Therapy-naive Patients Research Articles

P-055: The natural history of pediatric IBD according to the Paris classification

P-055: The natural history of pediatric IBD according to the Paris classification

P-056: Buccal epithelial cell chemokine release as a biomarker for clinical response to therapy in inflammatory bowel disease

P-056: Buccal epithelial cell chemokine release as a biomarker for clinical response to therapy in inflammatory bowel disease

CYP2B6 genotype, but not rifampicin-based anti-TB cotreatments, explains variability in long-term efavirenz plasma exposure.

We investigated the effects of rifampicin-based anti-TB treatment on plasma efavirenz exposure and the implications of CYP2B6 genotype. Antiretroviral therapy-naive Ugandan HIV patients without (n = 157) or with TB coinfection (n = 106) were enrolled and treated with efavirenz-based highly active antiretroviral therapy alone or with rifampicin-based anti-TB therapy, respectively. Efavirenz plasma concentration was determined on day 3 and weeks 1, 2, 8, 12, 16, 20, 24, 28 and 32. Rifampicin-based anti-TB cotreatment reduced plasma efavirenz exposure during the first 2 weeks (p < 0.05), but no significant effect was observed afterwards. Although not significant, rifampicin-based anti-TB cotreatment inconsistently increased efavirenz exposure over time, which was reduced immediately after completing anti-TB therapy. CYP2B6*6, *11 and ABCB1 c.4036A>G genotypes were significant predictors of efavirenz plasma exposure. Plasma efavirenz exposure is mainly influenced by CYP2B6 genotype, but not by rifampicin cotreatment. Therefore, no efavirenz dosage adjustment during rifampicin cotreatment is required in Ugandans.

Trans-conjunctival aqueous humor outflow in glaucomatous patients treated with prostaglandin analogues: an in vivo confocal microscopy study.

To analyze, using in vivo laser scanning confocal microscopy (LSCM), the conjunctival features in glaucomatous patients receiving prostaglandin analogues (PGA). Eighty eyes of 80 consecutive glaucomatous patients naive for therapy were enrolled; 30 eyes of 30 healthy subjects served as a control. Patients were randomized to: preservative-free (PF) and preserved latanoprost (groups 1 and 2, respectively), PF and preserved timolol (groups 3 and 4), and controls to vehicle of latanoprost or physiological buffered saline solution (groups 5 and 6). All subjects underwent LSCM of bulbar conjunctiva at baseline and 3 months after initiating therapy. The main outcomes were: mean density (MMD: cysts/mm(2)) and mean area (MMA: cysts/mm(2)) of epithelial microcysts. The relations between MMA and MMD with intraocular pressure (IOP), age, and mean defect (MD), were analyzed. At baseline, microcysts were found in all subjects. At month three, MMD did not change in all groups (p > 0.05). MMA significantly increased only in group 1 from 2,158.81 ± 524.09 to 3,877.77 ± 867.31, and in group 2 from 2,019.71 ± 541.03 to 5,560.39 ± 1,176.14, with values significantly higher in group 2 (p < 0.001). Significant relations were not found between MMD and MMA with IOP, MD, and age (p > 0.05). PGA increased MMA in therapy-naive glaucomatous patients, indicating a possible enhancement of the trans-conjunctival aqueous humor outflow. Therefore, conjunctiva seems an additional target tissue to evaluate the hydrodynamic pathways in glaucoma and modifications induced by medical therapy.

Tiotropium in patients with moderate COPD naive to maintenance therapy: a randomised placebo-controlled trial.

