Ivana Maida

Severe liver disease associated with prolonged exposure to antiretroviral drugs

Background: Liver damage is frequently seen in HIV-positive subjects, often resulting from coinfection with hepatitis B and/or C viruses (HCV), alcohol abuse, etc. However, the etiology of liver disease still remains unknown for a small subset of individuals. Methods: Cryptogenic liver disease (CLD) was defined as persistently elevated aminotransferases levels in the absence of hepatitis C and/or B viruses replication and of other common causes of liver disease (alcohol, medications, etc). We identified cases initially meeting this definition by examining all HIV-positive subjects attended during the year 2004 in 2 large HIV clinics in Spain. Their clinical charts were retrospectively reviewed, and their assessment completed when needed to rule out other less frequent causes of liver disease. The stage of liver fibrosis was assessed by liver biopsy and/or elastography. To assess which factors could be associated with CLD, HIV-positive controls were chosen and matched by age, gender, and CD4 status. Results: CLD was diagnosed in 17 (0.5%) out of 3200 HIV-positive patients. Their mean age was 43 years, 82.4% were male, and 76% had acquired HIV through homosexual relationships. The mean time from HIV diagnosis was >15 years, and all patients had been exposed to antiretroviral therapy. Nevirapine, stavudine, and didanosine were the drugs more frequently used by this subset of patients. None of them had liver function test abnormalities before initiating antiretroviral therapy. Advanced liver fibrosis (F3-F4 Metavir scores) was recognized in 10 (58.8%) individuals, and 9 (52.9%) had developed symptomatic liver complications, including ascites (8), portal thrombosis (6), variceal bleeding (5), and encephalopathy (2). In the case-control analysis, prolonged didanosine exposure was the only independent predictor of developing CLD in this population. Conclusions: CLD is an uncommon condition in HIV-positive individuals and might be associated with prolonged didanosine exposure. It may evolve causing severe liver complications, with variceal bleeding and portal thrombosis being particularly frequent.

Paradoxical CD4+ T-cell decline in HIV-infected patients with complete virus suppression taking tenofovir and didanosine.

Background: Tenofovir (TDF) and didanosine (ddI) are both adenosine analogues with convenient posology, strong potency and a relatively high genetic barrier for resistance. The popularity of this combination, however, has been questioned due to concerns about pharmacokinetic interactions and increased risk of pancreatitis and hyperglycemia. Less information is available about other possible side effects. Patients and methods: HIV-infected individuals who initiated a protease inhibitor-sparing regimen between September 2002 and June 2003 at five hospitals, and had at least one subsequent visit within the next 12 months, always with complete virus suppression, were retrospectively assessed. Only drug-naive individuals and patients who simplified a prior successful antiretroviral regimen were analysed. Results: Outcomes were analysed in 570 individuals according to treatment modality (98 drug-naive versus 472 simplified); the nucleoside analogue (NA) backbone (298 with TDF + ddI, 88 with ddI, 44 with TDF, and 140 with neither ddI nor TDF); and the third agent used (378 with non-nucleoside analogues versus 192 with NA). Significant CD4+ T-cell declines were seen in patients taking ddI + TDF with respect to all other NA combinations, including ddI or TDF separately. Patients exposed to high ddI doses or taking a third NA showed more pronounced CD4 declines. Plasma levels of ddI correlated with the extent of CD4+ T-cell loss. Conclusion: Patients receiving ddI + TDF-based combinations show CD4+ T-cell declines despite achieving complete virus suppression. This effect generally progresses with time. An imbalance in adenosine metabolites within CD4+ T lymphocytes may explain this phenomenon, which resembles the genetic purine nucleoside phosphorylase deficiency syndrome.

Noncirrhotic portal hypertension in HIV-infected patients: unique clinical and pathological findings.

