Emanuele Pontali

Bedaquiline and multidrug-resistant tuberculosis: a systematic and critical analysis of the evidence

The importance of adequately managing multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) cases for TB control and elimination are underlined in the new World Health Organization (WHO) “End TB Strategy” [1, 2] as part of pillar one (integrated, patient-centred care and prevention; element 2: treatment of all people with TB including drug-resistant TB, and patient support) and in the recently published “Framework towards TB elimination in low incidence countries” in its priority action 5 (optimise the prevention and care of drug-resistant TB) and the related background documents [3–5]. Furthermore, both in the End TB Strategy (pillar 3: intensified research and innovation) and in the Framework towards TB elimination in low incidence countries (priority action 7: invest in research and new tools) the need for new anti-TB drugs is strongly emphasised [1, 3, 6]. The reasons why new anti-TB drugs are needed are rather obvious if you look closely at the dimensions of the MDR-TB epidemic and the treatment successes achieved so far. Systematic review of the available scientific evidence on the role of bedaquiline in new effective M/XDR-TB regimens http://ow.ly/V68ZF

Ambulatory Multi-Drug Resistant Tuberculosis Treatment Outcomes in a Cohort of HIV-Infected Patients in a Slum Setting in Mumbai, India

Background India carries one quarter of the global burden of multi-drug resistant TB (MDR-TB) and has an estimated 2.5 million people living with HIV. Despite this reality, provision of treatment for MDR-TB is extremely limited, particularly for HIV-infected individuals. Médecins Sans Frontières (MSF) has been treating HIV-infected MDR-TB patients in Mumbai since May 2007. This is the first report of treatment outcomes among HIV-infected MDR-TB patients in India. Methods HIV-infected patients with suspected MDR-TB were referred to the MSF-clinic by public Antiretroviral Therapy (ART) Centers or by a network of community non-governmental organizations. Patients were initiated on either empiric or individualized second-line TB-treatment as per WHO recommendations. MDR-TB treatment was given on an ambulatory basis and under directly observed therapy using a decentralized network of providers. Patients not already receiving ART were started on treatment within two months of initiating MDR-TB treatment. Results Between May 2007 and May 2011, 71 HIV-infected patients were suspected to have MDR-TB, and 58 were initiated on treatment. MDR-TB was confirmed in 45 (78%), of which 18 (40%) were resistant to ofloxacin. Final treatment outcomes were available for 23 patients; 11 (48%) were successfully treated, 4 (17%) died, 6 (26%) defaulted, and 2 (9%) failed treatment. Overall, among 58 patients on treatment, 13 (22%) were successfully treated, 13 (22%) died, 7 (12%) defaulted, two (3%) failed treatment, and 23 (40%) were alive and still on treatment at the end of the observation period. Twenty-six patients (45%) experienced moderate to severe adverse events, requiring modification of the regimen in 12 (20%). Overall, 20 (28%) of the 71 patients with MDR-TB died, including 7 not initiated on treatment. Conclusions Despite high fluoroquinolone resistance and extensive prior second-line treatment, encouraging results are being achieved in an ambulatory MDR-T- program in a slum setting in India. Rapid scale-up of both ART and second-line treatment for MDR-TB is needed to ensure survival of co-infected patients and mitigate this growing epidemic.

Linezolid to treat MDR-/XDR-tuberculosis: available evidence and future scenarios.

The figures provided by the World Health Organization (WHO) in its 2013 global tuberculosis (TB) report are remarkable; TB continues to represent a significant clinical and public health problem worldwide [1]. The successes obtained by implementing and scaling-up the WHO public health strategies between 1995 and 2012 (i.e. 22 million lives saved and 56 million patients successfully treated) are outstanding. However, in spite of the dramatic decrease in incidence, prevalence and mortality [1] much needs to be done, and the new WHO post-2015 strategy (which is focused on the concept of TB elimination) is providing further guidance [2–4]. New experimental evidence on anti-TB regimes based on low-efficacious linezolid dosage to treat XDR-TB patients http://ow.ly/C9YpZ

Effectiveness and safety of bedaquiline-containing regimens in the treatment of MDR- and XDR-TB: A multicentre study

Large studies on bedaquiline used to treat multidrug-resistant (MDR-) and extensively drug-resistant tuberculosis (XDR-TB) are lacking. This study aimed to evaluate the safety and effectiveness of bedaquiline-containing regimens in a large, retrospective, observational study conducted in 25 centres and 15 countries in five continents. 428 culture-confirmed MDR-TB cases were analysed (61.5% male; 22.1% HIV-positive, 45.6% XDR-TB). MDR-TB cases were admitted to hospital for a median (interquartile range (IQR)) 179 (92–280) days and exposed to bedaquiline for 168 (86–180) days. Treatment regimens included, among others, linezolid, moxifloxacin, clofazimine and carbapenems (82.0%, 58.4%, 52.6% and 15.3% of cases, respectively). Sputum smear and culture conversion rates in MDR-TB cases were 63.6% and 30.1%, respectively at 30 days, 81.1% and 56.7%, respectively at 60 days; 85.5% and 80.5%, respectively at 90 days and 88.7% and 91.2%, respectively at the end of treatment. The median (IQR) time to smear and culture conversion was 34 (30–60) days and 60 (33–90) days. Out of 247 culture-confirmed MDR-TB cases completing treatment, 71.3% achieved success (62.4% cured; 8.9% completed treatment), 13.4% died, 7.3% defaulted and 7.7% failed. Bedaquiline was interrupted due to adverse events in 5.8% of cases. A single case died, having electrocardiographic abnormalities that were probably non-bedaquiline related. Bedaquiline-containing regimens achieved high conversion and success rates under different nonexperimental conditions. Bedaquiline is safe and effective in treating MDR- and XDR-TB patients http://ow.ly/6MWK30adHkw