Background:The benefits of pharmacotherapy with tiotropium HandiHaler 18 μg for patients with chronic obstructive pulmonary disease (COPD) have been previously demonstrated. However, few data exist regarding the treatment of moderate disease (Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage II).Aims:To determine whether tiotropium improves lung function/patient-reported outcomes in patients with GOLD stage II COPD naive to maintenance therapy.Methods:A randomised 24-week double-blind placebo-controlled trial of tiotropium 18 μg once daily (via HandiHaler) was performed in maintenance therapy–naive patients with forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio <0.7 and post-bronchodilator FEV1 ⩾50 and <80%.Results:A total of 457 patients were randomised (238 tiotropium, 219 placebo; mean age 62 years; FEV1 1.93 l (66% predicted)). Tiotropium was superior to placebo in mean change from baseline in post-dose FEV1 area under the curve from 0 to 3 h (AUC0–3h) at week 24 (primary endpoint): 0.19 vs. −0.03 l (least-squares mean difference 0.23 l, P<0.001). FVC AUC0–3h, trough and peak FEV1 and FVC were significantly improved with tiotropium versus placebo (P<0.001). Compared with placebo, tiotropium provided numerical improvements in physical activity (P=NS). Physician’s Global Assessment (health status) improved (P=0.045) with less impairment on the Work Productivity and Activity Impairment questionnaire (P=0.043) at week 24. The incidence of exacerbations, cough, bronchitis and dyspnoea was lower with tiotropium than placebo.Conclusions:Tiotropium improved lung function and patient-reported outcomes in maintenance therapy–naive patients with GOLD stage II COPD, suggesting benefits in initiating maintenance therapy early.

The characteristics of the HIV subtype B epidemic in Slovenia

Slovenia is a small Central European country with a relatively modest burden of HIV disease, with fewer than 1 per 1,000 inhabitants infected. The HIV epidemic mostly affects men who have sex with men (MSM), with subtype B as the most represented subtype in over 85% of patients. The aim of this study was to establish the properties of the subtype B HIV epidemic in Slovenia up to the end of 2012. For the purpose of this study, data and sequences were gathered from 3 previous studies conducted in Slovenia examining the prevalence of transmitted drug resistance among therapy naive HIV-1 positive patients diagnosed in the years 2000-2012. Only subtype B sequences were selected for this study (determined by the REGA HIV-1 Subtyping tool, v2.0), a total of 223 partial pol gene sequences were included, representing 52% of all patients newly diagnosed in 13 years. The maximum likelihood (ML) phylogenetic tree was constructed using PhyML 3.0 and transmission clusters were identified according to the approximate likelihood ratio test branch support values (>0.90). The Monte Carlo Markov chain method available in the BEAST package v1.7.1 was employed, using a relaxed clock model with uncorrelated lognormal distribution and the Bayesian skyline coalescent model. The clusters previously identified in the ML analysis were reviewed and confirmed according to posterior probability values (>0.990). Combined analysis (ML and Bayesian analysis) revealed 8 major clusters (n≥10 patients), 1 group of 4 patients, 2 trios and 12 transmission pairs. Among 223 included individuals, 146 (65.5%) patients belonged to large transmission clusters comprising 10 or more individuals and 34 (15.2%) patients to small clusters of 2-4 patients, leaving only 43 (19.3%) of the Slovenian patients infected with subtype B without an epidemiological link observed by phylogenetic inference. Statistical analysis examining the characteristics of patients found in large clusters revealed significantly fewer patients in a cluster diagnosed prior to 2005 (p=0.0388) and significantly more patients reported Slovenia as the country in which the infection occurred (p<0.0001) compared to other countries. In conclusion, several introductions of HIV subtype B occurred in Slovenia. The majority of patients were found with a transmission link, exhibiting a closed HIV community, with the virus being transmitted predominantly between individuals within Slovenia.

