[Show abstract][Hide abstract] ABSTRACT: Microbial translocation (MT) through the gut accounts for immune activation and CD4+ loss in HIV and may influence HCV disease progression in HIV/HCV co-infection. We asked whether increased MT and immune activation may hamper anti-HCV response in HIV/HCV patients.
98 HIV/HCV patients who received pegylated-alpha-interferon (peg-INF-alpha)/ribavirin were retrospectively analyzed. Baseline MT (lipopolysaccharide, LPS), host response to MT (sCD14), CD38+HLA-DR+CD4+/CD8+, HCV genotype, severity of liver disease were assessed according to Early Virological Response (EVR: HCV-RNA <50 IU/mL at week 12 of therapy or ≥2 log(10) reduction from baseline after 12 weeks of therapy) and Sustained Virological Response (SVR: HCV-RNA <50 IU/mL 24 weeks after end of therapy). Mann-Whitney/Chi-square test and Pearson's correlation were used. Multivariable regression was performed to determine factors associated with EVR/SVR.
71 patients displayed EVR; 41 SVR. Patients with HCV genotypes 1-4 and cirrhosis presented a trend to higher sCD14, compared to patients with genotypes 2-3 (p = 0.053) and no cirrhosis (p = 0.052). EVR and SVR patients showed lower levels of circulating sCD14 (p = 0.0001, p = 0.026, respectively), but similar T-cell activation compared to Non-EVR (Null Responders, NR) and Non-SVR (N-SVR) subjects. sCD14 resulted the main predictive factor of EVR (0.145 for each sCD14 unit more, 95%CI 0.031-0.688, p = 0.015). SVR was associated only with HCV genotypes 2-3 (AOR 0.022 for genotypes 1-4 vs 2-3, 95%CI 0.001-0.469, p = 0.014).
In HIV/HCV patients sCD14 correlates with the severity of liver disease and predicts early response to peg-INF-alpha/ribavirin, suggesting MT-driven immune activation as pathway of HIV/HCV co-infection and response to therapy.
PLoS ONE 01/2012; 7(2):e32028. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of the study was to determine whether the incidence of first-line treatment discontinuations and their causes changed according to the time of starting highly active antiretroviral therapy (HAART) in an Italian cohort.
We included in the study patients from the Italian COhort Naïve Antiretrovirals (ICoNA) who initiated HAART when naïve to antiretroviral therapy (ART). The endpoints were discontinuation within the first year of >or= 1 drug in the first HAART regimen for any reason, intolerance/toxicity, poor adherence, immunovirological/clinical failure and simplification. We investigated whether the time of starting HAART (stratified as 'early', 1997-1999; 'intermediate', 2000-2002; 'recent', 2003-2007) was associated with the probability of reaching the endpoints by a survival analysis.
Overall, the 1-year probability of discontinuation of >or= 1 drug in the first regimen was 36.1%. The main causes of discontinuation were intolerance/toxicity (696 of 1189 patients; 58.5%) and poor adherence (285 of 1189 patients; 24%). The hazards for all-reason change were comparable according to calendar period [2000-2002, adjusted relative hazard (ARH) 0.82, 95% confidence interval (CI) 0.69-0.98; 2003-2007, ARH 0.94, 95% CI 0.76-1.16, vs. 1997-1999; global P-value = 0.08]. Patients who started HAART during the 'recent' period were less likely to change their initial regimen because of intolerance/toxicity (ARH 0.67, 95% CI 0.51-0.89 vs. 'early' period). Patients who started in the 'intermediate' and 'recent' periods had a higher risk of discontinuation because of simplification (ARH 15.26, 95% CI 3.21-72.45, and ARH 37.97, 95% CI 7.56-190.64, vs. 'early' period, respectively).
It seems important to evaluate reason-specific trends in the incidence of discontinuation in order to better understand the determinants of changes over time. The incidence of discontinuation because of intolerance/toxicity has declined over time while simplification strategies have become more frequent in recent years. Intolerance/toxicity remains the major cause of drug discontinuation.
