Michèle Grappin

Does hepatitis C virus co-infection accelerate clinical and immunological evolution of Hiv-infected patients?

Objective:To study the influence of hepatitis C virus (HCV) co-infection on clinical and immunological evolution of HIV-infected patients. Design:A longitudinal study of HIV-infected individuals with or without HCV infection, identified at the Infectious Diseases Department of Dijon University Hospital and enrolled in a historical cohort, was performed. Methods:One hundred and nineteen HIV-infected people co-infected with HCV and 119 matched individuals infected with HIV alone were included in the cohort (median participation time 3 years; range, 2 months to 11.5 years). Clinical progression was defined as one or more of the following: a 30% decrease in the Karnofsky index; a 20% loss of body weight; an AIDS-defining illness (for non-AIDS patients); death (except by accident, suicide or overdose). Immunological progression was defined as a 50% decrease in the initial CD4 T-cell count (for patients with an initial count > 100 × 106 cells/l). Effects of HCV co-infection were evaluated using Kaplan-Meier survival analysis and significance was tested using univariate (log-rank and Petos tests) and multivariate methods (Coxs model). Results:In univariate analysis, immunological progression was not statistically different between the HCV-positive group and the HCV-negative group, whereas clinical progression was significantly faster in HCV-positive patients (P < 0.005, log–rank test). In a multivariate Cox model, clinical progression remained significantly associated with infection by HCV [hazard ratio (HR), 1.64; 95% confidence interval (CI), 1.06–2.55; P < 0.05]. Stratified multivariable analysis retained HCV as a significant prognostic factor of clinical progression (HR, 10.9; 95% CI, 1.09–109.3; P < 0.05) and immunological progression (HR, 2.31; 95% CI, 1.16–4.62; P < 0.02) for patients with an initial CD4 count above 600 × 106 cells/l. Conclusions:Clinical progression is more rapid in HIV–HCV co-infected patients than in HIV-seropositive patients are not infected by HCV. The prognostic value of HCV infection for both clinical and immunological progression is significant at early stages of HIV infection. These findings may argue for active management of hepatitis C infection in co-infected individuals, especially for asymptomatic patients whose CD4 count is above 600 × 106 cells/l, to predict and prevent accelerated progression of HCV and HIV diseases.

Association between Insulin resistance and hepatitis C virus chronic infection in HIV-hepatitis C virus-coinfected patients undergoing antiretroviral therapy

Summary: Insulin resistance (IR) in the context of highly active antiretroviral therapy (HAART) is becoming more common in HIV‐infected patients. Patients with chronic hepatitis C virus (HCV) infection have an increased risk of IR and type 2 diabetes mellitus. A cross‐sectional study was performed to investigate whether chronic HCV infection constitutes a risk factor for IR in HIV‐HCV‐coinfected patients undergoing HAART. Inclusion criteria were positive HCV viremia and a sustained increase of alanine aminotransferase of at least twice the normal value. A total of 29 HIV‐HCV patients, 76 HIV patients, and 121 HCV controls were tested for IR and body mass index (BMI). IR was measured using the homeostasis model assessment. In HIV‐HCV and HIV patients, fat redistribution and lipid profile were assessed. There was no significant difference in age, CD4 cell count, HIV viral load, or duration of HAART between the HIV‐HCV and HIV groups. HIV‐HCV patients and HCV controls had a significant increase in IR when compared with HIV patients (0.25 ± 0.28 and 0.21 ± 0.34 versus 0.04 ± 0.37; p = .01 and p = .003, respectively). Lipoatrophy was observed more frequently in HIV‐HCV patients in comparison with HIV patients (41% versus 14%; p = .003). In HIV‐HCV patients, total cholesterol and triglyceride levels were significantly lower than in HIV patients. In multivariate analysis, IR, BMI, triglyceride levels, and peripheral fat wasting were the independent variables associated with HCV infection. Our findings suggest that chronic HCV infection is a significant factor associated with the development of metabolic abnormalities and with modifications in body composition in HIV patients receiving antiretroviral treatment.

