCV)-related cirrhosis. METHODS We included in this prospective cohort study 166 coinfected patients with compensated cirrhosis, who received peg-IFN plus RBV, to assess the time from the starting date of HCV therapy to the first hepatic decompensation and death due to any cause. RESULTS SVR was observed in 43 (25%) individuals. Two (4.6%) patients with SVR developed liver decompensation vs 33 (26.8%) individuals without SVR (P = .002). The incidence of liver-related complications was 0.89 cases per 100 person-years (95% confidence interval [CI], .11-3.1) in SVR patients and 6.4 cases per 100 person-years (95% CI, 4.5-8.9) in non-SVR patients. Factors independently associated with liver decompensation were non-SVR (hazard ratio [HR], 8.1; 95% CI, 1.08-61.5; P = .042) and MELD score ≥9 at baseline (HR, 2.9; 95% CI, 1.2-7.2; P = .016). Two (4.6%) patients with SVR died due to any cause compared with 22 (17.9%) individuals without SVR (P = .02). MELD score ≥9 (HR, 3.1; 95% CI, 1.3-7.7; P = .011) and non-SVR (HR, 8.0; 95% CI, 1.07-61; P = .043) were independently associated with overall mortality. CONCLUSIONS The achievement of SVR following peg-IFN plus RBV markedly reduces the incidence of liver-related decompensation and the overall mortality in HIV/HCV-coinfected patients with compensated cirrhosis.

Natural History of Compensated Hepatitis C Virus-Related Cirrhosis in HIV-Infected Patients

OBJECTIVE To provide information about the incidence and predictors of liver decompensation and death due to liver failure in human immunodeficiency virus (HIV)-infected patients with compensated hepatitis C virus (HCV)-related cirrhosis. METHODS Prospective cohort study of 154 HIV-HCV-coinfected patients with a new diagnosis of Child-Pugh-Turcotte (CPT) class A compensated cirrhosis. We evaluated time from diagnosis to the first liver decompensation and death from liver disease, as well as predictors of these outcomes. RESULTS Thirty-six patients (23.4%) developed liver decompensation. The incidence of liver decompensation was 6.40 cases per 100 person-years (95% confidence interval [CI], 4.18-9.38 cases per 100 person-years). Factors independently associated with liver decompensation were lack of HCV therapy (hazard ratio [HR], 3.38; 95% CI, 1.09-10.53; P = .035), baseline CD4 cell counts <or=300 cells/mm3 (HR, 2.12; 95% CI, 1.14-5.04; P = .021), CPT score 6 versus 5 (HR, 3.33; 95% CI, 1.39-7.69; P = .007), and a diagnosis of cirrhosis based on data other than biopsy or transient elastography (HR, 2.09; 95% CI, 1.05-4.16; P = .036 ). Fifteen patients (9.7%) died; 11 (73%) of these 15 died from liver disease (mortality due to liver failure, 2.44 deaths per 100 person-years; 95% CI, 1.21-4.36 deaths per 100 person-years). Hepatic encephalopathy as the first liver decompensation (HR, 20.67; 95% CI, 2.71-157.57; P = .003), baseline CD4 count <or=300/mm3 (HR, 0.24; 95% CI, 0.07-0.78; P = 0.17), and baseline CPT score 6 (HR, 4.50; 95% CI, 1.63-12.37; P = .004) were independently associated with liver-related death. CONCLUSIONS The incidence of clinical liver events in HIV-HCV-coinfected patients with CPT class A compensated cirrhosis is close to that previously reported in HCV-monoinfected patients. Lower baseline CD4 cell counts, lack of therapy against HCV, and higher CPT score are the factors related to the occurrence of clinical liver events. Minimal changes in CPT score have strong impact in the prognosis of this population.

Q fever: epidemiology, clinical features and prognosis. A study from 1983 to 1999 in the South of Spain.