Background:Liver disease of unknown cause in HIV-infected persons is rare but increasingly being reported. Noncirrhotic portal hypertension is the main feature in a subset of these patients, in whom gastrointestinal bleeding is the most frequent and potentially life-threatening clinical presentation. Methods:We describe the epidemiological, clinical and histological features of 12 HIV-positive individuals presenting with noncirrhotic portal hypertension. Results:An interpretable liver biopsy was available in 11, and cirrhosis was absent in all patients. Three patients had nodular regenerative hyperplasia of the liver, whereas eight showed morphological features previously described as ‘hepatoportal sclerosis’. In four of the later group, a distinctive lesion was noted characterized by massive absence of portal veins along with focal fibrous obliteration of small portal veins. All patients had been treated with didanosine for long periods and inflammatory and thrombotic processes hypothetically triggered by this purine analogue in the hepatic microvasculature might result in this form of obliterative portal venopathy. Conclusion:Noncirrhotic portal hypertension is a rare but unique entity presenting in HIV-positive individuals generally with prior prolonged exposure to didanosine, which shows an obliteration of portal veins as the most distinctive histological finding in the liver.

Modulation by α- and γ-tocopherol and oxidized low-density lipoprotein of apoptotic signaling in human coronary smooth muscle cells∗

Apoptosis may play an important role in atherogenesis. Oxidized low-density lipoprotein (oxLDL) promotes apoptosis in the arterial wall in addition to several other proatherogenic effects. Tocopherol supplements have been suggested to protect against coronary heart disease (CHD) in epidemiological studies. The effects of oxLDL and alpha- and gamma-tocopherol on apoptotic signaling pathways are poorly understood. Thus, the goal of the study was to investigate these pathways in the presence of copper-oxidized LDL and tocopherols in human coronary smooth muscle cells (SMC). We showed that oxLDL-mediated apoptosis, assessed by DNA fragmentation, terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) assay, and caspase activation stimulated several transcription factors and proapoptotic dynamic movements of the Bcl-2 family proteins through the mitogen-activated protein kinase (MAPK) and Jun kinase pathways. alpha-Tocopherol and gamma-tocopherol significantly reduced these molecular events and cell death effectors caspase-3 and -8. Under our experimental conditions, alpha-tocopherol was significantly more effective than gamma-tocopherol, and oxLDL-mediated apoptosis increased c-Jun, cyclic AMP-responsive element-binding, Ets-like element kinase-dependent 7, and activating transcription factor-2 proteins as well as nuclear activity of the activated protein-1 complex in human coronary SMC. Moreover, our results demonstrate that tocopherols may exert their antiatherogenic effects at least in part via reduction of the MAPK and JunK cascade together with a protective profile of apoptotic genes of the Bcl-2 family. These data are consistent with the beneficial effects of tocopherols on atherogenesis seen in experimental studies and on CHD in epidemiological surveys.

Predictors of Virological Response to Atazanavir in Protease Inhibitor-Experienced Patients

Abstract Background: Atazanavir (ATV) is the latest approved HIV protease inhibitor (PI). Even though it is very convenient (only two capsules once a day), concerns have risen about its potency. Method: The clinical performance of ATV 400 mg once a day was examined in all PI-experienced patients who were included in the ATV expanded access program conducted in a single institution. The predictive value of baseline drug resistance HIV genotypes, ATV plasma trough levels, and the genotypic inhibitory quotient (GIQ) on the virological response at week 24 was assessed. Results: Data from 92 patients were analyzed. ATV was prescribed as part of a rescue intervention (45%), a simplification strategy (11%), or an attempt to ameliorate hyperlipidemias (23%) or other toxicities (16%). Tenofovir (TDF) was concomitantly used with ATV in 78% of patients. None received ritonavir boosting. In patients with detectable viremia at baseline (65%), the median HIV RNA drop was 0.7 logs. The median ATV Cmin was 0.12 μg/mL (IQR, 0.05-0.22 μg/mL), which is clearly above the IC90 (90% inhibitory concentration) for ATV in wild-type viruses. The virological response did not correlate significantly with ATV Cmin. The median number of protease resistance mutations was lower in patients showing virological response than in nonresponders (1 vs. 5; p = .07). A higher HIV RNA drop was associated with a higher GIQ (p = .02; β = –5.4; 95% CI, –10 to –1). Only 4 patients (4%) discontinued treatment due to ATV-related toxicities (hyperbilirubinemia in 1). Bilirubin levels were associated with ATV plasma concentrations (p = .05; β = 3.2; 95% CI, –0.1 to 6.5). The rate of hypertriglyceridemia and hypercholesterolemia declined significantly with respect to baseline. Conclusion: ATV is relatively safe and provides significant virological response in PI-experienced patients, mainly among those with a low number of protease resistance mutations. The GIQ predicts accurately the virological response in patients receiving ATV. Hyperbilirubinemia is associated with higher ATV plasma levels.