Role of Long-Term Nucleoside-Analogue Therapy in Lipodystrophy and Metabolic Disorders in Human Immunodeficiency Virus—Infected Patients

The role of nucleoside analogues (NAs) in lipodystrophy (LD) syndrome in human immunodeficiency virus (HIV)-infected patients remains controversial. We studied the prevalence of LD in previously untreated patients randomized to receive different NA combinations (in the ALBI-ANRS 070 trial) for 6 months. At month 30 of follow-up, 37 (31%) of 120 patients had >/=1 morphologic change, and 21 (57%) of 37 had isolated peripheral lipoatrophy; corresponding values for the patients who received only NAs throughout follow-up were 20 (30%) of 66 and 14 (67%) of 21, respectively. In multivariate analysis, factors associated with presence of LD at month 30 were initial assignment to the group receiving stavudine and didanosine (odds ratio [OR], 6.7; P=.02), age (OR for being 10 years older, 3.6; P=.002), and HIV RNA level at month 30 (OR, 0.4; P=.007). No difference was observed in cholesterol and glucose levels as a function of any pattern of antiretroviral exposure. Exposure to stavudine and didanosine was associated with LD syndrome (predominantly lipoatrophy).

The evolution of hepatitis B virus serological patterns and the clinical relevance of isolated antibodies to hepatitis B core antigen in HIV infected patients

BACKGROUND/AIMS The evolution of hepatitis B virus (HBV) serological patterns and the clinical relevance of isolated anti-HBc pattern are not well established in HIV infected patients. METHODS A cohort of 240 patients was followed for 6.9+/-3.4 years, with iterative HBV serologic assays performed (mean interval of 2.2 years). RESULTS Five patients without HBV markers at baseline subsequently developed positive anti-HBs (incidence 0.66/100 patient-year), as did two patients with chronic HBs antigenemia (incidence 1.66/100 patient-year). Only one patient with isolated anti-HBc pattern developed HBs chronic antigenemia. Persistent isolated anti-HBc pattern was observed in 37 patients (13 with detectable blood HBV DNA) and was strongly associated with positive hepatitis C virus (HCV) viremia (hazard ratio=9.5, confidence interval 95%: 4.5-20.0, P<0.0001). Hepatic lesions were more severe in HCV infected patients with persistent isolated anti-HBc pattern than in those without (Knodell score 9.2+/-4.6 versus 6.7+/-5.0, P=0.04). In time updated analysis, this pattern was not associated with an increased risk of hepatotoxicity, by contrast with HCV infection or positive HBs antigenemia. CONCLUSIONS In HIV infected patients, HBV serological status must be systematically and regularly assessed, and systematic HBV vaccination must be proposed in those without HBV marker. Isolated anti-HBc pattern must be considered in the management of hepatitis C, but not for antiretroviral therapy.

Value of Patient Self-Report and Plasma Human Immunodeficiency Virus Protease Inhibitor Level as Markers of Adherence to Antiretroviral Therapy: Relationship to Virologic Response

Three methods of adherence to antiretroviral therapy were evaluated for 149 patients infected with human immunodeficiency virus (HIV): plasma level of protease inhibitors (PIs), patient self-report, and routine biological parameters associated with the use of some antiretroviral drugs. Adherence to therapy was estimated from a score calculated from answers to a self-administered questionnaire and on the basis of measurement of relevant plasma and blood levels. Of the 149 patients, 112 had a virologic response, and 122 had adequate trough PI levels. Plasma PI levels and virologic outcome were significantly correlated (P<.0001). The adherence score was significantly correlated with virologic response (P<.001). Macrocytosis was significantly associated with virologic response in the patients treated with zidovudine or stavudine (P=.006). PI level was the higher significant predictor of virologic response (P=.0003). Self-reported adherence (P=.01) and macrocytosis (P=.05) were also independently associated with antiretroviral efficacy.