OBJECTIVES Clinical polymorphism is a main feature of Q fever and, depending upon the geographic location, differences in its clinical picture have been described. The objective of this study was to determine the epidemiology, clinical features and prognosis of acute Q fever in our area. METHODS From 1985 to 1999, consecutive cases of Q fever, presented as febrile syndrome and attended in a tertiary teaching hospital in Sevilla, Spain, were included and followed prospectively. RESULTS Two hundred and thirty-one cases of acute Q fever were included. A non-focalized febrile syndrome lasting from 7 to 28 days (fever of intermediate duration) was the most frequent presentation (n=208, 90%). One hundred and forty-eight patients had hepatitis. Overall, 53% of the cases were urban and contact with animals was referred in 39% of the patients. No relationship between clinical presentation and possible route of infection was observed. Prognosis was excellent (100% cured), although in 18 patients fever was prolonged more than 28 days and three patients developed life-threatening organ affection. Antimicrobial treatment was more effective if it was administered in the first two weeks (median defervescence of fever: 3 days versus 5.5 days, p<0.01). CONCLUSIONS Acute Q fever is a common cause of fever of intermediate duration, even in urban areas. Elevation of hepatic enzymes was the most frequent laboratory finding. Severe organ affection is uncommon and the overall prognosis of the disease is excellent. Early treatment seems to shorten the duration of the disease.

Cerebrospinal fluid tumor necrosis factor-α, interleukin-1β, interleukin-6, and interleukin-8 as diagnostic markers of cerebrospinal fluid infection in neurosurgical patients

Objective: To evaluate whether cerebrospinal fluid concentrations of tumor necrosis factor (TNF)‐α, interleukin (IL)‐1β, IL‐6, or IL‐8 may be used as diagnostic markers for the differential diagnosis of aseptic vs. bacterial meningitis and/or ventriculitis in neurosurgical patients. Design: Prospective, observational study. Setting: University teaching hospital. Subjects: A total of 112 cerebrospinal fluid samples from 14 asymptomatic patients with normal cerebrospinal fluid after neurosurgery, 27 asymptomatic and 19 symptomatic patients with postneurosurgical aseptic meningitis, 32 patients with postneurosurgical cerebrospinal fluid infection, and 20 with severe subarachnoid and/or cerebral hemorrhage. Measurements and Main Results: Specific ELISA kits were used to analyze TNF‐α, IL‐1β, IL‐6, and IL‐8 concentrations on cerebrospinal fluid samples. Elevations in cerebrospinal fluid concentrations of TNF‐α, IL‐1β, IL‐6, and IL‐8 were induced by different diseases or neurosurgical procedures, but cerebrospinal fluid bacterial infection induced the highest concentrations. To discriminate between aseptic cerebrospinal fluid pleocytosis and cerebrospinal fluid infection with a specificity of 95%, cerebrospinal fluid leukocyte count >1700/mL, TNF‐α >150 pg/mL, and IL‐1β >90 pg/mL showed sensitivities of 51%, 74%, and 90%, respectively. Sufficiently sensitive and specific cutoff points could not be found for cerebrospinal fluid IL‐6 or IL‐8. Conclusion: Cerebrospinal fluid IL‐1β appears to be the best biochemical marker of cerebrospinal fluid infection in neurosurgical patients.

Efficacy of pegylated interferon plus ribavirin treatment in HIV/hepatitis C virus co-infected patients receiving abacavir plus lamivudine or tenofovir plus either lamivudine or emtricitabine as nucleoside analogue backbone

OBJECTIVES To compare the response to hepatitis C virus (HCV) therapy among human immunodeficiency virus (HIV)/HCV co-infected patients receiving a nucleos(t)ide reverse transcriptase inhibitor [N(t)RTI] backbone consisting of abacavir plus lamivudine with that observed in subjects who receive tenofovir plus lamivudine or emtricitabine. METHODS A total of 256 subjects, enrolled in a cohort of 948 HIV-infected patients who received pegylated interferon and ribavirin from October 2001 to January 2006, were included in this study. All patients were taking one protease inhibitor or one non-nucleoside reverse transcriptase inhibitor and abacavir plus lamivudine or tenofovir plus lamivudine or emtricitabine as N(t)RTI backbone during HCV therapy. Sustained virological response (SVR) rates in both backbone groups were compared. RESULTS In an intention-to-treat analysis, 20 out of 70 (29%) individuals under abacavir and 83 out of 186 (45%) under tenofovir showed SVR (P = 0.02). N(t)RTI backbone containing tenofovir was an independent predictor of SVR in the multivariate analysis [adjusted odds ratio (95% CI), 2.6 (1.05-6.9); P = 0.03]. The association between abacavir use and lower SVR was chiefly seen in patients with plasma HCV-RNA load higher than 600 000 IU/mL and genotype 1 or 4. Among patients treated with ribavirin dose <13.2 mg/kg/day, 3 (20%) of those under abacavir versus 22 (52%) under tenofovir reached SVR (P = 0.03), whereas the rates were 31% and 38% (P = 0.4), respectively, in those receiving >/=13.2 mg/kg/day. CONCLUSIONS HIV-infected patients who receive abacavir plus lamivudine respond worse to pegylated interferon plus ribavirin than those who are given tenofovir plus lamivudine or emtricitabine as N(t)RTI backbone, especially in those receiving lower ribavirin doses.

