Pharmacokinetics of lopinavir determined with an ELISA test in youths with perinatally acquired HIV.

OBJECTIVE: To investigate the plasma levels of lopinavir by enzyme-linked immunosorbent assay (ELISA) in a cohort of patients who were vertically infected with human immunodeficiency virus 1 (HIV). METHODS: Plasma levels of lopinavir (Cmin) were determined by ELISA test in patients treated with lopinavir/ritonavir-based combined antiretroviral therapy who had achieved virological response after 4 wk of therapy. Reference lopinavir concentrations were Cmin 1-8 µg/mL. Correlation between lopinavir plasma concentration and continuous variables was evaluated by mean of Pearson correlation coefficient. Differences in lopinavir (LPV) concentration for binary categorical variables were assessed by Mann-Whitney test, while for variables with more than two categories Kruskal-Wallis test was used. RESULTS: Thirty-four patients were enrolled; median age was 133 mo (15-265). The median lopinavir dose tested was 383.5 mg/kg (IQR: 266.6-400 mg/kg), with a median plasma concentration of 8.8 µg/mL (IQR: 5-14 µg/mL). Lopinavir Cmin was <1 µg/mL in only one sample (2.9 %), while 14 samples had Cmin between 1 and 8 µg/mL (41.2 %) and 19 (55.9 %) > 8 µg/mL. No significant correlations were found between plasma concentrations of lopinavir and the continuous variables considered in the study. A negative but, not completely significant, correlation was found between plasma drug concentration and body mass index (r = -0.29; p = 0.09). CONCLUSIONS: The use of a simple and relatively cost-effective methodology might render therapeutic drug monitoring (TDM) appeal in the daily clinical practice.

Inflammation markers correlate with common carotid intima-media thickness in patients perinatally infected with human immunodeficiency virus 1.

OBJECTIVES: To investigate common carotid intima-media thickness in a cohort of patients who were vertically infected with human immunodeficiency virus 1 (HIV-1). METHODS: We conducted a cross-sectional observational study. Human immunodeficiency virus 1-infected patients were compared with age-, sex-, and body mass index-matched healthy participants. Common carotid intima-media thickness was measured in all participants on both sides of the neck, and the mean intima-media thickness was calculated. Metabolic parameters and markers of inflammation were measured only in HIV-1-infected patients. Statistical analysis was performed by multiple regression and by a matrix of Pearson correlation coefficients. The Student t test was used to compare mean common carotid intima-media thickness values between groups. RESULTS: Forty patients (21 female) with HIV-1 infection acquired from birth with a mean age ± SD of 16.3 ± 4.7 years and 27 healthy participants (11 female) with a mean age of 17.7 ± 4.6 years were included in the study. Mean common carotid intima-media thickness in the HIV-1-infected group (0.450 ± 0.088 mm) was significantly higher (P < .05) than in the control group (0.407 ± 0.079 mm). No significant association was found between intima-media thickness and a specific antiretroviral regimen, exposure to combined antiretroviral agents, and HIV status. In multiple regression analyses, higher levels of insulin (P= .007) and elevated levels of glycated hemoglobin (P= .01) were associated with intima-media thickness changes. CONCLUSIONS: Patients perinatally infected with HIV have increased common carotid intima-media thickness compared with healthy individuals. These changes were more pronounced with increasing age and inflammation markers. Interventions that improve cardiovascular risk profiles should be considered in HIV-infected young adults.

Effects of hepatitis C virus infection on the pharmacokinetics of ritonavir-boosted atazanavir in HIV-1-infected patients.

Most antiretrovirals are metabolized in the liver, and overexposure could be more common in human immunodeficiency virus (HIV)-infected patients with hepatic impairment. Careful monitoring of potential drug-related liver injury in clinical practice is necessary. The aim of our study was to analyze the trough concentrations (C (trough)) of atazanavir (ATV) in the plasma of HIV/hepatitis C virus (HCV)-co-infected patients and to compare the values with those of a HIV-infected control population. C (trough) values (22-26 h after last intake) of atazanavir, following the administration of atazanavir/ritonavir 300/100 mg once daily as part of antiretroviral therapy, were assessed by HPLC. We also collected data on dosing of atazanavir, and on demographic (age, gender, and ethnicity), physiological (weight and body mass index), and clinical parameters (CD4+ cell count, HIV-RNA viremia, co-medication, and hepatitis C co-infection). A total of 28 Caucasian HIV-infected adults were studied, of whom 13 were HIV/HCV co-infected. No baseline characteristics differed between the two cohorts, except statistically significant differences regarding ALT, AST, and total bilirubin. The median (range) plasma ATV C (trough) levels were 0.62 (0.05-3.22) µg/ml in HIV patients and 0.32 (0.04-3.37) µg/ml in HIV/HCV patients. Thus, there was no significant difference in plasma trough levels of atazanavir in the two cohorts. In our patients with mild impairment of hepatic function caused by HCV infection, atazanavir C (trough) was comparable in HIV-infected and HIV/HCV-co-infected patients.