HIV Medicine 09/2009; 11(2):104-13. · 3.16 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Highly-active antiretroviral therapy (HAART) has proven remarkably effective for prolonging the life of patients with human immunodeficiency virus (HIV). However, while most HAART agents are safe, many have the potential to cause liver toxicity. Physicians must therefore consider the possibility of drug-induced liver injury in the management of HIV-infected patients, especially those with certain risk factors such as coinfection with hepatitis B virus (HBV) or hepatitis C virus (HCV), female gender, alcohol abuse, older age, or obesity. Understanding how, when, and why drug-related liver damage occurs is key to managing these patients safely and effectively. Knowledge of HAART-related liver effects will help ensure that patients receive the most benefit with the least toxicity from any given drug regimen. As more information about the mechanisms of drug related liver injury is known, clinicians will be better able to tailor therapies to suit individual situations, resulting in greater patient safety and outcomes.
Journal of the International Association of Physicians in AIDS Care (JIAPAC) 03/2009; 8(1):30-42.
[Show abstract][Hide abstract] ABSTRACT: The aims were to estimate among patients with hepatitis C virus (HCV) infection the prevalence of alcohol and coffee intake and smoking habit, the reliability of these self-reported data and the possible change of patients' habit after their first contact with a Viral Hepatitis Service.
229 patients were initially interviewed personally at the Viral Hepatitis Service and after 6 months they were re-interviewed by phone in regard to their alcohol, coffee drinking and smoking habits.
Alcohol drinkers were 55.5% of males and 35.3% of females. Most subjects drank coffee daily, both men (90.0%) and women (84.9%). The proportion of current smokers was higher in males (43.6%) than females (26.9%). We found a fair to good reliability of self-reported data regarding patients' habits, alcohol and coffee intake, and number of cigarettes smoked daily. We observed a statistically significant decrease in alcohol and coffee intake and cigarettes smoked between baseline and follow-up interviews.
We found a fairly high proportion of HCV-infected patients who regularly drink alcohol and coffee beverages and smoke cigarettes, especially among males. The reliability of self-reported data on these habits seems satisfactory. More decisive action to modify these habits, especially alcohol intake, is required in these patients.
Digestive and Liver Disease 02/2009; 41(8):599-604. · 3.16 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to compare amprenavir pharmacokinetics in HIV/hepatitis C virus (HCV)-co-infected cirrhotic patients receiving non-boosted fosamprenavir 700 mg twice daily with HCV/HIV-co-infected non-cirrhotic subjects and HIV-mono-infected subjects receiving fosamprenavir/ritonavir 700/100 mg twice daily. Liver stiffness at baseline and alanine aminotransferase levels at baseline and during follow-up were measured in order to find a correlation between drug levels and liver fibrosis or hepatotoxicity.
Amprenavir plasma concentration was determined by HPLC. Liver stiffness was measured by transient elastometry. Liver function tests were determined every 1-3 months during follow-up.
Nineteen HIV-infected patients were included. Eight had chronic HCV hepatitis (group NC), five had HCV-related liver cirrhosis (group C) and six were HIV-mono-infected (group M). In group C patients, amprenavir C(trough), AUC(0-12) and half-life were 86%/83%, 64%/55% and 58%/59% lower when compared with controls and co-infected subjects without cirrhosis, respectively; conversely, drug clearance in cirrhotics was 181%/124% higher. In 3/5 cirrhotic patients (60%) and in 2/14 non-cirrhotic patients (14%), C(trough) was below the minimum target concentration of 400 ng/mL; nonetheless, in all these patients, HIV viral load was undetectable. No correlation was found between amprenavir pharmacokinetics and liver stiffness or hepatotoxicity at follow-up.
On the basis of these data, it seems reasonable to boost fosamprenavir with ritonavir even in cirrhotic patients; amprenavir pharmacokinetics could not be predicted by liver stiffness and seem not to predict hepatotoxicity at follow-up.