Application of transient elastometry to differentiate mild from moderate to severe liver fibrosis in HIV/HCV co-infected patients.

BACKGROUND/AIMS Transient elastometry (TE) is accurate for detecting cirrhosis (F=4) in human immunodeficiency virus (HIV)/hepatitis C virus (HCV) co-infected patients. However, this procedure is less precise to differentiate mild (F < or = 1) from moderate to severe (F > or = 2) fibrosis using the cut-off value of 7.2kPa, a level previously proposed by some authors. Because of this, we elaborated and validated cut-off values of liver stiffness (LS) to better discriminate F < or = 1 from F > or = 2 in HIV/HCV co-infected subjects to aid therapy decisions. METHODS One hundred and ninety-seven co-infected patients with liver biopsy and TE measurement, without prior therapy against HCV infection, were included. RESULTS To diagnose F < or = 2, a cut-off of 9.0kPa showed a positive predictive value of 87%. To discard F > or = 2, a cut-off of 6.0kPa showed a negative predictive value of 90%. Considering all the patients, 61 (31%) patients yielded LS values < or = 6.0kPa and 81 (41%) patients showed LS values > or = 9.0kPa. There were no severe classification errors as the NPV of L < or = S6.0kPa for F > or = 3 was 100% and the NPV LS > or = 9.0kPa for F=0 was also 100%. CONCLUSIONS The usefulness of TE can be enhanced using two different cut-off values to identify patients with F < or = 1 and F > or = 2.

Prediction of response to pegylated interferon plus ribavirin in HIV/hepatitis C virus (HCV)-coinfected patients using HCV genotype, IL28B variations, and HCV-RNA load.

BACKGROUND & AIMS This study aimed at developing a predictive algorithm based on interleukin 28B (IL28B) genotype, hepatitis C virus (HCV) genotype, and plasma HCV-RNA load, which could accurately allow us to define the probability of response to pegylated interferon (Peg-IFN) plus ribavirin (RBV) therapy in HIV/HCV-coinfected patients. METHODS Five hundred and twenty-one treatment-naive HIV-infected patients, who initiated HCV therapy with Peg-IFN/RBV, were analysed in an on-treatment basis. Patients were categorized as unlikely responders, uncertain responders, and anticipated responders (<20%, 20-60%, and >60% probability to achieve SVR, respectively). RESULTS HCV genotype, baseline HCV-RNA load, and IL28B genotype were confirmed as independent predictors of SVR in a logistic regression analysis. A stepwise algorithm based on these three variables was created based on 321 patients and evaluated in the remaining 200 patients. Unlikely responders included patients with genotype 1 or 4, HCV-RNA load ≥600,000IU/ml, and rs12979860 non-CC (rate of SVR: 17.3%). Anticipated responders were those with HCV genotype 2-3, patients harboring HCV genotype 4 and IL28B CC, as well as those who simultaneously bore HCV genotype 1, HCV-RNA load <600,000IU/ml, and IL28B CC (rate of SVR 74.1%, 77.8%, and 64.4%, respectively). The area under the receiver operating characteristic curve of the model was 0.77 (0.733-0.814). CONCLUSIONS The combined use of IL28B genotype, HCV genotype, and HCV-RNA load enables to easily identify patients with a high and very low likelihood of SVR. HCV therapy could be deferred in the latter patients, until more effective options are available, at least if they do not show advanced liver fibrosis.