Antiretroviral use in Italian children with perinatal HIV infection over a 14-year period.

BACKGROUND: Information on the use of new antiretroviral drugs in children in the real setting of clinical fields is largely unknown. METHODS: Data from 2554 combined antiretroviral therapy (cART) regimens administered to 911 children enrolled in the Italian Register for HIV infection in children, between 1996 and 2009, were analysed. Factors potentially associated with undetectable viral load and immunological response to cART were explored by Cox regression analysis. RESULTS: Proportion of protease inhibitor (PI)-based regimens significantly decreased from 88.0% to 51.2% and 54.9%, while proportion on non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens increased from 4.5% to 38.8% and 40.2% in 1996-1999, 2000-2004 and 2005-2009, respectively (p < 0.0001). Significant change in the use of each antiretroviral drug occurred over the time periods (p < 0.0001). Factors independently associated with virological and immunological success were as follows: later calendar periods, younger age at regimen (only for virological success) and higher CD4(+) T-lymphocyte percentage at baseline. Use of unboosted PI was associated with lower adjusted hazard ratio (aHR) of virological or immunological success with respect to NNRTI- and boosted PI-based regimens, with no difference among these two latter types. CONCLUSION: Use of new generation antiretroviral drugs in Italian HIV-infected children is increasing. No different viro-immunological outcomes between NNRTI- and boosted PI-based cART were observed.

HIV and accelerated atheroprogression: role of antiretroviral therapy.

The introduction of effective and potent treatments for human immunodeficiency virus (HIV) infection resulted in prolonged survival and better quality of life of HIV-infected patients. However, the longer survival and the anti-HIV medication side effects caused the emergence of new clinical issues, such as the increase in cardiovascular risk, favored by multiple factors, partly related to HIV infection itself, partly to the anti-HIV molecules. HIV infection itself may affect cardiovascular risk through chronic inflammation induced by uncontrolled viral replication, whereas long-term antiretroviral therapy may increase the cardiovascular risk through several mechanisms. Thus, due to the multiple and conflicting causes of cardiovascular disorders in HIV-infected patients, clinicians should take into consideration all modifiable risk factors, in order to implement an effective prevention of this clinical issue.

Patient-reported outcomes and low-level residual HIV-RNA in adolescents perinatally infected with HIV-1 after switching to one-pill fixed-dose regimen.

The choice of an antiretroviral regimen can often impact on adherence, treatment satisfaction and therefore influence on clinical outcome. These concerns are particularly true in adolescents. In this setting, adherence is usually affected by multifactor events and biopsychosocial factors, which connect and changeover time. We evaluated the effect of a switch to a single-pill fixed-dose regimen on patient-reported outcomes, virologic and immunologic outcomes, and safety in a cohort of adolescents with perinatal HIV-1 infection. In addition, we evaluated the effect on low-level residual HIV-RNA. An open-label, non-randomised study was performed: 12 adolescents with a confirmed viremia <50 copies/mL treated with lamivudine or emtricitabine, tenofovir and efavirenz were switched to one-pill fixed-dose regimen of emtricitabine/tenofovir/efavirenz. At the end of follow-up, the new regimen was associated with improvements in treatment satisfaction, HIV-symptoms, whereas adherence remained high. No immunological or virological significative changes were observed. No side-effects were registered. Moreover, the low-level residual HIV-RNA was <3 copie/mL in all patients. One-pill fixed-dose regimen is an added value that favours adherence, reduces HIV-symptoms, improves patients' satisfaction and could better control of HIV-RNA in adolescents, too.

Pharmacokinetics and short-term safety and tolerability of etravirine in treatment-experienced HIV-1-infected children and adolescents.