Journal of Antimicrobial Chemotherapy 02/2009; 63(3):575-8. · 5.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background: The association between baseline (BL) metabolic parameters and rapid (RVR), early (EVR) and sustained (SVR) virologic response in HIV/HCV co-infected patients treated with PegIFN/RBV has been assessed. Methods: At fasting total cholesterol (T Chol), LDL, HDL and triglycerides (TGD) plasma level were measured in all patients at BL. HOMA-IR score (HOmeostasis Model of Assessment) was calculated as fasting insulin (mIU/L) × fasting glucose (mmol/L) ÷ 22.5 [Normal range 0,7-2,25]. RVR, EVR and SVR were defined as negative qualitative HCV-RNA (COBAS 2.0) at week 4 and12 and 6 months after treatment interruption. Results: 96 HIV/HCV patients who consecutively started PegIFN/RBV were enrolled [median age 42.5 years (IQR 40-45.5), 16 female, 57.6% with F3-4 (METAVIR classification), 29.2% cirrhotics; 46.8% with HCV genotype (G) 2 or 3]; 85 subjects were on HAART, 76% with a PI based regimen. Mean level of T Chol was 161 mg/dl (±41.5), LDL 98 (±30.5), HDL 44.5 (±13.5) and TGD 145 (±87.6). RVR was reached by 42.1% (G1-4: 22.4%; G2-3: 64.4%), EVR by 61.9% (G1-4: 38.7%; G2-3: 90.6%) and SVR by 37.1% (G1-4: 19%; G2-3: 64.2). At multivariate analysis variables related with RVR: G1-4 [AOR 0.005(IC95% 0.007-0.3)], TGD > 150 mg/dl [AOR 0.16(0.03-0.8)], HOMA score <3 [AOR 7.3(1.4-38.5)] and LDL (for each unit more) [AOR 1.0(1.0-1.05)]. Variables related with EVR: G1-4 [AOR 0.04(0.009-0.2)], TGD > 150 mg/dl [AOR 0.2(0.06-0.8)] and HOMA score <3 [AOR 5.4(1.4-20.4)]. Variables related with SVR: G1-4 [AOR 0.1(0.04-0.5)], HOMA score <3 [AOR 5.8(1.5-21.8)] and HCV-RNA<400 x 103UI/ml [AOR 4.7(1.3-17.2)]. Conclusions: Metabolic parameters are key factors to predict RVR, EVR and SVR in HIV/HCV co-infected subjects treated with PegIFN/RBV. Our analysis suggest a direct role of hypertriglyceridemia and a possible impact of the HAART related metabolic impairments.
Infectious Diseases Society of America 2008 Annual Meeting; 10/2008
[Show abstract][Hide abstract] ABSTRACT: To investigate the association between insulin resistance and rapid virologic response.
All consecutive HIV/hepatitis C virus coinfected patients who started peg-interferon alpha-2a (180 microg/week) and ribavirin 1000-1200 mg/day were analysed.
Insulin resistance was defined according to the homeostasis model of assessment-insulin resistance calculated as fasting insulin (mIU/l) x fasting glucose (mmol/l)/22.5. Rapid virologic response was defined as testing negative for hepatitis C virus-RNA after 4 weeks of therapy. Fasting levels of insulin and glucose in plasma were measured in all patients on the first day of treatment. Hepatitis C virus-RNA was determined by quantitative PCR assay (version 3.0). Hepatitis C virus-RNA was measured by qualitative PCR assay (COBAS 2.0) after 4 weeks of treatment.
Seventy-four HIV/hepatitis C virus coinfected patients were enrolled [mean age 41.7 years (SD 5.3), 61 men, 54.1% with advanced fibrosis (F3-4 according to METAVIR classification), 52.4% with infection by hepatitis C virus genotype 1 or 4]. Rapid virologic response was reached by 30 subjects. In the multivariate analysis the independent predictors of rapid virologic response were: genotype 1 or 4 [adjusted odds ratio 0.18 (0.06-0.55)], hepatitis C virus-RNA < 400.000 UI/ml [adjusted odds ratio 0.229 (0.09-0.92)] and homeostasis model of assessment-insulin resistance more than 3.00 [adjusted odds ratio 0.1 (0.05-0.6)].
The homeostasis model of assessment-insulin resistance score should be evaluated and possibly corrected before starting anti-hepatitis C virus therapy.
