Treatment of hepatitis B virus with combination therapy now and in the future.

Chronic Hepatitis B continues as a significant public health problem despite the availability of safe and effective antivirals and a highly effective protective vaccine. Current therapy, however rarely leads to cure and lifelong therapy is often required, contributing to poor uptake and ongoing morbidity. New insights into the hepatitis B viral life cycle and the host immune response have expanded the potential targets for drug therapies with interesting antiviral candidates and novel immunotherapeutic approaches in early stage development. Yet, HBV persistence is multifactorial - due to an intrahepatic reservoir and ongoing HBV-mediated immune dysregulation, making "cure" unlikely to be realized through even the most efficacious monotherapy. Building on the success seen in the treatment of hepatitis C (HCV) and human immunodeficiency virus (HIV), combination therapy may be an essential strategy to improve efficacy and decrease viral breakthrough. Combinations acting on immune and viral targets are particularly attractive. However, creating synergy while balancing efficacy and safety remains a clear challenge. Various approaches to combination therapy are reviewed, highlighting strengths and challenges of each potential strategy. Overall, combination therapies are attractive as the next step towards cure and are a key strategy for achieving treatment with finite durations and durable endpoints.

Efficacy and Safety of Direct Acting Antivirals for the Treatment of Mixed Cryoglobulinemia.

OBJECTIVES: Mixed cryoglobulinemia is strongly associated with hepatitis C virus (HCV) infection and ranges from being asymptomatic to causing life-threatening vasculitis. In those with symptoms, treatment with pegylated interferon (pegIFN) and ribavirin (RBV) reduces mortality. However, few data are available on the safety and efficacy of antiviral therapy with direct acting antivirals (DAAs) in the treatment of HCV-related cryoglobulinemia. METHODS: Patients treated for HCV-related cryoglobulinemia with DAA±pegIFN were retrospectively evaluated at a tertiary care center. Primary outcomes were virological, immunological, and clinical response. Complete (normalization), partial (>50% reduction), or non-response (<50% reduction) were used to describe change in cryocrit or vasculitic manifestations at week 12 post treatment. Side effects, hospitalizations, and decompensating events were recorded. RESULTS: Eighteen symptomatic and 65 asymptomatic patients were reviewed (61% male, median age 58 years) including 10 with severe/life-threatening vasculitis. Sixty-six (79.5%) patients received pegIFN-free therapy. Sustained virological response (SVR) was attained in 16 (88.9%) symptomatic and 59 (90.8%) asymptomatic patients. Cryoglobulins disappeared in 5 (29.4%) symptomatic and 27 (52.9%) asymptomatic patients. Of symptomatic patients with SVR, clinical response was complete in 7 (38.8%) and partial response in 4 (22.2%). Of the 5 viral relapsers, 1 had a complete response during therapy with no symptomatic recurrence, while the other patients had no clinical response. Among 7 with severe vasculitis, 6 achieved SVR but only 1 had a complete clinical response, with 3 showing a partial response and 2 showing no improvement. All four with life-threatening vasculitis required plasmapheresis and three received rituximab. All achieved SVR leading to partial clinical response in two, but no response in two. Skin manifestations (39% reduction) were most likely to completely resolve with lower responses seen in renal (11.2% reduction) and neurological symptoms (11.1%). Eighty-two (98.8%) patients completed therapy, with 19 (22.8%) reporting adverse events. Hospitalization for decompensation or worsening vasculitis occurred in five (6.0%) and four (22.2) patients respectively. CONCLUSIONS: DAAs resulted in high rates of SVR in patients with cryoglobulinemia. Safety and tolerability were excellent; however, most patients did not have a complete clinical or immunological response, suggesting a delay to clinical response particularly in those with severe/life-threatening vasculitis. Further follow-up will be required to determine if clinical improvement continues after viral clearance.

Melioidosis in a returned traveller.

Melioidosis is an infection endemic to Southeast Asia and Northern Australia, and is associated with significant morbidity and mortality. The present report describes a case of chronic melioidosis in a returning traveller from the Philippines. Clinical suspicion of this illness is warranted in individuals with a history of travel to endemic regions. Safety in handling clinical specimens is paramount because laboratory transmission has been described.

La mélioïdose est une infection endémique en Asie du Sud-Est et en Australie occidentale. Elle s'associe à une morbidité et une mortalité importantes. Le présent rapport expose un cas de mélioïdose chronique chez un voyageur de retour des Philippines. La suspicion clinique de cette maladie s'impose chez les personnes qui ont voyagé dans des régions endémiques. Il est essentiel de respecter les règles de sécurité lors de la manipulation des échantillons cliniques, car des cas de transmission en laboratoire ont été signalés.

Bipolar patients can safely and successfully receive interferon-based hepatitis C antiviral treatment.