Evaluation of the Patient Medication Adherence Questionnaire As a Tool for Self-Reported Adherence Assessment in HIV-Infected Patients on Antiretroviral Regimens

Abstract Purpose: Adherence to antiretroviral medications is critically important for the success of therapy in patients treated for HIV infection. Patient self-report is a simple method to measure and explore adherence. Even though a variety of surveys have been developed to monitor self-reported adherence, there is no standardized instrument that may be used in routine clinical practice. The usefulness of the Patient Medication Adherence Questionnaire (PMAQ) was evaluated in HIV-infected patients on protease inhibitor (PI)-containing regimens. Method: Data from 149 patients were collected. Study participants completed the PMAQ and provided blood samples to measure plasma HIV-1 RNA concentrations and trough plasma levels of PI. Patients were considered adherent if they had a virologic response and/or had an adequate trough plasma level of PI. Results: A close relationship was found between patient reports of adherence during the previous 4 days and objective measures such as HIV RNA level and plasma levels of PI. Motivation with regard to antiretroviral treatment, confidence in personal skills, and an optimistic attitude to life were identified as important determinants of adherence. On the other hand, sociodemographic background, social support, alcohol and illicit drug use, bothersome symptoms, and depression were not associated with a lower medication adherence. Conclusion: Patients’ psychological and behavioral factors are central in the acceptance and adherence to antiretroviral therapy. To improve the feasibility and the reproducibility of the PMAQ, we propose a revised form of the PMAQ, focusing on the variables identified as strong predictors of adherence.

Cross-sectional study of the susceptibility of Candida isolates to antifungal drugs and in vitro-in vivo correlation in HIV-infected patients.

Objectives:To investigate (1) the frequency of clinical resistance to oral polyenes or azole treatment for oral candidiasis, (2) the frequency of resistant in vitro Candida strains, (3) the relationship between the susceptibilities of in vitro Candida species and in vivo status in HIV patients.Design:Prospective cross-sectional study.Setting:Tertiary care clinic at Bocage Hospital, Dijon, France.Patients:HIV-infected patients with and without oral candidiasis.Interventions:Clinical examination, oral swab for mycologic investigations.Main outcome measures:Clinical diagnosis of oral candidiasis, identification of the antifungal treatment given within the previous month, identification of Candida species, antimycogramm and determination of the minimal inhibitory concentration (MIC) for fluconazole, and measurement of T-helper cell count.Results:Within a 2-month period, 154 HIV-infected patients were studied: 46 heterosexuals, 51 intravenous drug users (IVDU), 52 homosexuals and five blood transfusion recipients. The percentages of patients with oral candidiasis were: 41, 80, 44 and 20%, respectively (P<0.05); the mean T-helper cell counts were 200, 135, 210 and 238×106/l cells, respectively (P <0.05). Twenty-two patients (14.3%) had received recent azole treatment and 29 (18.8%) recent oral polyene treatment. Among the 84 patients with and the 70 patients without oral candidiasis, 78 and 28 Candida strains were isolated, respectively. Although Candida albicans represented the majority of Candida species (88 strains, 83%), the non-albicans strains were isolated more frequently in patients who had received recent antifungal treatment. No strains were resistant to ketoconazole, miconazole or econazole; however, six (5.6%), 16 (15%) and 10 (9.5%) were intermediately susceptible to the three drugs, respectively. Twelve (1 3.6%) of the 88 C. albicans, five of the six C. (Torulopsis) glabrata, one of the five C. tropicalis and all three C. krusei strains were resistant to fluconazole. These resistant strains were separated as follows: 41.1% of C. albicans strains resistant to fluconazole were isolated from patients who had received recent azole therapy, 1 7.6% from patients who received recent oral polyene, and 3.7% from patients who had not received any recent antifungal treatment (P= 0.004). The mean MIC of these three categories of isolates were 3.6, 1.6 and 0.6mg/l, respectively (P=0.06).Conclusions:Oral candidiasis and fluconazole-resistant Candida isolates are more frequently found in IVDU. Treatments using azoles select non-albicans strains and are associated with decreased susceptibilities of C. albicans strains to fluconazole in particular. These findings show that prolonged azole treatment in severely immunocompromised patients should be avoided.

