opc-67683 and HIV-Infections

Success rates for treatment of extensively drug resistant tuberculosis (XDR-TB) are low due to limited treatment options, delayed diagnosis and inadequate health care infrastructure. Areas covered: This review analyses existing programmes of prevention, diagnosis and treatment of XDR-TB. Improved diagnostic procedures and rapid molecular tests help to select appropriate drugs and dosages. Drugs dosages can be further tailored to the specific conditions of the patient based on quantitative susceptibility testing of the M. tuberculosis isolate and use of therapeutic drug monitoring. Pharmacovigilance is important for preserving activity of the novel drugs bedaquiline and delamanid. Furthermore, biomarkers of treatment response must be developed and validated to guide therapeutic decisions. Expert commentary: Given the currently poor treatment outcomes and the association of XDR-TB with HIV in endemic regions, a more patient oriented approach regarding diagnostics, drug selection and tailoring and treatment evaluation will improve treatment outcome. The different areas of expertise should be covered by a multidisciplinary team and may involve the transition of patients from hospitalized to home or community-based treatment.

Topics: Antitubercular Agents; Biomarkers; Clinical Trials as Topic; Coinfection; Diarylquinolines; Extensively Drug-Resistant Tuberculosis; HIV Infections; Humans; Mycobacterium tuberculosis; Nitroimidazoles; Oxazoles; Practice Guidelines as Topic; Precision Medicine

Increasing numbers of children with drug-resistant tuberculosis are accessing second-line antituberculosis drugs; these are more toxic than first-line drugs. Little is known about the safety of new antituberculosis drugs in children. Knowledge of adverse effects, and how to assess and manage these, is important to ensure good adherence and treatment outcomes.. A Pubmed search was performed to identify articles addressing adverse effects of second-line antituberculosis drugs; a general search was done for the new drugs delamanid and bedaquiline. This review discusses adverse effects associated with oral second-line antituberculosis drugs. The spectrum of adverse effects caused by antituberculosis drugs is wide; the majority are mild or moderate, but these are important to manage as it could lead to non-adherence to treatment. Adverse effects may be more common in HIV-infected than in HIV-uninfected children.. Although children may experience fewer adverse effects from oral second-line antituberculosis drugs than adults, evidence from prospective studies of the incidence of adverse events in children is limited. Higher doses of second-line drugs, new antituberculosis drugs, and new drug regimens are being evaluated in children: these call for strict pharmacovigilance in children treated in the near future, as adverse effect profiles may change.

Topics: Age Factors; Antitubercular Agents; Child; Diarylquinolines; Dose-Response Relationship, Drug; HIV Infections; Humans; Nitroimidazoles; Oxazoles; Tuberculosis, Multidrug-Resistant

Multidrug-resistant and extensively drug-resistant tuberculosis (MDR- and XDR-TB) are major public health concerns worldwide. Their association with HIV/AIDS infection has contributed to the slowing down of TB incidence decline over the last two decades, therefore representing one of the most important barriers to reach TB elimination.. The aim of this manuscript is to critically review the recent scientific evidence on the management of drug-resistant TB (essentially MDR- and XDR-TB) in subjects coinfected with HIV, focusing on the two new recently-approved anti-TB drugs delamanid and bedaquiline. The medical search-engine PubMed was used, selecting the time-period January 2013 - February 2015, and using the following. drug-resistant TB, multidrug resistant TB (or MDR-TB), extensively drug-resistant TB (or XDR-TB), delamanid and bedaquiline.. The TB/HIV co-epidemic can be faced by implementing the 12 TB/HIV collaborative activities recommended by the World Health Organization. They are focused on the systematic screening of individuals to detect the Mycobacterium tuberculosis infection in HIV-positives, as well as HIV infection in TB patients in order to ensure a rapid initiation of the anti-retroviral therapy (ART). The clinical and public health management of HIV-positive individuals with MDR-TB is complex and expensive, given the cost of second line anti-TB drugs (including the new drugs, delamanid and bedaquiline) and ART. Political commitment and more investment to identify shorter, cheaper and effective anti-TB and HIV regimens as well as better diagnostics and, hopefully, a vaccine will contribute to boost the efforts to eliminate TB.

