Judit Morello

Usefulness of monitoring ribavirin plasma concentrations to improve treatment response in patients with chronic hepatitis C

Ribavirin in combination with pegylated interferon alpha is the current standard treatment for chronic hepatitis C. Adequate exposure to ribavirin seems crucial for achieving the best virological response. However, anaemia is a frequent, dose-dependent limiting side effect of ribavirin use. Therefore, therapeutic drug monitoring of ribavirin plasma concentrations could be a useful tool for individualizing ribavirin dosing. Herein, we review the relationship between ribavirin plasma concentrations and both virological response and toxicity, in order to define an optimal therapeutic range for ribavirin.

Raltegravir and etravirine are active against HIV type 1 group O.

Abstract The activity of raltegravir and etravirine was assessed in vitro in HIV-1 group O isolates. Despite the presence of some natural polymorphisms associated with resistance to raltegravir (V72I, L74I, S153A, V201I, and T206S) and etravirine (G190A), both drugs showed significant antiviral activity. Subsequently, the clinical benefit was shown in an HIV-1 group O-infected individual in whom enfuvirtide was replaced by raltegravir. Therefore, individuals infected with HIV-1 group O might benefit from raltegravir and/or etravirine therapy.

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.

Trends in the prescription of antiretroviral drugs and impact on plasma HIV-RNA measurements

BACKGROUND The choice of antiretroviral drugs has evolved over the last decade. Recognition of trends and determinants of changes may help to make predictions on prescription patterns. METHODS Longitudinal analyses were performed every 6 months from 1996 to 2006, of all HIV-infected individuals who attended at one HIV/AIDS referral centre located in Madrid, Spain. RESULTS A total of 2602 different individuals attending during the study period were examined over 23 consecutive time-points. The number and proportion of patients under antiretroviral therapy significantly increased in the period 1996-99, with a plateau since then around 1100 patients, which represented around two-thirds of the patients seen at each time-point after the year 2000. The proportion of patients under antiretroviral therapy having undetectable viraemia significantly increased from 34.5% in 1996 to 80% in 2006. The relative use of nucleoside reverse transcriptase inhibitors (NRTIs) and protease inhibitors (PIs) has risen in recent years, while prescription of non-nucleoside reverse transcriptase inhibitors has declined compared with the period 1999-2001, when it peaked. Among NRTIs, the use of zalcitabine, stavudine and didanosine has dramatically declined or vanished, while zidovudine, lamivudine, abacavir and tenofovir have gained relevance. Among PIs, indinavir and nelfinavir have almost disappeared, being replaced by ritonavir-boosted PIs, mainly atazanavir and lopinavir. After its first introduction in the year 1999, efavirenz has been generally preferred over nevirapine. CONCLUSIONS The choice of antiretroviral drugs has evolved during the last decade, with safety and convenience issues driving most changes in prescription patterns, while antiviral success has dramatically increased.

Increase in serum bilirubin in HIV/hepatitis-C virus-coinfected patients on atazanavir therapy following initiation of pegylated-interferon and ribavirin.

Atazanavir use is associated with increases in serum bilirubin. Ribavirin, used to treat hepatitis-C infection, cause hemolysis and may worsen hyperbilirubinemia. We studied HIV/hepatitis-C virus-coinfected patients who initiated hepatitis-C therapy. Hyperbilirubinemia grade 3–4 increased from 9% to 45% after the start of hepatitis-C treatment in patients who used atazanavir concomitantly. Atazanavir use and hemoglobin (Hb) drops were predictors of increases in bilirubin. A substantial proportion of patients under atazanavir-therapy experienced significant hyperbilirubinemia and jaundice following initiation of hepatitis-C therapy.

RETRACTED ARTICLE: Simplification From Protease Inhibitors to Once- or Twice-Daily Raltegravir: The ODIS Trial

Abstract This article has been removed from the archive because of a court ruling, pending a final verdict.

Approaches for understanding and predicting drug interactions in human immunodeficiency virus-infected patients

Introduction: Knowledge of drug interactions is vital to maximize antiretroviral efficacy and avoid drug-related toxicities. Treatment of co-morbidities has become a difficult task in HIV-infected individuals because pharmacokinetic and/or pharmacodynamic interactions are common when other medications are prescribed along with antiretroviral agents. Areas covered: This article provides an update of the most relevant drug interactions that occur between antiretroviral agents and other drugs. The article additionally revisits how these drug interactions can be prevented from occurring as well as how they can be managed. Expert opinion: Interactions between antiretrovirals and other drugs are frequent in clinical practice. The most common are those affecting drug metabolism due to induction or inhibition of the CYP450, leading to abnormal drug exposure. It is by this mechanism that most HIV protease inhibitors, non-nucleoside reverse transcriptase inhibitors and maraviroc often interact with other medications. In contrast, nucleoside reverse transcriptase inhibitors and some integrase inhibitors, which do not or only marginally affect CYP450, are relatively free of significant pharmacokinetic interactions, although nucleoside analogs might be involved in some pharmacodynamic interactions.