AIDS (London, England) 04/2008; 22(7):857-61. · 4.91 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We evaluated the efficacy of tenofovir (TDF) - and didanosine (ddI)-containing backbones in HIV-infected experienced subjects. We included in the study 245 subjects who started a TDF/ddI-containing HAART with HIV-RNA > 3 log(10) cp/ml and an available genotypic resistance test at baseline. At baseline, median CD4 counts and HIV-RNA were 278 cell/mmc and 4.32 log(10) cp/ml, respectively. Seventy-four subjects (30.2%) discontinued TDF and/or ddI, 23 of them for drug-related toxicities or intolerance. One-hundred and twenty-six (51.4%) subjects achieved virologic success (HIV-RNA < 50 copies/ml in two consecutive determinations) in a median time of 6.1 months; higher HIV-RNA levels (HR: 0.66, 95% CI: 0.54- 0.79, p < 0.001 for each additional log(10) copies/ml), and the total number of mutations either for PI and NNRTI at baseline (HR: 0.87, 95% CI: 0.81-0.92, p < 0.001 for each additional mutation) were both predictors of virologic success. M184V was marginally associated with virologic success (HR: 1.34, 95% CI: 0.94-1.90, p = 0.10 vs no M184V), whilst the number of TAMs was not associated. One-hundred-thirty-three (54.3%) subjects achieved immunologic success (increase of > or = 100 cells/mm(3) from baseline) in a median time of 7.5 months; immunologic success was associated with HIV-RNA levels at baseline (HR: 0.91, 95% CI: 0.79-0.98, p = 0.04 for each additional log(10) copies/ml), the total number of mutations either for PI or NNRTI (HR: 0.91, 95% CI: 0.85-0.98, p = 0.01 for each additional mutation) and CD4 count at baseline (HR: 1.11, 95% CI: 1.00-1.23, p = 0.05 for each additional 100 cells/mm(3)). Results obtained by the on-treatment analyses were comparable. In our study, HAART containing TDF/ddI seem associated with a virologic and immunologic response, when such regimens are chosen according to a genotypic resistance test.
[Show abstract][Hide abstract] ABSTRACT: Simplified regimens containing protease-inhibitors (PI)-sparing combinations were used in patients with virological suppression after prolonged highly active antiretroviral therapy. This study evaluated the total HIV-1 DNA quantitation as a predictor of long-term success for PI-sparing simplified therapy. Sixty-two patients were enrolled in a prospective non-randomized cohort. All patients have been receiving a triple-therapy regimen, two nucleoside reverse transcriptase inhibitors (NRTIs) plus one PI, for at least 9 months and were characterized by undetectable plasma HIV-1 RNA levels (<50 cp/ml) for at least 6 months. Patients were changed to a simplified PI-sparing regimen to overcome PI-associated adverse effects. HIV-DNA levels in peripheral blood mononuclear cells (PBMCs) were evaluated at baseline and at the end of follow-up. Patients with proviral DNA levels below the median value (226 copies/10(6) PBMCs) had a significant higher CD4 cell count at nadir (P = 0.003) and at enrolment (P = 0.001) with respect to patients with HIV-DNA levels above the median value. At month 18, 53 out of 62 (85%) patients on simplified regimen showed virological success, 4 (6.4%) patients experienced virological failure and 5 (8%) patients showed viral blip. At logistic regression analysis, HIV-DNA levels below 226 copies/10(6) PBMCs at baseline were associated independently to a reduced risk of virological failure or viral blip during simplified therapy (OR 0.002, 95% CI 0.001-0.46, P = 0.025). The substitution of PI with NRTI or non-NRTIs may represent an effective treatment option. Indeed, treatment failure or viral blip were experienced by 6% and 8% of the patients on simplified therapy, respectively. In addition, sustained suppression of the plasma viral load was significantly correlated with low levels of proviral DNA before treatment simplification.
Journal of Medical Virology 08/2007; 79(7):880-6. · 2.37 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Baseline and follow-up predictors of new AIDS-defining events or death (ADE/death) among patients who started HAART late in their disease history have rarely been assessed simultaneously.
ADE and mortality rates were assessed using Cox regression analyses. Variables were tested for prediction of ADE/death within the first 3 months of therapy and from month 3, thereafter.
751 HIV-infected patients with <200 CD4+/mm(3) before HAART were followed for a median of 49 months. 207 new ADE occurred (7.06 [6.16-8.10] per 100 patient-years). ADE/deaths clustered within the first 3 months of treatment (106/207, 51%). Higher CD4+ T-cell counts during the follow-up (per log(e) cells/mm(3): hazard ratio [HR] 0.51; 0.41-0.64; p < .001) and use of antiretroviral therapy (HR 0.38; 95% CI 0.21-0.69; p = .001) appeared to protect from ADE/death after month 3. Conversely, increasing follow-up with HIV RNA >400 copies/mL correlated with ADE/death (per month: HR 1.09; 95% CI 1.06-1.12; p = .001). Use of boosted protease inhibitors as first-line HAART and HCV-seropositivity were additional risk factors. Baseline CD4+ T-cell count and HIV RNA had a predominant impact in the first 3 months after HAART initiation.