Topics: Antitubercular Agents; Coinfection; Diarylquinolines; Disease Management; Extensively Drug-Resistant Tuberculosis; HIV Infections; Humans; Mycobacterium tuberculosis; Nitroimidazoles; Oxazoles; Tuberculosis, Multidrug-Resistant; World Health Organization

Delamanid is a nitroimidazole, a novel class of drug for treating tuberculosis, and is primarily metabolized by albumin into the metabolite DM-6705. The aims of this analysis were to develop a population pharmacokinetic (PK) model to characterize the concentration-time course of delamanid and DM-6705 in adults with drug-resistant tuberculosis and to explore a potential drug-drug interaction with bedaquiline when coadministered.. Delamanid and DM-6705 concentrations after oral administration, from 52 participants (of whom 26 took bedaquiline concurrently and 20 were HIV-1 positive) enrolled in the DELIBERATE trial were analyzed using nonlinear mixed-effects modeling.. Delamanid PK were described by a one-compartment disposition model with transit compartment absorption (mean absorption time of 1.45 h [95% confidence interval 0.501-2.20]) and linear elimination, while the PK of DM-6705 metabolite were described by a one-compartment disposition model with delamanid clearance as input and linear elimination. Predicted terminal half-life values for delamanid and DM-6705 were 15.1 h and 7.8 days, respectively. The impact of plasma albumin concentrations on delamanid metabolism was not significant. Bedaquiline coadministration did not affect delamanid PK. Other than allometric scaling with body weight, no patients' demographics were significant (including HIV).. This is the first joint PK model of delamanid and its DM-6705 metabolite. As such, it can be utilized in future exposure-response or exposure-safety analyses. Importantly, albumin concentrations, bedaquiline coadministration, and HIV co-infection (dolutegravir coadministration) did not have an effect on delamanid and DM-6705 PK.

Topics: Adult; Albumins; Antitubercular Agents; Diarylquinolines; HIV Infections; Humans; Nitroimidazoles; Oxazoles; Tuberculosis, Multidrug-Resistant

Topics: Adolescent; Adult; Antitubercular Agents; Child; Compassionate Use Trials; Diarylquinolines; Drug Therapy, Combination; Female; HIV Infections; Humans; Internationality; Male; Middle Aged; Nitroimidazoles; Oxazoles; Tuberculosis, Multidrug-Resistant; Young Adult

Bedaquiline and delamanid have been approved for treatment of multidrug-resistant (MDR) tuberculosis in the past 5 years. Because of theoretical safety concerns, patients have been unable to access the two drugs in combination. Médecins Sans Frontières has supported the use of combination bedaquiline and delamanid for people with few treatment options since 2016. We describe early safety and efficacy of regimens containing the bedaquiline and delamanid combination in patients with drug-resistant tuberculosis in Yerevan, Armenia; Mumbai, India; and Khayelitsha, South Africa.. We retrospectively analysed a cohort of all patients who received 6-12 months of oral bedaquiline and delamanid in combination (400 mg bedaquiline once per day for 2 weeks, then 200 mg bedaquiline three times per week and 100 mg delamanid twice per day) in MSF-supported projects. We report serious adverse events, QTc corrected using the Fridericia formula (QTcF) interval data, and culture conversion data during the first 6 months of treatment.. Between Jan 1, 2016, and Aug 31, 2016, 28 patients (median age 32·5 years [IQR 28·5-40·5], 17 men) were included in the analysis. 11 (39%) of 28 patients were HIV-positive. 24 patients (86%) had isolates resistant to fluoroquinolones; 14 patients (50%) had extensively drug-resistant tuberculosis. No patient had an increase of more than 500 ms in their QTcF interval. Four patients (14%) had six instances of QTcF increase of more than 60 ms from baseline but none permanently discontinued the drugs. 16 serious adverse events were reported in seven patients. Of 23 individuals with positive baseline cultures, 17 (74%) converted to negative by month 6 of treatment.. Use of the bedaquiline and delamanid combination appears to reveal no additive or synergistic QTcF-prolonging effects. Access to bedaquiline and delamanid in combination should be expanded for people with few treatment options while awaiting the results of formal clinical trials.. Médecins Sans Frontières (MSF).

Topics: Adult; Antitubercular Agents; Armenia; Arrhythmias, Cardiac; Cohort Studies; Diarylquinolines; Drug Therapy, Combination; HIV Infections; Humans; India; Nitroimidazoles; Oxazoles; Retrospective Studies; South Africa; Tuberculosis, Multidrug-Resistant

Delamanid, recently available for the treatment of multidrug-resistant tuberculosis (MDR TB), has had limited use outside clinical trials. We present the early treatment results for 53 patients from 7 countries who received a delamanid-containing treatment for MDR TB. Results show good tolerability and treatment response at 6 months.

Topics: Adolescent; Antitubercular Agents; Female; Hepatitis C; HIV Infections; Humans; Male; Nitroimidazoles; Oxazoles; Retrospective Studies; Tuberculosis, Multidrug-Resistant