Incidence of Neutropenia and Infections During Combination Treatment of Chronic Hepatitis C with Pegylated Interferon Alfa-2a or Alfa-2b Plus Ribavirin

Background:Combination therapy with pegylated interferon (peginterferon) plus ribavirin is associated with several side effects, including neutropenia and infection.Aims:To evaluate the incidence of neutropenia and infection between all consecutive patients with hepatitis C who were treated in two centers with peginterferon-alfa-2a and peginterferon-alfa-2b, in combination with ribavirin and actively monitored for occurrence of any infection. Methods:A total of 319 consecutive patients with chronic hepatitis C received once-weekly peginterferon alfa-2b at a weight-adjusted dose (n = 162) or peginterferon alfa-2a at a flat dose (n = 157), plus ribavirin.Results:Neutropenia was observed in 53 patients overall (17%). There were 73 infections in 73 subjects (23% of the treated population); 4/73 required hospitalization. Infections included respiratory infections (n = 23), cellulitis (n = 17), dental abscesses (n = 13), gastroenteric infections (n = 2), and other types of infections (n = 18). The incidence of all infections was significantly associated with age, especially over 60 years (p < 0.01) but not with neutropenia or type of pegylated interferon.Conclusions:During the treatment with pegylated interferons and ribavirin, we did not find a correlation between neutropenia and infections. This result provides a support for the notion that current guidelines for pegylated interferons dose reduction in the treatment of chronic hepatitis C for hematologic toxicity could be overly strict.

Sexual transmission is associated with spontaneous HCV clearance in HIV-infected patients

BACKGROUND/AIMS There are conflicting data regarding the incidence and factors implicated in the spontaneous clearance of hepatitis C virus (HCV) after acute infection. The aim of this study was to determine the epidemiological factors that predict the resolution of acute HCV infection without therapy in patients with human immunodeficiency virus (HIV) infection. METHODS We conducted a retrospective, multivariate analysis of epidemiological data from HIV-infected patients presenting from 2000 to 2007 with evidence of past or present HCV infection. Data were collected from one American and two European HIV treatment clinics. A final cohort of 769 HIV-infected patients referred for treatment with available test results for antibody to HCV, HCV RNA, and hepatitis B surface antigen were included for the analysis. We calculated spontaneous clearance rates based on race, geographical location, gender, transmission risk factors, and hepatitis B virus coinfection. RESULTS Patients who admitted to a history of injection drug use spontaneously cleared the HCV infection significantly less often (11.6%) than those in whom sexual transmission was the presumed route of HCV infection (21.9%) (p=0.004). This difference was more pronounced when heterosexual contact as the source of infection was analyzed separately. Multivariate analysis identified heterosexual HCV transmission (OR 2.81, 95% CI 1.55-5.09) and hepatitis B surface antigen carrier status (OR 10.3, 95% CI 4.29-24.73) as independent factors predicting spontaneous HCV clearance. No differences according to gender, race or geographical origin were observed. CONCLUSIONS In summary, sexual transmission, particularly heterosexual, and hepatitis B virus coinfection were the only factors associated with spontaneous HCV clearance in this HIV-infected population.

Switch from Ritonavir-Boosted to Unboosted Atazanavir Guided by Therapeutic Drug Monitoring