OBJECTIVES: To evaluate the pharmacokinetics, weight-based dose selection and short-term safety and tolerability of etravirine in HIV-1-infected children and adolescents. DESIGN: Phase I, nonrandomized, open-label study in two stages. METHODS: Children and adolescents aged at least 6 years to 17 years or less on a stable lopinavir/ritonavir-based antiretroviral regimen with HIV-1 RNA plasma viral load less than 50 copies/ml were enrolled. In both stages, etravirine (4 mg/kg twice daily in stage I, 5.2 mg/kg twice daily in stage II), added to the existing antiretroviral regimen, was administered for 7 days followed by a morning dose and 12-h pharmacokinetic assessment on day 8. Pharmacokinetic parameters were determined using noncompartmental analysis. Data were compared with those previously established in HIV-1-infected adults on a similar etravirine (200 mg twice daily) combination antiretroviral regimen. RESULTS: Twenty-one patients were recruited to each stage; 19 and 20 had evaluable pharmacokinetics in stages I and II, respectively. Mean (SD) maximum plasma concentrations in stages I and II were 495 (453) and 757 ng/ml (680), respectively; area under the plasma concentration-time curve over 12 h was 4050 (3602) and 6141 ng h/ml (5586), respectively. Statistical/qualitative comparisons showed comparable exposures with adults in stage II; however, the upper 90% confidence interval fell outside the predefined range. Plasma viral load remained undetectable on day 8 in all patients, and etravirine was well tolerated at both doses. CONCLUSION: Etravirine 5.2 mg/kg was well tolerated in this study and this dose was selected for further investigation in clinical trials.

Nevirapine-based regimens in routine clinical settings: results from a large Italian cohort of HIV-1 infected adults.

UNLABELLED: We assessed the safety and efficacy of different nevirapine-based regimens in patients starting this drug in a large cohort of Caucasian subjects during the 1999-2007 periods. METHODS: A retrospective database review of all patients receiving nevirapine was performed; clinical, biochemical (hepatic and metabolic profiles), immuno-virological parameters were evaluated in the overall population and in different subgroups (according to gender, therapy-experience and HBV/HCV co-infection). We determined risk factors related to dyslipidemia development and to nevirapine interruption within 1 year. RESULTS: We evaluated 277 patients; 58 (20.9%) were naïve, 180 (65%) females and 137 (49.5%) HBV/HCV co-infected. After 48 weeks, 73.6% patients continued antiretroviral regimens. Among these, nevirapine showed little hepatic and metabolic impact, as well as good immuno-virological outcome despite sex, drug experience and co-infection. Factors related to development of dyslipidemia were higher in total cholesterol, female gender with high CD4 count and male gender with low CD4 count (p<0.05). Factors related to discontinue nevirapine were age and HBV/HCV co-infection (p<0.05). CONCLUSIONS: We observed a high rate of discontinuation probably because of the special composition of our population (huge proportion of women and co-infected individuals). Nevertheless, nevirapine was a well-tolerated drug with a favorable impact on hepatic, metabolic and immuno-virological parameters in all the analyzed subgroups.

Lamivudine resistance mutations in European patients with hepatitis B and patients co-infected with HIV and hepatitis B.

Evaluation of resistance pattern in patients with chronic hepatitis B. Retrospective study of hepatitis B virus (HBV) resistance mutations in patients found viraemic after first-line treatment. HBV viral load was determined by a real-time polymerase chain reaction and the substitutions in HBV-DNA were studied by polymerase sequencing test. First line treatment had failed in 12 out of 33 patients (36%) receiving anti-HBV drugs. The 12 patients with persistent viraemia were all lamivudine (LAM) experienced and 7 had a polymerase sequencing test available. LAM substitution mutations L180M + M204V/I were found in six out of seven cases, with an accompanying V173L mutation in three cases. These mutations were also related with changes in HBsAg. The use of potent drugs in the first line anti-HBV therapy may reduce the resistance mutations in the future.

Osteonecrosis in human immunodeficiency virus (HIV)-infected patients: a multicentric case-control study.

Osteonecrosis (ON) is a rare disabling complication occurring in patients with human immunodeficiency virus (HIV) infection at a higher frequency than in the general population despite effective combination antiretroviral therapy being made available, as recently documented by several retrospective studies. We designed a multicentric case-control study among HIV-infected patients cared for at institutions in the Italian CISAI group (Italian Study Group for Adverse Events in HIV Infection) to search for additional predictors of ON in this special population. All centers which observed at least one case of ON were requested to report data for central re-evaluation. Parallel HIV-positive, ON-free controls were randomly selected and matched with confirmed cases of ON for sex, age and CD4 T-cell counts at the time of HIV diagnosis. Fifteen cases and controls were included in the final sample. Univariate statistical analyses revealed a significant association between ON and exposure to steroids (P = 0.001), exposure to one or more drugs in addition to HAART (Highly Active Anti-Retroviral Therapy) (P = 0.03), high titers of total serum IgE (P = 0.02), loss of working ability (P = 0.03), triglycerides levels over 200 mg/dL before antiretrovirals (P = 0.03) and cholesterol levels over 200 mg/dL before and after antiretrovirals (P = 0.03 and 0.05, respectively). High serum IgE levels and loss of working ability in advance of ON appeared for the first time as possible predictors of ON in HIV patients, while long-term exposure to steroids, combined hyperlipemia and chronic treatment with other drugs in addition to antiretrovirals were confirmed. Predicting and preventing ON in the individual HIV-infected patient is therefore a clinically challenging opportunity.