HIV-1 Coreceptor Tropism in India

Recent studies show an increase in the frequency of X4-tropism in African HIV-1 subtype C (HIV-1C) strains and among Indian children with a longer duration of infection. There is limited availability of comprehensive data on HIV-1 tropism in Indian HIV-1C strains and impact on coreceptor antagonist drug susceptibility. We evaluated coreceptor tropism trends over 2 decades and maraviroc resistance-associated V3 loop substitutions among the Indian HIV-1C strains. We performed genotypic tropism testing using Geno2Pheno10% on primary samples from patients (n = 224) and on Indian HIV-1C sequences downloaded from the Los Alamos database (n = 528, 1991-2010). We also studied maraviroc resistance-associated substitutions in R5-tropic HIV-1C (n = 992) and subtype B sequences (n = 576). Among primary samples, 88% belonged to HIV-1C and 11.2% was predicted as X4-tropic, with higher prevalence noted among patients from north-eastern India (19.1%) and significant association with intravenous drug users (P = 0.04). X4-tropism prevalence was higher among antiretroviral therapy-experienced (18.8%) compared with antiretroviral therapy-naive patients (9.1%). Indian database HIV-1C sequences showed X4-tropism at 4%. An increase in the X4 tropism frequency was seen over the years 1991 (1.6%) through 2012 (10%). We found a high frequency of 19T substitution (826/992; 83.3%) among HIV-1C V3 loop compared with subtype B. The predominance of R5-tropism in Indian HIV-1C strains despite a marginal temporal increase in X4-tropism prevalence highlights the likely effectiveness of coreceptor antagonists in India. Our frequent observation of common maraviroc resistance-associated substitutions among Indian R5-tropic HIV-1C raises the possibility that they may be natural polymorphisms, indicating the need for further elucidation.

Quasispecies tropism and compartmentalization in gut and peripheral blood during early and chronic phases of HIV-1 infection: possible correlation with immune activation markers

HIV quasispecies was analysed in plasma and proviral genomes hosted by duodenal mucosa and peripheral blood cells (PBMC) from patients with early or chronic infection, with respect to viral heterogeneity, tropism compartmentalization and extent of immune activation. Seventeen HIV-1-infected combined antiretroviral therapy naive patients were enrolled (11 early infection and six chronic infection). V3 and nef genomic regions were analysed by ultra-deep pyrosequencing. Sequences were used to infer co-receptor usage and to construct phylogenetic trees. As markers of immune activation, plasma sCD14 and soluble tumour necrosis factor receptor II (sTNFRII) levels were measured. Median diversity of HIV RNA was lower in patients with early infection versus chronic infection patients. Overall, direct correlation was observed between V3 diversity and X4 frequency; V3 diversity of HIV RNA was inversely correlated with CD4 T-cell count; median sCD14 and sTNFRII values were similar in early and chronic patients, but X4 frequency of HIV RNA was directly correlated with plasma sCD14. The proportion of patients harbouring X4 variants and median intra-patient X4 frequency of proviral genomes tended to be higher in chronic infection than early infection patients. More pronounced compartmentalization of proviral quasispecies in gut compared with PBMC samples was observed in patients with early infection compared with chronic patients. The loss of gut/PBMC compartmentalization in more advanced stages of HIV infection was confirmed by longitudinal observation. More studies are needed to understand the pathogenetic significance of early HIV quasispecies compartmentalization and progressive intermixing of viral variants in subsequent phases of the infection, as well as the role of immune activation in tropism switch.

Opportunistic Diseases in HIV-Infected Patients in Gabon following the Administration of Highly Active Antiretroviral Therapy: A Retrospective Study

Opportunistic diseases cause substantial morbidity and mortality to human immunodeficiency virus (HIV)-infected patients. Highly active antiretroviral therapy (HAART) leading to immune reconstitution is the most effective treatment of preventing opportunistic diseases. This retrospective study established an epidemiologic profile of opportunistic diseases 10 years after the introduction of HAART. The HIV antiretroviral therapy-naive patients matching inclusion criteria were included. The primary outcome was the prevalence of opportunistic diseases. From January 1, 2002 to September 30, 2010, 654 opportunistic diseases were identified in 458 patients. Pulmonary tuberculosis, herpes zoster, cerebral toxoplasmosis, oral candidiasis, and severe pneumonia accounted for 22.05%, 15.94%, 14.19%, 14.19%, and 9.39%, respectively. Cryptococcal meningitis and pneumocystosis accounted for 0.44% and 0.21%, respectively. The prevalence of opportunistic diseases in Gabon remains high. New guidelines emphasize the importance of initiating antiretroviral therapy early to reconstitute the immune system, and reduce disease risk, and treat the primary opportunistic infection of pulmonary tuberculosis.