AIM: Patients with bipolar disease are often not considered for hepatitis C virus (HCV) antiviral treatment and are excluded from clinical trials because of the risk of interferon-induced exacerbation of their underlying mood disorder. As this risk has not been well quantified in bipolar patients, we evaluated the safety and efficacy of HCV treatment in this population. METHODS: A retrospective analysis of HCV patients evaluated at The Ottawa Hospital between January 2000 and February 2008 (n=910) was carried out. Information on demographics, psychiatric history and treatment, baseline liver biopsy and blood work, treatment initiation, adherence, and therapeutic outcomes was collected. This was compared between bipolar patients (B), those with a history of depression (D), and those with no mental health disorders (N). RESULTS: Of 38 bipolar patients (4.2%), 16 (42.1%) initiated HCV treatment, a rate similar to that in patients with a history of depression (41.4%) and in those without psychiatric illness (32.6%). On-treatment psychiatric complications were comparable between the bipolar and depression groups (B=68.8%, D=54.8%; P=0.29) and were higher than in those without psychiatric illness (N=37.1%; P=0.01). Manic episodes were rare. [B=2 (12.5%), D=1 (0.9%), N=1 (0.7%)]. Interferon dose reduction or discontinuation rates for psychiatric complications (B=12.5%, D=7.9%, N=7.4%; P=NS), completion rates (B=50%, D=69%, N=58%), and sustained virologic response rates (genotype 1: B=33%, D=45%, N=49%) were similar between the groups. CONCLUSION: Stable bipolar patients have similar rates of on-treatment psychiatric complications as patients with a history of depression. With pharmacologic intervention and close clinical monitoring, well-selected bipolar patients can successfully complete treatment and achieve outcomes comparable to those in nonbipolar patients.

Gender differences in clinical, immunological, and virological outcomes in highly active antiretroviral-treated HIV-HCV coinfected patients.

OBJECTIVE: The influence of biological sex on human immunodeficiency virus (HIV) antiretroviral treatment outcome is not well described in HIV-hepatitis C (HCV) coinfection. METHODS: We assessed patients' clinical outcomes of HIV-HCV coinfected patients initiating antiretroviral therapy attending the Ottawa Hospital Immunodeficiency Clinic from January 1996 to June 2008. RESULTS: We assessed 144 males and 39 females. Although similar in most baseline characteristics, the CD4 count was higher in females (375 vs 290 cells/muL). Fewer females initiated ritonavir-boosted regimens. The median duration on therapy before interruption or change was longer in males (10 versus 4 months) (odds ratio [OR] 1.40 95% confidence interval: 0.95-2.04; P = 0.09). HIV RNA suppression was frequent (74%) and mean CD4 count achieved robust (over 400 cells/muL) at 6 months, irrespective of sex. The primary reasons for therapy interruption in females and males included: gastrointestinal intolerance (25% vs 19%; P = 0.42); poor adherence (22% vs 15%; P = 0.31); neuropsychiatric symptoms (19% vs 5%; P = 0.003); and lost to follow-up (3% vs 13%; P = 0.08). Seven males (5%) and no females discontinued therapy for liver-specific complications. Death rate was higher in females (23% vs 7%; P = 0.003). CONCLUSION: There are subtle differences in the characteristics of female and male HIV-HCV coinfected patients that influence HIV treatment decisions. The reasons for treatment interruption and change differ by biological sex. This knowledge should be considered when starting HIV therapy and in efforts to improve treatment outcomes.

Reaction mechanisms of Li(0.30)La(0.57)TiO3 powder with ambient air: H+/Li+ exchange with water and Li2CO3 formation.

The proton/lithium exchange property of the lithium lanthanum titanate Li(0.30)La(0.57)TiO(3) (named LLTO) is shown to occur at room temperature under ambient air. The (1)H and (7)Li MAS NMR, TGA analysis and IR spectroscopy techniques are used to probe reaction mechanisms. XRPD analysis gives evidence of the topotactic character of this exchange reaction. As for exchange in aqueous solution, it is shown that Li(0.30)La(0.57)TiO(3) is able to dissociate water on the grain surface and then to exchange H(+) for Li(+) into the perovskite structure. Lithium hydroxide is then formed on the grain surface and afterwards reacts with CO(2) contained in air to form Li(2)CO(3). It is shown that this mechanism is reversible. When the aged sample (aging in air for 5 months at room temperature) is annealed at 400 degrees C for two hours, the initial LLTO sample is totally recovered, a mass loss is observed and the carbonate signal in IR spectra disappears, demonstrating the reversibility of the carbonation reaction process.

NMR investigations of Li(+) ion dynamics in the NASICON ionic conductors [Formula: see text].