Safety and efficacy of pegylated interferon and ribavirin in adolescents with human immunodeficiency virus and hepatitis C virus acquired perinatally.

Limited evidence is available currently regarding the efficacy and safety of pegylated interferon (PEG-IFN) and ribavirin in patients co-infected perinatally with human immunodeficiency virus (HIV) and hepatitis C virus (HCV). No information is available on whether or not these patients should be treated earlier for infection with HCV. This report describes four patients with HIV and HCV co-infection acquired perinatally, who were treated with PEG-IFN and ribavirin for chronic viral hepatitis caused by HCV.

Whole body bone scintigraphy in tenofovir-related osteomalacia: a case report.

INTRODUCTION: Tenofovir disoproxil fumarate (Viread((R))) is the only nucleotide reverse transcriptase inhibitor currently approved for the treatment of HIV. It is frequently prescribed not only for its efficacy but also for its decreased side effect profile compared with other nucleotide analogs. In addition, it is now increasingly recognized as a cause of acquired Fanconi's syndrome in individuals with HIV. CASE PRESENTATION: We describe a 48-year-old woman infected with HIV, with chronic renal insufficiency, who developed Fanconi's syndrome after inclusion of tenofovir disoproxil fumarate in her antiretroviral therapy. A whole body bone scintigraphy was performed, revealing an abnormal distribution of radiotracer uptake, with characteristic changes compatible with osteomalacia. All symptoms disappeared after tenofovir discontinuation and mineral supplementation. No other explanation for the sudden and complete resolution of the bone disease was found. CONCLUSION: The case highlights the role of whole body bone scintigraphy in the diagnosis of tenofovir-related osteomalacia.

Five-year follow-up of children with perinatal HIV-1 infection receiving early highly active antiretroviral therapy.

BACKGROUND: Early highly active antiretroviral therapy (HAART), started within the first months of age, has been proven to be the optimal strategy to prevent immunological and clinical deterioration in perinatally HIV-infected children. Nevertheless, data about long-term follow-up of early treated children are lacking. METHODS: We report data from 40 perinatally HIV-infected-children receiving early HAART, with a median follow-up period of 5.96 years (interquartile range [IQR]:4.21-7.62). Children were enrolled at birth in the Italian Register for HIV Infection in Children. Comparison with 91 infected children born in the same period, followed-up from birth, and receiving deferred treatment was also provided. RESULTS: Nineteen children (47.5%) were still receiving their first HAART regimen at last follow-up. In the remaining children the first regimen was discontinued, after a median period of 3.77 years (IQR: 1.71-5.71) because of viral failure (8 cases), liver toxicity (1 case), structured therapy interruption (3 cases), or simplification/switch to a PI-sparing regimen (9 cases). Thirty-nine (97.5%) children showed CD4+ T-lymphocyte values>25%, and undetectable viral load was reached in 31 (77.5%) children at last visit. Early treated children displayed significantly lower viral load than not-early treated children, until 6 years of age, and higher median CD4+ T-lymphocyte percentages until 4 years of age. Twenty-seven (29.7%) not-early treated vs. 0/40 early treated children were in clinical category C at last follow-up (P < 0.0001). CONCLUSION: Our findings suggest that clinical, virologic and immunological advantages from early-HAART are long-lasting. Recommendations indicating the long-term management of early treated children are needed.

Efficacy and safety of darunavir and etravirine in an antiretroviral multi-experienced youth with vertically HIV-1 infection.

Multiclass-drug resistance, often caused by poor treatment compliance, is a challenging problem in all categories of HIV-infected patients. Selective pressure is higher in youth for both biological and behavioral reasons. We report the case of a 15-year-old Caucasian male, with vertically acquired HIV-1 infection, who failed several lines of antiretroviral therapy and was successfully treated with darunavir/ritonavir and etravirine.

Infectious complications of cancer chemotherapy in HIV patients.

The outcome for HIV-infected patients with cancer has dramatically improved in the highly active antiretroviral therapy (HAART) era, probably due to improvements in immune status and bone marrow function that allow the possibility of increased drug-dose intensity with a higher complete remission rate. Although data regarding the optimal management of these cancers are lacking, current studies suggest that patients with HIV-associated malignancies could be treated using approaches similar to those for their counterparts in the general population (ie, with chemotherapy, radiation, and appropriate use of supportive measures). In the HAART era, the AIDS-related mortality rate has decreased by approximately 70%, and so the cause of the growing number of reports of cancers in HIV patients is unclear. Clearly, non-AIDS-defining malignancies account for more morbidity and mortality than AIDS-defining malignancies. Prevention strategies are needed to adequately deal with HIV-associated cancers in an aging and growing HIV-positive population.