Hepatocyte expression of TRAIL pathway regulators correlates with histopathological and clinical parameters in chronic HCV infection

Background and aimsTreatment with pegylated interferon-alpha (PEG-IFN) and ribavirin is the backbone of standard therapy of HCV by mechanisms that are not completely understood. Besides a direct antiviral effect, different immunomodulatory and apoptotic effects have been discussed. Tumor necrosis factor-related apoptosis inducing-ligand (TRAIL) is a member of the tumor necrosis factor (TNF) family with immunomodulatory as well as pro- and antiapoptotic effects and is putatively involved in control of HCV infection. Thus, we analyzed the expression of the TRAIL/TRAIL-receptor system, caspase-8 and cFLIP and examined their prognostic and predictive value for HCV infection and antiviral therapy, respectively. MethodsWe immunohistochemically analyzed liver biopsies of 116 therapy-naive HCV patients before treatment with PEG-IFNα and ribavirin in comparison to healthy liver tissue. Expression levels of TRAIL, TRAIL-R1 to TRAIL-R4, caspase-8 and cFLIP were correlated with sustained virologic response (SVR), genotype and staging of chronic hepatitis. ResultsCaspase-8, cFLIP, TRAIL-R2 and TRAIL-R4 were strongly upregulated in HCV patients, whereas TRAIL-R3 was downregulated. SVR correlated with high expression of TRAIL and pro-apoptotic TRAIL-R2 on HCV infected hepatocytes. ConclusionsOur results suggest a pathophysiological role of TRAIL in both, HCV infection and therapy. Further studies need to elaborate possible TRAIL-related targets for clinical applications.

Chronic Lymphocytic Leukemia Patients Have a Preserved Cytomegalovirus-Specific Antibody Response despite Progressive Hypogammaglobulinemia

Chronic lymphocytic leukemia (CLL) is characterized by progressive hypogammaglobulinemia predisposing affected patients to a variety of infectious diseases but paradoxically not to cytomegalovirus (CMV) disease. Moreover, we found reactivity of a panel of CLL recombinant antibodies (CLL-rAbs) encoded by a germ-line allele with a single CMV protein, pUL32, despite differing antibody binding motifs. To put these findings into perspective, we studied prospectively relative frequency of viremia, kinetics of total and virus-specific IgG over time, and UL32 genetic variation in a cohort of therapy-naive patients (n=200). CMV-DNA was detected in 3% (6/200) of patients. The decay of total IgG was uniform (mean, 0.03; SD, 0.03) and correlated with that of IgG subclasses 1-4 in the paired samples available (n=64; p<0.001). Total CMV-specific IgG kinetics were more variable (mean, 0,02; SD, 0,06) and mean decay values differed significantly from those of total IgG (p=0.034). Boosts of CMV-specific antibody levels were observed in 49% (22/45) of CMV-seropositive patients. In contrast, VZV- and EBV-specific IgG levels decayed in parallel with total IgG levels (p=0.003 and p=0.001, respectively). VZV-specific IgG even became undetectable in 18% (9/50) of patients whereas CMV-specific ones remained detectable in all seropositive patients. The observed CMV-specific IgG kinetics were predicated upon the highly divergent kinetics of IgG specific for individual antigens - glycoprotein B-specific IgG were boosted in 51% and pUL32-specific IgG in 32% of patients. In conclusion, CLL patients have a preserved CMV-specific antibody response despite progressive decay of total IgG and IgG subclasses. CMV-specific IgG levels are frequently boosted in contrast to that of other herpesviruses indicative of a higher rate of CMV reactivation and antigen-presentation. In contrast to the reactivity of multiple different CLL-rAbs with pUL32, boosts of humoral immunity are triggered apparently by other CMV antigens than pUL32, like glycoprotein B.