A careful monitoring of patients with low CD4+ is particularly necessary during the first few months of HAART. Length and extent of viral replication during the follow-up appeared to induce a significantly higher risk of HIV disease progression afterwards, implying that new drugs and new strategies aimed at ensuring long-term suppression of HIV RNA are of outstanding importance.
HIV Clinical Trials 01/2007; 8(3):112-20. · 2.30 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The association between human immunodeficiency virus (HIV) DNA load and immunologic parameters was investigated in 163 HIV-infected patients with undetectable plasma viremia during highly active antiretroviral therapy (HAART). Patients with HIV DNA below the 25th percentile (133 copies/10(6) peripheral blood mononuclear cells) had higher pre-HAART (P = 0.001) and current (P = 0.005) CD4 counts and a prolonged duration of treatment (P = 0.001). At adjusted analysis, prolonged duration of treatment was independently associated with lower (P = 0.006) and undetectable (P < 0.001) HIV DNA values.
Journal of Clinical Microbiology 12/2005; 43(12):6183-5. · 4.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A longitudinal study of the replication capacity of HIV strains isolated from 18 patients failing highly active antiretroviral therapy (HAART) was undertaken at the time of genotypic guided change of therapy and after 12 months. Patients were divided in two groups according to the response to therapy: immune responders (12 patients with immune recovery defined as having more than 100 CD4 cells compared to baseline value), and failing patients (six patients without immune recovery). At enrollment no significant difference in terms of CD4 cell count and HIV plasma viremia was detected between the two groups. One year after change of therapy, all patients experienced a decrease in the replication capacity of HIV strains. The HIV replication capacity of the failing and of immune-responder patients decreased from 60% (range 14-96%) to 26.4% (range 0.4-74.5) and from 46.8% (range 15-98%) to 3.6% (range 0.1-26.8%), respectively. At month 12, the difference of HIV replication capacity between the two groups reached a statistical significance (P<0.03). After the change of therapy, an increase in the number of drug resistance mutations in the protease gene was detected in both groups with a higher prevalence of M36I mutation in immune responders. The HIV strains of patients failing HAART showed a progressive impaired replication capacity. The degree of the impairment in viral replication correlated with the viro-immunological discordant response to HAART and with the acquisition of new drug resistant mutations in the protease gene. In patients failing HAART, the impaired replication capacity of HIV strains could justify the persistence of an immune recovery.
Journal of Medical Virology 04/2004; 72(4):511-6. · 2.37 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Whether highly active antiretroviral therapy (HAART) should be modified in patients with persistent increases in CD4(+) T cells despite detectable viral loads is an unresolved question. Forty-three heavily pretreated human immunodeficiency virus (HIV)-infected patients with virologic failure during HAART were studied before a change of therapy guided by genotypic analysis and during follow-up. Patients with an increase in CD4(+) cell count (>100 cells/ml) over pre-HAART values were considered to be discordant patients (20 individuals), whereas patients with a lower increase or no increase in CD4(+) cell count were considered failing patients (23 individuals). Based on univariate analysis, a high CD4(+) cell count before antiretroviral treatment, homosexual behavior as a risk factor for HIV infection, reduced drug exposure to nonnucleoside reverse transcriptase inhibitors, low replicative capacity of HIV isolates, and more frequent detection of HIV isolates with a non-B subtype, an R5 biological phenotype, and M184V and T215Y/F mutations were factors associated with a discordant response to HAART. Based on multivariate analysis, only the M184V mutation remained significantly associated with a viroimmunologic discordant response (odds ratio, 25.48; 95% confidence interval, 1.43 to 453.93). No difference in lamivudine exposure was found between discordant (95%) and failing (91%) patients. Twelve months after the genotypic analysis-guided change of therapy, 3 discordant (15%) and 6 failing patients (26%) achieved undetectable viral loads (<50 copies/ml), whereas in patients with HIV RNA loads of >500 copies/ml, discordant responses were observed in 5 out of 15 discordant patients and in 4 out of 16 failing patients. A relationship between the M184V mutation and a viroimmunologic discordant response to HAART was found. After the genotypic analysis-driven change of therapy, similar rates of virologic suppression were detected in the two groups.
Journal of Clinical Microbiology 08/2003; 41(7):3007-12. · 4.07 Impact Factor