Sleep disturbances in HIV-HCV coinfected patients: indications for clinical management in the HCV cure era (ANRS CO13 HEPAVIH cohort).

OBJECTIVES: Although common among patients coinfected with HIV and hepatitis C virus (HCV), sleep disturbances (SD) are still poorly documented in this population in the HCV cure era. This longitudinal study aimed at analysing SD in HIV-HCV coinfected patients and identifying their clinical and sociobehavioural correlates. METHODS: We used 5-year annual follow-up data from 1047 participants in the French National Agency for Research on Aids and Viral Hepatitis Cohort 13 'Hépatite et VIH' (ANRS CO13 HEPAVIH) cohort of HIV-HCV coinfected patients to identify clinical (medical records) and behavioural (self-administered questionnaires) correlates of SD (mixed-effects logistic regression). SD were identified using one item documenting the occurrence of insomnia or difficulty falling asleep (ANRS 'Action Coordonnée 24' self-reported symptoms checklist), and two items documenting perceived sleep quality (Center for Epidemiologic Studies Depression and WHO Quality of Life HIV-specific brief scales). RESULTS: Seven hundred and sixteen (68.4%) patients with completed self-administered questionnaires reported SD at their most recent follow-up visit. In the multivariable model, hazardous alcohol consumption (Alcohol Use Disorders Identification Test-Consumption score ≥ 4 for men, ≥ 3 for women) (adjusted odds ratio = 1.61; 95% confidence interval: 1.09-2.36), depressive symptoms (6.78; 4.36-10.55) and the number of other physical and psychological self-reported symptoms (1.10; 1.07-1.13) were associated independently with SD after adjustment for sex, age and employment status. HCV cure was not associated significantly with SD. CONCLUSION: SD remain frequent in HIV-HCV coinfected patients and are associated with a series of modifiable behavioural risk factors. Independent of HCV cure, improved screening and comprehensive management of alcohol use, physical and psychological self-reported symptoms and depression are essential in this population. Closer investigation of these risk factors of SDs may both increase sleep quality and indirectly improve patients' clinical outcomes.

Alternative methods to analyse the impact of HIV mutations on virological response to antiviral therapy.

BACKGROUND: Principal component analysis (PCA) and partial least square (PLS) regression may be useful to summarize the HIV genotypic information. Without pre-selection each mutation presented in at least one patient is considered with a different weight. We compared these two strategies with the construction of a usual genotypic score. METHODS: We used data from the ANRS-CO3 Aquitaine Cohort Zephir sub-study. We used a subset of 87 patients with a complete baseline genotype and plasma HIV-1 RNA available at baseline and at week 12. PCA and PLS components were determined with all mutations that had prevalences >0. For the genotypic score, mutations were selected in two steps: 1) p-value < 0.01 in univariable analysis and prevalences between 10% and 90% and 2) backwards selection procedure based on the Cochran-Armitage Test. The predictive performances were compared by means of the cross-validated area under the receiver operating curve (AUC). RESULTS: Virological failure was observed in 46 (53%) patients at week 12. Principal components and PLS components showed a good performance for the prediction of virological response in HIV infected patients. The cross-validated AUCs for the PCA, PLS and genotypic score were 0.880, 0.868 and 0.863, respectively. The strength of the effect of each mutation could be considered through PCA and PLS components. In contrast, each selected mutation contributes with the same weight for the calculation of the genotypic score. Furthermore, PCA and PLS regression helped to describe mutation clusters (e.g. 10, 46, 90). CONCLUSION: In this dataset, PCA and PLS showed a good performance but their predictive ability was not clinically superior to that of the genotypic score.

Prevalence of and factors associated with hepatic steatosis in patients coinfected with hepatitis C virus and HIV: Agence Nationale pour la Recherche contre le SIDA et les hépatites virales CO3 Aquitaine Cohort.