One-Year Progression-Free Survival of Therapy-Naive Patients With Malignant Pheochromocytoma and Paraganglioma

The natural history of malignant pheochromocytoma or paragangliomas (MPP) remain unknown. The primary aim of this study was to define progression-free survival at 1 year in therapy-naive patients with MPP. Secondary objectives were to characterize MPP and to look for prognostic parameters for progression at 1 year. The files of MPP followed up between January 2001 and January 2011 in two French Endocrine Networks were retrospectively reviewed. Therapy-naive patients were enrolled. The main outcome was progression-free survival at 1 year in therapy-naive MPP patients according to Response Evaluation Criteria In Solid Tumors 1.1 criteria. Ninety files (46 men, 44 women, mean age of 47.5 ± 15 years) were reviewed on site by one investigator. MPP characteristics were as follows: presence of an adrenal primary, a mitotic count exceeding 5 per high power field, hypertension, inherited disease, and presence of bone metastases in 50%, 22%, 60%, 49%, and 56% patients, respectively. Fifty-seven of the 90 patients with MPP (63%) were classified as therapy-naive. The median follow-up of these 57 patients was 2.4 years (range, 0.4-5.7). At 1 year, progression-free survival was 46% (CI 95: 33-59). Twenty-six of 30 (87%) patients with progression at 1 year had exhibited progressive disease at the first imaging workup performed after a median of 5.7 months. No prognostic parameter was identified. Half of the therapy-naive patients with MPP achieved stable disease at 1 year. In symptom-free patients with MPP, a wait-and-see antitumor policy seems appropriate as first line. Modality for a prospective follow-up is proposed.

Anthracycline-containing regimens for treatment of follicular lymphoma in adults.

Anthracycline-containing regimens (ACR) are the most prevalent regimens in the management of patients with advanced follicular lymphoma (FL). However, there is no proof that they are superior to non-anthracycline-containing regimens (non-ACR). To compare the efficacy of ACRs to other chemotherapy regimens, in the treatment of FL. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 3), MEDLINE (January 1966 to April 2013), smaller databases, relevant conference proceedings (2004 to 2012) and the National Medical Library (April 2013). We included randomized controlled trials (RCTs) comparing ACR with non-ACR for adult patients with FL. We excluded trials in which immunotherapy, radiotherapy alone or stem-cell transplantation were used in one arm alone. Our primary outcome was overall survival (OS). Secondary outcomes included disease control, as measured by progression-free survival (PFS) or remission duration (RD). Two review authors assessed the quality of trials and extracted data. We contacted study authors for additional information. We analyzed trials separately according to resemblance of the chemotherapeutic regimens in study arms, other than the addition of anthracyclines ('same' versus 'different' chemotherapy). Hazard ratios (HR) and risk ratios (RR) with 95% confidence intervals (CI) were estimated and pooled using the fixed-effect model. Eight RCTs, conducted between 1974 and 2011, and involving 2636 patients were included in this meta-analysis. All trials included therapy-naive patients. Rituximab was used in one trial only. Follow-up was between three and five years in most trials (range three to 18 years). All trials were published in peer-reviewed journals.Five trials compared similar chemotherapeutic regimens, except for the anthracycline. In three studies reporting overall survival specifically in FL patients, there was no statistically significant difference between ACR and non-ACR arms (HR 0.99; 95% CI 0.77 to 1.29; I(2) = 0%). ACR significantly improved disease control (HR 0.65; 95% CI 0.52 to 0.81; four trials). Progression or relapse at three years were reduced (RR 0.73; 95% CI 0.63 to 0.85). Anthracyclines did not significantly increase rates of complete response (RR 1.05; 95% CI 0.94 to 1.18) or overall response (RR 1.06; 95% CI 1.00 to 1.12), but heterogeneity was substantial.Overall, ACR were more often associated with cytopenias, but not with serious infections or death related to chemotherapy. Cardiotoxicity, albeit rare, was associated with anthracycline use (RR 4.55; 95% CI 0.92 to 22.49; four trials).Three trials added anthracycline to one arm of two different regimens. None showed benefit to ACR regarding OS, yet there was a trend in favor of anthracyclines for disease control. Results were heterogeneous.We judged the overall quality of these trials as moderate as all are unblinded, some are outdated and are not uniform in outcome definitions. The use of anthracyclines in patients with FL has no demonstrable benefit on overall survival, although it may have been mitigated by the more intense regimens given in the control arms of three of five trials. ACR improved disease control, as measured by PFS and RD with an increased risk for side effects, notably cardiotoxicity. The current evidence on the added value of ACR in the management of FL is limited. Further studies involving immunotherapy during induction and maintenance may change conclusion.