NMR studies of (7)Li and (31)P nuclei are reported in the 150-900 K temperature range for the [Formula: see text] NASICON compounds with x = 0.8, 0.7, 0.6 and 0.3. Magic angle spinning (MAS mode) experiments were performed at room temperature on the (7)Li and (31)P nuclei. The linewidth and the spin lattice relaxation times of these nuclei are studied versus temperature in the static mode. The spectra recorded in the MAS mode show that the (7)Li ions occupy three chemical sites, the occupation of which being very sensitive to the x values but not sensitive to the coexistence of the two varieties [Formula: see text] and [Formula: see text] observed at room temperature in compounds with x≤0.5. On the other hand, the (31)P nucleus MAS spectra are very sensitive to lithium content but also to the variety coexistence. T(1) measurements were performed in a static mode on the (7)Li and (31)P nuclei. In all the compounds, the (7)Li spin lattice relaxation time exhibits two branches with several minima, indicating the complex dynamics for this ion. One of these minima appears in the same temperature range as the minimum of the (31)P nucleus T(1), strongly suggesting a cross-relaxation process between these nuclei. T(1ρ) measurements on (7)Li (static mode) allow us to show a slow motion different from the one probed by the T(1). The analysis of the T(1ρ) behaviour with temperature and composition allows us to ascribe the motion probed by this time to the oxygen ion motion which monitors the opening and closing of the lithium pathways. A qualitative interpretation of the (7)Li  T(1) results is done; it takes into account the cross-relaxation phenomena between (31)P and (7)Li and quadrupolar fluctuations.

Investigation in thorium phosphate by NMR II-phosphorus dipolar networks.

With through space and through bond experiments in two-dimensional NMR we analyze the transformation from the thorium phosphate-hydrogen phosphate hydrate (TPHPH) to the beta form of the thorium phosphate diphosphate (beta-TPD) in relation with the phosphorus networks. These techniques are complementary: the through space coupling gives an insight on the dipolar phosphorus networks while the through bond coupling is particularly efficient in the detection of the P2O7 groups. With these experiments we show that in a first step, by heating the precursor TPHPH above 250 degrees C, it transforms into an alpha form of TPD. This transformation is due to the complete condensation of hydrogen phosphate groups HPO4 into P2O7 entities. By heating alpha-TPD above 950 degrees C it transforms into its well-known beta form. The alpha form is characterized by a hygroscopic behavior: some water molecules are present near the P2O7 groups that makes non-equivalent their phosphorus nuclei. PO4 dipolar networks are always present in the alpha form. The main effect of these PO4 and P2O7 units is to give the system a channel structure and the water enters in them.

17O NMR in room temperature phase of La2Mo2O9 fast oxide ionic conductor.

A room temperature (17)O NMR study of La(2)Mo(2)O(9), a fast oxide ionic conductor exhibiting a phase transition at 580 degrees C between a low-temperature alpha-phase and a high-temperature beta-phase, is presented. Four partly overlapping quasi-continuous distributions of oxygen sites are evidenced from 1D magic angle spinning (MAS) and 2D triple quantum MAS NMR experiments. They can be correlated with the three oxygen sites O1, O2 and O3 of the high-temperature crystal structure. The low-temperature phase is characterized by two distributed sites of type O1, which proves that the symmetry is lower than in the cubic high-temperature phase. Two-dimensional experiments show that there is no dynamic exchange process, on the NMR time-scale, between the different oxygen sites at room temperature, which agrees well with conductivity results.

NMR study of Li+ ion dynamics in the perovskite Li(3x)La(1/3-x)NbO3.

(7)Li and (6)Li nuclear magnetic resonance (NMR) experiments are carried out on the perovskite Li(3x)La(1/3-x)NbO(3). The results are compared to those obtained on the titanate Li(3x)La(2/3-x)TiO3 (LLTO) in order to investigate the effect, on the lithium ion dynamics, of the total substitution of Nb(5+) for Ti(4+) in the B-site of the ABO(3) perovskites. The XRD patterns analysis reveals that this substitution leads to a change in the distribution of the La(3+) ions in the structure. La(3+) ions distribution is very important, in regard to ionic conductivity, because these immobile ions can be considered as obstacles for the long-range Li+ motion. If compared to the titanates, the compounds of the niobate solid solution have a bigger unit cell volume, a smaller number of La(3+) ions, and a higher number of vacancies. These should favor the motion of the mobile ions into the structure. This is not experimentally observed. Therefore, the interactions between the mobile species and their environment greatly influence their mobility. (7)Li and (6)Li NMR relaxation time experiments reveal that the Li relaxation mechanism is not dominated by quadrupolar interaction. (7)Li NMR spectra reveal the presence of different Li+ ion sites. Some Li+ ions reside in an isotropic environment with no distortion, some others reside in weakly distorted environments. T(1), T(1)(rho), and T(2) experiments allow us to evidence two motions of Li+. As in LLTO, T(1) probes a fast motion of the Li+ ions inside the A-cage of the perovskite structure and T(1)(rho) a slow motion of these ions from A-cage to A-cage. At variance with what has been observed in LLTO, these different Li+ ions can be differentiated through the spin-lattice relaxation times, T(1) and T(1)(rho), as well as through the transverse relaxation time, T(2).