BACKGROUND: Hepatic steatosis is a common feature in liver biopsies from patients with chronic hepatitis C and is associated with fibrosis progression. Patients with HIV infection and hepatitis C virus (HCV) coinfection have more rapid progression of liver fibrosis than patients with HCV infection alone. The prevalence and factors associated with hepatic steatosis are not well defined in HCV-HIV-coinfected patients. METHODS: Steatosis was assessed among 148 HCV-HIV-coinfected patients of the Aquitaine Cohort. Steatosis was graded as follows: none, mild (1%-10% of hepatocytes), moderate (11%-30%), severe (31%-60%), and massive (more than 60%). Epidemiologic, clinical, biologic, and therapeutic data were retrieved from the cohort database to investigate the risk factors. RESULTS: Steatosis was present in 67% of patients (95% confidence interval [CI]: 59% to 74%) and was at least moderate in 30% (95% CI: 23% to 38%). Steatosis was macrovesicular or mixed (macro- and microvesicular) in 40.5% and 52.8% of patients, respectively. Necroinflammatory activity was the only factor independent of steatosis (adjusted odds ratio = 5.3, 95% CI: 1.6 to 17.9). When necroinflammatory activity was removed from the model, HCV genotype 3 and body mass index (BMI) were significantly associated with steatosis. CONCLUSIONS: Liver inflammation, HCV genotype 3, and BMI are associated with steatosis, a common finding in HCV-HIV-coinfected patients.

Pravastatin in HIV-infected patients treated with protease inhibitors: a placebo-controlled randomized study.

PURPOSE: The objectives of the study were to assess the effects of pravastatin on plasma HIV RNA, lipid parameters, and protease inhibitor (PI) concentrations in patients treated with PI-containing regimens and with total cholesterol (TC) > or = 5.5 mmol/L. METHOD: A clinical trial including patients randomized to receive pravastatin or matching placebo for 12 weeks was implemented. RESULTS: Twelve patients were included in the pravastatin group and 9 in the placebo group. At week 12 (W12), no patient had experienced virological failure. Between week 0 (W0) and W12, the median differences for TC were -1.4 mmol/L in the pravastatin group and +0.2 mmol/L in the placebo group (p = .005); for LDL, they were -1.0 mmol/L and +0.3 (p = .007), respectively. A significant decrease of the PI concentration (12 hours after administration) ratio W12 - W0/W0 was noticed in the pravastatin group (-0.2 [interquartile range, -0.3 to -0.1] as compared with the placebo group (0.1 [IQR, 0.0 to 0.3]) (p = .03). When the study was restricted to patients treated with lopinavir/ritonavir, a decrease from 3.8 microg/mL at baseline to 2.9 mug/mL at W12 was noticed in the pravastatin arm (p = .04) but not in the control arm (p = 1.00). No clinical adverse event reached a severity of grade 3. CONCLUSION: We observed in this study that the use of pravastatin in PI-treated patients was not associated with major change in the plasma HIV RNA on 12 weeks of follow-up. However, we found a trend of decrease of the trough PI concentration at W12, suggesting a possible drug-drug interaction of pravastatin on PI metabolism.

Interpretation of genotype and pharmacokinetics for resistance to fosamprenavir-ritonavir-based regimens in antiretroviral-experienced patients.

In this study, named the Zephir study (Telzir-pharmacokinetics), 121 antiretroviral-experienced human immunodeficiency virus (HIV) patients failing on highly active antiretroviral therapy (HAART) were included in a prospective cohort and received a fosamprenavir-ritonavir (700 mg/100 mg twice a day)-based regimen. The impact of baseline HIV type 1 (HIV-1) mutations, pharmacokinetic (PK) parameters, and genotype inhibitory quotient (GIQ) on the virological response at week 12 (W12) was assessed. HIV reverse transcriptase and protease were sequenced at W0. The response at W12 was defined as<2.3 log10 HIV-1 RNA copies/ml or a virus load decrease of>or=1 log10 copies/ml. W4 amprenavir PK were determined by high-performance liquid chromatography. Patients had a median of nine previous treatments over 8 years. Median W0 values were as follows: 295 CD4+/microl, 4.4 log10 HIV-1 RNA copies/ml, and 6 protease- and 5 nucleotide reverse transcription inhibitor-related mutations. Respective values for minimum concentration of drug in serum (Cmin) and area under the concentration-time curve (AUC) from 0 to 24 h were 1,400 ng/ml and 35 mg.h/ml. At W12, 52% of the patients were successes, with a median decrease of -0.7 log10 HIV-1 RNA copies/ml. The Zephir mutation score included 12 IAS protease mutations associated with poorer virological response: L10I/F/R/V, L33F, M36I, M46I/L, I54L/M/T/V, I62V, L63P, A71I/L/V/T, G73A/C/F/T, V82A/F/S/T, I84V, L90M, and polymorphism mutations I13V, L19I, K55R, and L89M. Comparing<4 versus>or=4 mutations, HIV-1 RNA decreases were -2.3 log10 copies/ml versus -0.1 log10 copies/ml (P<10(-4)) with 93% versus 19% successes (P<10(-4)), respectively. This score predicted W12 failure with 94% sensitivity, versus 31% for the ANRS 2005 algorithm. Cmin (<1,600 ng/ml), AUC (<40 mg.h/ml), and GIQ (<300) values were associated with failure (all P values were <10(-4)). The need to test genotype-based algorithms using different patient databases before their implementation in clinical practice is highlighted. Specific mutations, PK and GIQ, provide relevant information for monitoring fosamprenavir-ritonavir-based HAART.