Reduction of complement factor H binding to CLL cells improves the induction of rituximab-mediated complement-dependent cytotoxicity

A main effector mechanism of rituximab (RTX) is the induction of complement-dependent cytotoxicity (CDC). However, this effector function is limited, because CLL cells are protected from complement-induced damage by regulators of complement activation (RCAs). A prominent RCA in fluid phase is factor H (fH), which has not been investigated in this context yet. Here, we show that fH binds to CLL cells and that human recombinant fH-derived short-consensus repeat 18–20 (hSCR18–20) interferes with this binding. In complement-based lysis assays, CLL cells from therapy-naive patients were differently susceptible to RTX-induced CDC and were defined as CDC responder or CDC non-responder, respectively. In CDC responders, but notably also in non-responders, hSCR18–20 significantly boosted RTX-induced CDC. Killing of the cells was specific for CD20+ cells, whereas CD20− cells were poorly affected. CDC resistance was independent of expression of the membrane-anchored RCAs CD55 and CD59, although blocking of these RCAs further boosted CDC. Thus, inhibition of fH binding by hSCR18–20 sensitizes CLL cells to CDC and may provide a novel strategy for improving RTX-containing immunochemotherapy of CLL patients.

Rapid onset of efficacy of rasagiline in early Parkinson’s disease

Rasagiline is a monoamine oxidase type-B inhibitor used as monotherapy or in addition to levodopa in the treatment of Parkinson's disease (PD). This naturalistic single-blind study was aimed at evaluating the rapidity of onset effect of rasagiline on motor symptoms in a cohort of early relatively elderly PD patients. 102 outpatients (55 males, median age 71 years) have been selected: 26 were PD therapy-naive and 76 received rasagiline as add-on therapy. The third section of the Unified Parkinson's Disease Rating Scale (UPDRSIII) and the Hoehn-Yahr (HY) scale were assessed at baseline and after 1 and 4 weeks thereafter. The mean UPDRS III total score (-6.7 at week 1 and -8.9 at week 4) and single items, as well as mean HY score (-0.40 at week 1 and -0.67 at week 4), significantly decreased from baseline (p < 0.001). Improvements were significant in both therapy-naive and add-on therapy patients: the mean decreases from baseline to week 4 in UPDRSIII and HY score were -8.8 and -0.46, and -9.0 and -0.74, respectively, in the two subgroups. The mean decrease from baseline in UPDRSIII and HY score did not significantly differ in patients aged > or ≤71 years. Rasagiline had a rapid therapeutic effect from the first week of therapy, which further improved at 4 weeks. The rapid onset of action and the absence of a dose titration are important issues in the management of the PD patient.