Noncirrhotic portal hypertension in HIV infection

Purpose of review Liver disease in the HAART era is one of the leading causes of morbidity and mortality in HIV-infected individuals in Western countries. Even if the majority of cases rely on identifiable causes (viral hepatitis, steatohepatitis, alcohol abuse, drug toxicity, etc.), the cause of liver abnormalities remains unknown for a subset of patients, some of whom present with noncirrhotic portal hypertension (NCPH). Recent findings In 2006, the first reports of NCPH in HIV-infected patients attracted special attention. Typically, individuals unaware of any underlying liver illness presented with variceal bleeding, occasionally fatal. Interestingly, severe portal hypertension occurred in the absence of liver function impairment in most cases. Liver biopsy revealed a distinctive histological feature characterized by massive absence of portal veins along with focal obliteration of small portal veins. After extensive ruling out of other causes, the role of antiretroviral toxicity (particularly didanosine exposure) emerged as the major contributor to this condition. Other potential factors could be an enhanced microbial translocation from the gut and prothrombotic conditions. Summary NCPH is an uncommon condition, although increasingly being reported in HIV-infected individuals. It generally presents as a clinical episode of decompensated portal hypertension, generally with gastrointestinal bleeding. Long-lasting HIV infection and prolonged antiretroviral exposure are universally recognized in these patients. The involvement of didanosine has been highlighted in most series. Removal of this drug and prevention of variceal bleeding episodes are currently the most effective prophylactic and therapeutic interventions.

Rate and predictors of success in the retreatment of chronic hepatitis C virus in HIV/hepatitis C Virus coinfected patients with prior nonresponse or relapse.

Background:In hepatitis C virus (HCV)/HIV-coinfected patients who failed a course of suboptimal hepatitis C therapy, retreatment with adequate doses and duration of pegylated interferon (pegIFN) plus ribavirin (RBV) is advisable in the presence of compensated advanced liver fibrosis. Methods:The efficacy and safety of pegIFN-α2a (180 μg/wk) plus RBV (<75 kg: 1000 mg/d; ≥75 kg: 1200 mg/d) given for 12 months was prospectively assessed in HIV/HCV patients with nonresponse or relapse to a prior course of suboptimal hepatitis C therapy. The main endpoint was the achievement of sustained virological response (SVR). Results:A total of 52 patients were enrolled in the study (78% HCV genotypes 1 or 4; 56% with advanced liver fibrosis). Prior suboptimal regimens were IFN monotherapy (20%), IFN plus RBV (29%), and pegIFN plus RBV 800 mg/d (51%). Overall, 61% were nonresponders and 39% relapsers. Retreatment provided SVR in 30.8% of patients (19.5% for genotypes 1/4 vs. 72.7% for genotypes 2/3; P = 0.002). In multivariate analysis, HCV genotypes 2/3 [OR 22.2, 95% confidence interval (CI), 2.9-166.7, P = 0.003] and RBV plasma trough concentrations at week 4 [OR 3.9 (95% CI, 1.3-11.8), P = 0.01] were the only independent predictors of SVR. Conclusions:Retreatment with pegIFN-α2a plus weight-based RBV for 12 months permits to achieve HCV clearance in nearly one-third of HIV/HCV-coinfected patients who failed a prior suboptimal course of hepatitis C therapy. Patients with HCV genotypes 2/3 and those with RBV plasma trough levels above 2.07 μg/mL show the highest chances of SVR.

Measurement of Ribavirin Plasma Concentrations by High-performance Liquid Chromatography Using a Novel Solid-phase Extraction Method in Patients Treated for Chronic Hepatitis C

Ribavirin (RBV) in combination with pegylated interferon is the current standard treatment for chronic hepatitis C. Exposure to RBV seems crucial for achieving the best virologic response. However, RBV may cause anemia in a dose-dependent manner. Therefore, monitoring RBV plasma levels could be useful for individual tailoring of RBV dosing. A rapid assay was developed to quantify RBV using high-performance liquid chromatography and ultraviolet detection. Extraction of RBV from plasma was performed using a novel method based on ultrafiltration in one step that allows direct injection into the high-performance liquid chromatography without any prior steps of dryness or reconstitution. The method was validated over the range of 0.05 to 5.0 μg/mL following the EMEA Validation of Analytical Procedures (CPMP/ICH/281/95) recommendations. The clinical interest of this assay was evaluated in a subset of patients under RBV therapy. Mean RBV plasma concentrations at steady state were higher in responders compared with nonresponders (3-3.2 μg/mL versus 2.2-2.3 μg/mL).