Hepatitis B vaccination in HIV-infected patients: a survey of physicians and patients participating in the Aquitaine cohort.

UNLABELLED: In France, HIV-infected (HIV+) patients are frequently coinfected with hepatitis B virus (HBV) or at risk for this infection. Physicians and their patients should be more committed to HBV prevention than the average population. AIMS: To gain insight into the attitude towards HBV and its vaccination in HIV+ patients from the Aquitaine Cohort and their attending physicians in France. METHODS: A cross-sectional survey based on self-administered questionnaires was performed from November 2002 to June 2003. It targeted 198 physicians from the clinical group on AIDS epidemiology (Groupe d'Epidémiologie Clinique du SIDA en Aquitaine, GECSA) or participating in medical HIV networks in southwestern France; and 512 patients from the cohort. Questions concerned the following items for the physicians: HBV status, prescription of HBV serology and vaccination (frequency, type, schedule), risk factors assessed, reasons for non-vaccination; and for the patients: HBV status, information received, risk factors, attitude towards vaccination. RESULTS: 93% of physicians and 22% of patients stated they were vaccinated against HBV. HBV serological status was reported to be systematically ascertained by 75% of physicians, but post-vaccinal testing was only prescribed by 23% of them. The main reasons for not prescribing more often HBV vaccine were forgetting (79%), difficulty to identify subjects at risk (44%) and being afraid of post-vaccinal complications (32%). Thirty percent of patients reported not to have received any information on HBV vaccination. Overall, 44% considered not to be at risk of infection but 82% of them had been confronted with at least one risk. The main reasons for not having been vaccinated were mostly worry about AIDS (70%), not having been asked by physician (65%) or afraid of complications (58%); nonetheless, 42% of patients were willing to be vaccinated. CONCLUSIONS: Results from this survey underline the need for specific health actions to be undertaken concerning hepatitis B vaccination in HIV+ patients as well as their health care providers.

Avascular necrosis in HIV-infected patients: a case-control study from the Aquitaine Cohort, 1997-2002, France.

Using a case-control study design, we studied the factors associated with HIV-related avascular necrosis (AN). During a 6-year period, 12 symptomatic AN cases were validated, and each case was individually matched with 3 control cases. A conditional logistic regression model showed that current alcohol consumption and a history of steroid use were the only factors associated with the occurrence of AN.

Occult hepatitis B virus infection in HIV-infected patients with isolated antibodies to hepatitis B core antigen: Aquitaine cohort, 2002-2003.

We prospectively assessed the prevalence of occult hepatitis B virus (HBV) infection by investigating HBV replication in 160 human immunodeficiency virus (HIV)-infected patients with isolated antibodies to hepatitis B core antigen. This prevalence was 0.6% (1 case/160 patients; 95% confidence interval, 0%-3.4%). A second serum sample was collected later from 52 of the patients. HBV DNA was once again undetectable in all patients, except for the sole patient who had previously been found to be HBV DNA positive.

Fibrosis is worse in HIV-HCV patients with low-level immunodepression referred for HCV treatment than in HCV-matched patients.