Concentration of Circulating Oxidized LDL in HIV-Infected Patients Treated with Antiretroviral Agents: Relation to HIV-Related Lipodystrophy

Abstract Background: Circulating oxidized LDL (ox-LDL) is associated with clinical manifestations of atherosclerosis. The aim of the study was to investigate the concentrations of ox-LDL in HIV-infected patients under antiretroviral therapy with (HIV-LD) or without (HIV-nLD) HIV-related lipodystrophy. Method: A total of 44 HIV-infected men were enrolled in the study. Half of them had HIV-LD. The control group included 12 age- and body mass index (BMI)-matched HIV-uninfected men. Ox-LDL concentration and C-reactive protein level were determined. Insulin sensitivity was measured using the homeostasis model assessment (HOMA-IR). LD was assessed by using a validated score calculated from clinical and biological data. Results: HIV-infected patients had significantly higher ox-LDL concentrations when compared to HIV-negative controls (0.8 ±0.3 mg/dL vs. 0.60 ±0.1 mg/dL; p = .007). HIV-LD patients had significantly higher ox-LDL concentrations than HIV-nLD patients (0.91 ±0.38 and 0.69 ±0.16; p = .04). In HIV-LD patients, current therapy with protease inhibitors (PIs); duration of PI therapy; HOMA-IR; and time exposure to stavudine, efavirenz, ritonavir, saquinavir, and amprenavir were significantly higher than in HIV-nLD patients. In multivariate analysis, time exposures to stavudine and ox-LDL concentration were independently related to lipodystrophy. Conclusion: The high concentration of ox-LDL was found in HIV-infected patients under antiretroviral therapy, especially in those with lipodystrophy.

Low Trough Plasma Concentrations of Nevirapine Associated with Virologic Rebounds in HIV-Infected Patients Who Switched from Protease Inhibitors

BACKGROUND: The substitution of a nonnucleoside reverse-transcriptase inhibitor (NNRTI) for protease inhibitors (PIs) has demonstrated its suitability to maintain virologic response. However, the switch from PIs to an NNRTI could fail for a number of reasons, including NNRTI-associated toxicity and emergence of NNRTI-resistant variants. OBJECTIVE: To describe the virologic failures among 74 HIV-infected patients who switched from PIs to nevirapine. METHODS: Virologic failure was defined as any rebound of the plasma HIV-RNA (pVL) levels >1000 copies/mL on one occasion or 2 consecutive intermittent viremia episodes defined as increases of the pVL >20 copies/mL but <1000 copies/mL. Virologic failures were investigated retrospectively by determining nevirapine trough concentrations and performing genotypic resistance analysis. RESULTS: The mean nevirapine concentration was significantly lower in patients with virologic failure in comparison with patients with virologic response (2572 ± 1642 vs 4550 ± 2084 ng/mL, respectively; p = 0.003). In multivariate analysis, the mean duration of undetectable pVL before the switch and the mean plasma concentration of nevirapine were significantly associated with virologic success with relative rates of 1.39 (95% CI 1.10 to 1.76, p = 0.006) and 2.7 (95% CI 1.37 to 5.41, p = 0.01), respectively. In patients with pVL >1000 copies/mL, nevirapine mutations and nucleoside reverse-transcriptase inhibitor mutations were found in 80% of the cases. CONCLUSIONS: The risk of virologic failure after the switch from PI to nevirapine is higher in cases of inadequate nevirapine plasma concentrations. Our data support prospective monitoring of nevirapine plasma concentrations to detect low concentrations prior to the emergence of resistance mutations.

Exercise stress testing for detection of silent myocardial ischemia in human immunodeficiency virus-infected patients receiving antiretroviral therapy.

The prevalence of silent myocardial ischemia (SMI) and the factors associated with SMI were evaluated in patients infected with human immunodeficiency virus (HIV) who had been receiving highly active antiretroviral therapy (HAART) for > or =12 months and did not have known coronary artery disease or cardiac symptoms. Patients prospectively underwent exercise stress testing. The prevalence of SMI was 11% (11 of 99 patients). Patients who had SMI were significantly older than were patients who did not (mean+/-SD, 51+/-8 years vs. 42+/-9 years; P=0.001) and were more likely to have trunk obesity (54% of patients vs. 17%; P=.004). A significant correlation was found between a positive exercise test result and obesity (correlation,.006), waist-to-hip ratio (.007), and glucose and cholesterol levels (.04; P=.03). In multivariate analysis, age, central fat accumulation, and cholesterol level were independent variables associated with the detection of SMI. Exercise testing might be recommended for patients with HIV who have central fat accumulation and hypercholesterolemia.