The Interaction of CD4 T-Cell Count and Nevirapine Hepatotoxicity in China

Nevirapine (NVP), a still widely used nonnucleoside reverse transcriptase inhibitor, can cause severe hepatotoxicity. Previous studies suggest that CD4 cell counts more than 250 cells per microliter in women and more than 400 cells per microliter in men are risk factors for NVP-related hepatotoxicity. These studies have informed Chinese national treatment guidelines. We evaluate whether current Chinese guidelines for NVP use are appropriate. Longitudinal data were pooled from 2 clinical trials between 2005 and 2009 across mainland China. Five hundred sixty-six antiretroviral therapy-naive Chinese patients were given NVP-containing antiretroviral therapy for 24 weeks. Hepatotoxicity was defined as alanine aminotransferase, aspartate transaminase, or total bilirubin level greater than 1.25 times the upper limit of normal range. Severe hepatotoxicity was defined as greater than 5 times the upper limit of normal range. One hundred ninety-seven (36.1%) patients developed hepatotoxicity during treatment, including 42 (7.7%) patients with severe hepatotoxicity. CD4 cell count more than 250 cells per microliter was an independent predictor for hepatotoxicity both in men [relative risk = 1.22 (95% confidence interval: 1.04 to 1.44)] and in women [relative risk = 1.72 (95% confidence interval: 1.20 to 2.46)]. Severe hepatotoxicity was also more common among all persons with CD4 >250 cells per microliter. Hepatotoxicity was a common adverse effect of NVP among men and women with CD4 >250 cells per microliter. Chinese treatment guidelines should be considered to reflect this risk.

Efficacy and Safety of Oral Chelators in Treatment of Patients With Wilson Disease

Wilson disease is a genetic copper storage disorder that causes hepatic and neurologic symptoms. Chelating agents (D-penicillamine, trientine) are used as first-line therapies for symptomatic patients, but there are few data from large cohorts. We assessed the safety of D-penicillamine and trientine therapy and outcomes of patients with Wilson disease. We performed a retrospective analysis of data on 380 patients with Wilson disease from tertiary care centers in Germany and Austria, and 25 additional patients from the EUROWILSON registry. Chelator-based treatment regimens were analyzed for their effect on neurologic and hepatic symptoms and for adverse events that led to discontinuation of therapy (Kaplan-Meier estimation; data were collected for a mean of 13.3 y after therapy began). Changes in medication were common, resulting in analysis of 471 chelator monotherapies (326 patients receiving D-penicillamine and 141 receiving trientine). Nine of 326 patients treated with D-penicillamine and 3 of 141 patients given trientine underwent liver transplantation. Adverse events leading to discontinuation of treatment were more frequent among those receiving D-penicillamine than trientine (P = .039). Forty-eight months after therapy, hepatic deterioration was reported in only 4 of 333 patients treated initially with a chelating agent. Hepatic improvements were observed in more than 90%, and neurologic improvements were observed in more than 55%, of therapy-naive patients, and values did not differ significantly between treatments. However, neurologic deterioration was observed less frequently in patients given D-penicillamine first (6 of 295) than those given trientine first (4 of 38; P = .018). Chelating agents are effective therapies for most patients with Wilson disease; D-penicillamine and trientine produce comparable outcomes, although D-penicillamine had a higher rate of adverse events. Few patients receiving chelation therapy had neurologic deterioration, which occurred more frequently in patients who received trientine.

Evolution and viral characteristics of a long-term circulating resistant HIV-1 strain in a cluster of treatment-naive patients

Transmitted resistant HIV may revert to wild-type in the absence of drug pressure due to reduced replication capacity (RC). We observed eight therapy-naive patients infected with HIV harbouring four mutations at nucleoside reverse transcriptase inhibitor (NRTI) resistance-related positions: M41L, T69S, L210E and T215S. If partial reverted resistance patterns like these are detected at baseline, concerns for more extensive resistance in the quasispecies often directs selection of first-line combination antiretroviral therapy (cART) towards more complex regimens. Genotypic resistance testing and phylogenetic analysis was performed using pol sequences of 400 therapy-naive patients and 1322 patients with at least one NRTI-related mutation. Reverse transcriptase (RT) genes were cloned into a reference strain and RC was investigated. Phylogenetic analysis showed that all eight patients are part of a transmission cluster (bootstrap value 92%). The patients resided in three distinct geographical regions and were either homosexually or heterosexually infected. Prior negative serology and analysis of base ambiguity demonstrated circulation for at least 7 years. In vivo evolution showed a mixture with wild-type (T215S/T) in only one untreated patient more than 6 years after diagnosis. The reverted resistance pattern did not confer a substantial reduction in RC compared with wild-type, explaining its persistence in vivo and long-term circulation in the population. Four patients started cART; three of them received quadruple cART. All patients showed good virological and immunological response. Long-term circulation transcending distinct regions and transmission groups suggests reversion occurred in previous hosts in the transmission chain. Identification of clusters using epidemiological data and active-partner tracing may broaden therapeutic options in cases of transmitted resistance.