Plasma concentration of atazanavir (ATV) may be reduced when coadministered with tenofovir (TDF) or proton pump inhibitors. Boosting ATV exposure with ritonavir (r) may make it possible to overcome these drug interactions. However, jaundice and loss of the metabolic advantages of ATV are more frequent using ATV/r than ATV alone. Herein, we assessed whether therapeutic drug monitoring (TDM) could make it possible to identify the subset of patients in whom removal of ritonavir could be attempted without risk of suboptimal plasma ATV exposure and subsequent virological failure. A total of 56 patients with undetectable plasma HIV-RNA under a stable triple regimen containing ATV 300/100 mg qd were switched to ATV 400 mg qd. Plasma ATV concentrations were measured using a reliable high-performance liquid chromatography method. Median plasma ATV C(min) fell from 880 to 283 ng/ml (p = 0.03) after removal of ritonavir. While all patients on ATV/r showed ATV plasma concentrations within therapeutic values (IC(min) above 150 ng/ml) before switching, four patients (7%) fell below this threshold after switching to ATV 400 mg qd. However, only one of this group experienced virological failure at week 24 of follow-up. TDF was part of the antiretroviral regimen in all four cases. From a total of 29 (52%) patients on ATV/r showing grade 3-4 hyperbilirubinemia, only 7 (12%) remained on it upon switching to ATV 400 mg qd (p < 0.001). Patients with complete viral suppression under ATV/r 300/100 mg qd may benefit from switching to ATV 400 mg qd guided by TDM, which may make it possible to minimize adverse events without compromising antiviral efficacy in most cases.

Serum homocysteine levels are increased in women with gestational diabetes mellitus

Serum homocysteine (sHcy) has been found to be elevated in patients with type 2 diabetes mellitus, as well as in other clinical conditions associated with insulin resistance and/or vascular diseases. The aims of this study were to measure the relationship between sHcy with biohumoral markers of insulin resistance in pregnant women affected with gestational diabetes mellitus (GDM). We studied 2 groups of pregnant women categorized, after a 100-g, 3-hour oral glucose tolerance test (OGTT) as nondiabetic (n = 78) or affected with GDM (n = 15), by measuring sHcy, serum folate, albumin, vitamin B(12), uric acid, and lipids. In both groups, peripheral insulin sensitivity was measured by using the OGTT-derived index of Matsuda and DeFronzo (ISI(OGTT)). Serum homocysteine was significantly higher in the group with GDM compared with nondiabetic women (5.88 +/- 2.26 micromol/L v 4.45 +/- 1.52 micromol/L; P =.003); was inversely related to serum folate (r = -.48; P =.0001), and was significantly related to serum albumin (r =.27; P =.009), 2-hour plasma glucose (r =.25; P =.01), as well as to serum uric acid (r =.23; P =.03). No relationship was observed between sHcy and serum vitamin B(12), serum triglycerides, total, or high-density lipoprotein (HDL) cholesterol, mean blood pressure and ISI(OGTT). Vitamin B(12) was correlated with ISI(OGTT) (r =.36; P =.0005) and inversely with mean blood pressure (r = -.24; P =.02). GDM remained significantly associated with higher sHcy concentrations also after adjusting for age, serum folate, albumin, uric acid, ISI(OGTT), and vitamin B(12) (P =.006). In conclusion, we found that sHcy is significantly increased in women with GDM, independently of other confounding variables, is significantly related to 2-hour OGTT plasma glucose, and seems unrelated to insulin resistance in these subjects.

Profile of Patients Triply Infected with HIV and the Hepatitis B and C Viruses in the HAART Era

HIV-HCV-HBV-coinfected patients were assessed to characterize the viral interactions in the setting of HIV coinfection and in the HAART era. All positive anti-HCV antibody and HBs antigen-positive HIV-infected patients were identified at five HIV clinics. Antihepatitis delta (HDV) antibody, serum HIV RNA, HCV RNA, and HBV DNA quantification and genotype determinations were performed. Out of 67 patients identified 47 (70%) were receiving anti-HBV therapy. HCV RNA and HBV DNA were detectable in 52.5% and 37% of patients, respectively. All possible patterns were found, regardless of anti-HBV therapy. HDV coinfection was associated with undetectable HCV RNA [RR 9.52 (95% CI 1.85-49.01); p = 0.007]. Independent factors predicting undetectable HBV DNA lacked HBeAg [RR 13.94 (95% CI 3.05-63.72); p = 0.001] and use of anti-HBV therapy [RR 11.42 (95% CI 2.43-53.54); p = 0.002]. Replication and genotypes of HCV or HBV had no impact on the replication of the other virus. In conclusion, in this cohort of triple infection (HBV/HCV/HIV) various viral patterns were identified. Spontaneous HCV clearance was frequent, and it was independently associated with HDV coinfection. In the absence of HBV therapy, HBV most often actively replicates. HBV/HCV replication or genotypes were not related to the replication of the other virus.