Hepatitis C virus (HCV) infection is frequent in human immunodeficiency virus (HIV)-infected patients. It is known to have an aggressive course in significantly immunosuppressed patients, and cirrhosis C has become one of the main causes of mortality in HIV-HCV coinfected patients since the improvement of antiretroviral therapy. The reasons for this severe fibrotic evolution are unclear. This prospective study compared chronic HCV lesions, liver immunocompetent cells, fibrosis and liver HCV loads in 2 cohorts of naive patients referred for HCV treatment: 33 HIV-HCV coinfected patients with CD4 >250/microL and 33 HCV-infected patients matched for the main risk factors of fibrosis. Fibrosis, particularly perisinusoidal fibrosis, was more marked in the coinfected patients. This occurred in the absence of a significant difference in disease activity. The number of CD3+ cells in the liver was higher in the HIV-HCV patients than in the HCV patients. Conversely, the number of liver CD4+ cells was lower in HIV-HCV patients than in HCV patients. The numbers of CD8+ and CD68+ cells were similar in the 2 groups. Finally, liver HCV load, assessed by immunostaining and reverse-transcription polymerase chain reaction, was similar in the 2 groups. We conclude that in the population of HIV-HCV coinfected patients with low-level immunosuppression referred for HCV treatment, fibrosis is worse than in HCV patients and the proportion of CD4+ lymphocytes among CD3+ cells is markedly decreased in the liver, whereas intrahepatic viral load is similar. Our data confirm the need to treat such patients against HCV, and suggest that HIV infection could favor fibrosis via the modulation of the intrahepatic immune response.

Prevalence of cryoglobulinemia and serological markers of autoimmunity in human immunodeficiency virus infected individuals: a cross-sectional study of 97 patients.

OBJECTIVE: Autommune diseases could constitute one emerging cause of morbidity in patients infected with human immunodeficiency virus (HIV) due to the chronicity of the infection and to the high level of B cell stimulation induced by HIV. We conducted a cross-sectional study investigating the clinical and biological signs of autoimmunity in HIV infected patients. METHODS: We studied the following plasma immunological variables: antinuclear antibodies (ANA) and antibodies to extractable nuclear antigens, antiphospholipids, anticardiolipins (aCL), antineutrophil cytoplasmic antibodies (ANCA), rheumatoid factor (RF), cryoglobulinemia, total complement, and C4 factor. HIV-RNA, CD4+ cell count, and serological status for hepatitis B (HBV) and C virus (HCV) were also studied. Clinical signs of autoimmune diseases were noted. RESULTS: In total, 97 patients were investigated (men 74%). Median age was 38 years (range 20-64). Median CD4+ count and HIV-RNA were 333/mm3 and 1662 copies/ml, respectively. Coinfection by HBV and HCV was present in 7% and 64% of the patients. In patients with HIV only, we detected cryoglobulinemia in 17% of patients, a positive RF in 19%, ANA > 1/100 in 21%, aCL in 51%, and ANCA > 1/20 in 17% (most of them type C by ELISA). There was a trend for a higher level of cryoglobulinemia and aCL in patients having CD4 lymphocyte counts > 350/mm3 than in others (25% vs 11%, p = 0.26, and 63% vs 42%, p = 0.23, respectively). Patients coinfected with HCV had a higher prevalence of cryoglobulinemia than HCV-free patients (42% vs 17%; p = 0.01). Prevalence of other immunological abnormalities was not different between patients with HIV only and HCV coinfected patients. Thirty patients expressed at least one clinical sign compatible with autoimmune disease. Patients with cryoglobulinemia more often had coinfection with HCV (OR 6.64, 95% CI 1.87-23.57) and IgM > 1.9 g/l (OR 6.16, 95% CI 2.15-17.67). CONCLUSION: Humoral immunological abnormalities are frequent in patients with HIV, but are rarely associated with severe clinical signs.

Comparison of 2 regimens that include interferon-alpha-2a plus ribavirin for treatment of chronic hepatitis C in human immunodeficiency virus-coinfected patients.

An open-label, randomized trial was conducted to compare the efficacy and safety of 2 regimens of interferon-alpha-2a (IFN-alpha-2a) plus ribavirin for management of chronic hepatitis C virus (HCV) infection in human immunodeficiency virus (HIV)-coinfected patients. Sixty-eight patients were randomized to receive IFN-alpha-2a at a dosage of either (1) 6 MU given 3 times per week for 24 weeks, followed by 3 MU 3 times per week for an additional 24 weeks (group A; 31 patients); or (2) 9 MU per day for 2 weeks, followed by 3 MU per day for 22 weeks, followed by 3 MU 3 times per week for 24 weeks (group B; 37 patients). Ribavirin was added at week 16 of therapy if HCV RNA remained detectable at week 12. Sustained virological response was achieved in 10 patients (15%; 6 in group A and 4 in group B). HCV genotypes 2 or 3 and a decrease in the HCV load of >or=3 log(10) copies/mL between inclusion and week 4 were associated with virological response. In conclusion, the combination of conventional IFN-alpha-2a and ribavirin has poor virological efficacy in HCV-HIV-coinfected patients.