Antiretroviral drug resistance in HIV-1 therapy-naive patients in Cuba

In Cuba, antiretroviral therapy rollout started in 2001 and antiretroviral therapy coverage has reached almost 40% since then. The objectives of this study were therefore to analyze subtype distribution, and level and patterns of drug resistance in therapy-naive HIV-1 patients. Four hundred and one plasma samples were collected from HIV-1 therapy-naive patients in 2003 and in 2007–2011. HIV-1 drug resistance genotyping was performed in the pol gene and drug resistance was interpreted according to the WHO surveillance drug-resistance mutations list, version 2009. Potential impact on first-line therapy response was estimated using genotypic drug resistance interpretation systems HIVdb version 6.2.0 and Rega version 8.0.2. Phylogenetic analysis was performed using Neighbor-Joining. The majority of patients were male (84.5%), men who have sex with men (78.1%) and from Havana City (73.6%). Subtype B was the most prevalent subtype (39.3%), followed by CRF20-23-24_BG (19.5%), CRF19_cpx (18.0%) and CRF18_cpx (10.3%). Overall, 29 patients (7.2%) had evidence of drug resistance, with 4.0% (CI 1.6%–4.8%) in 2003 versus 12.5% (CI 7.2%–14.5%) in 2007–2011. A significant increase in drug resistance was observed in recently HIV-1 diagnosed patients, i.e. 14.8% (CI 8.0%–17.0%) in 2007–2011 versus 3.8% (CI 0.9%–4.7%) in 2003 (OR 3.9, CI 1.5–17.0, p=0.02). The majority of drug resistance was restricted to a single drug class (75.8%), with 55.2% patients displaying nucleoside reverse transcriptase inhibitor (NRTI), 10.3% non-NRTI (NNRTI) and 10.3% protease inhibitor (PI) resistance mutations. Respectively, 20.7% and 3.4% patients carried viruses containing drug resistance mutations against NRTI+NNRTI and NRTI+NNRTI+PI. The first cases of resistance towards other drug classes than NRTI were only detected from 2008 onwards. The most frequent resistance mutations were T215Y/rev (44.8%), M41L (31.0%), M184V (17.2%) and K103N (13.8%). The median genotypic susceptibility score for the commonly prescribed first-line therapies was 2.5. This analysis emphasizes the need to perform additional surveillance studies to accurately assess the level of transmitted drug resistance in Cuba, as the extent of drug resistance might jeopardize effectiveness of first-line regimens prescribed in Cuba and might necessitate the implementation of baseline drug resistance testing.

Clinicians Versus Nomogram: Predicting Future Technetium-99m Bone Scan Positivity in Patients With Rising Prostate-specific Antigen After Radical Prostatectomy for Prostate Cancer

To compare the ability of clinicians vs a nomogram at predicting future bone scan positivity in patients with prostate cancer. This investigation was conducted during an advisory board meeting in June 2011. Details of 25 androgen deprivation therapy-naive prostate cancer patients were given to 24 prostate cancer experts, including urologists and oncologists. The clinicians were asked to predict the probability that the patients would have a positive bone scan if left untreated for 1 year. These predictions and those of the Slovin nomogram were compared with the actual occurrence of metastatic disease, and the discrimination ability was quantified using the concordance index (C index). A higher C index value was obtained with the Slovin nomogram (0.812) than with the clinicians (0.628). The nomogram outperformed all of the clinicians; individual clinician C index values varied between 0.47 and 0.75. The urologists provided superior predictions compared with the oncologists. Future bone scan positivity can be predicted more accurately using a nomogram than by expert clinicians. Nomograms should, therefore, become an integral part of the clinical decision-making process in the prostate cancer setting for patients with a rising prostate-specific antigen level after radical prostatectomy.