New anti-tuberculosis drugs and regimens: 2015 update

Over 480 000 cases of multidrug-resistant (MDR) tuberculosis (TB) occur every year globally, 9% of them being affected by extensively drug-resistant (XDR) strains of Mycobacterium tuberculosis. The treatment of MDR/XDR-TB is unfortunately long, toxic and expensive, and the success rate largely unsatisfactory (<20% among cases with resistance patterns beyond XDR). The aim of this review is to summarise the available evidence-based updated international recommendations to manage MDR/XDR-TB, and to update the reader on the role of newly developed drugs (delamanid, bedaquiline and pretomanid) as well as repurposed drugs (linezolid and meropenem clavulanate, among others) used to treat these conditions within new regimens. A nonsystematic review based on historical trials results as well as on recent literature and World Health Organization (WHO) guidelines has been performed, with special focus on the approach to managing MDR/XDR-TB. The new, innovative global public health interventions, recently approved by WHO and known as the “End TB Strategy”, support the vision of a TB-free world with zero death, disease and suffering due to TB. Adequate, universally accessed treatment is a pre-requisite to reach TB elimination. New shorter, cheap, safe and effective anti-TB regimens are necessary to boost TB elimination. The new WHO post-2015 End TB Strategy will support the efforts that research on new drugs and regimens requires http://ow.ly/LnJER

Natural killer cells in HIV controller patients express an activated effector phenotype and do not up-regulate NKp44 on IL-2 stimulation

Control of HIV replication in elite controller (EC) and long-term nonprogressor (LTNP) patients has been associated with efficient CD8+cytotoxic T-lymphocyte function. However, innate immunity may play a role in HIV control. We studied the expression of natural cytotoxicity receptors (NKp46, NKp30, and NKp44) and their induction over a short time frame (2–4 d) on activation of natural killer (NK) cells in 31 HIV controller patients (15 ECs, 16 LTNPs). In EC/LTNP, induction of NKp46 expression was normal but short (2 d), and NKp30 was induced to lower levels vs. healthy donors. Notably, in antiretroviral-treated aviremic progressor patients (TAPPs), no induction of NKp46 or NKp30 expression occurred. More importantly, EC/LTNP failed to induce expression of NKp44, a receptor efficiently induced in activated NK cells in TAPPs. The specific lack of NKp44 expression resulted in sharply decreased capability of killing target cells by NKp44, whereas TAPPs had conserved NKp44-mediated lysis. Importantly, conserved NK cell responses, accompanied by a selective defect in the NKp44-activating pathway, may result in lack of killing of uninfected CD4+NKp44Ligand+ cells when induced by HIVgp41 peptide-S3, representing a relevant mechanism of CD4+ depletion. In addition, peripheral NK cells from EC/LTNP had increased NKG2D expression, significant HLA-DR up-regulation, and a mature (NKG2A−CD57+killer cell Ig-like receptor+CD85j+) phenotype, with cytolytic function also against immature dendritic cells. Thus, NK cells in EC/LTNP can maintain substantially unchanged functional capabilities, whereas the lack of NKp44 induction may be related to CD4 maintenance, representing a hallmark of these patients.

Multidrug-resistant tuberculosis in Europe, 2010-2011.

Ongoing transmission, high levels of drug resistance, and poor diagnostic

Adherence to combination antiretroviral treatment in children.

Abstract Purpose: To assess the level of nonadherence to combination antiretroviral therapy of HIV-infected children and to identify the main problems faced by caregivers when giving medicines to children. Method: A questionnaire was administered to the caregivers of HIV-infected children who were under combination antiretroviral treatment and were followed at our institution. Results: We evaluated 44 children (mean age, 9.4 years); 13 were treated with a two-drug regimen, 30 with a three-drug regimen, and 1 with a four-drug regimen. Each child received a mean of 8.1 pills and/or syrup doses. In 54.5% of treatments, food restrictions were necessary. The mother was the main person giving medicines to the child (56.8%). A complete written schedule of the child’s treatment was present in 50% of families. About 20.5% and 31.8% of children had missed at least one dose of antiretroviral drugs in the last 3 days before assessment and since last visit (1-2 months earlier), respectively. Main problems reported by caregivers were: (a) too many medicines/ pills (34%); (b) difficulty in swallowing pills (29.5%); (c) taking medicines at school or out of home (27.3%); (d) child resisting/refusing therapy/spitting out (25%); and (e) food interactions (22.7%). Conclusion: The observed high level of nonadherence was similar to what was reported by other pediatric studies. Specific interventions aimed at improving compliance in pediatric patients were identified: improvement of anti-HIV drug formulations, better counselling for children and their families, and tailoring of antiretroviral treatment. However, caution is necessary in generalizing our results due to the small sample size and to the heterogeneity of the cohort.

Drug-resistant tuberculosis.

Purpose of review This review discusses the recent evidence on epidemiology, diagnosis, and treatment of drug-resistant and multidrug-resistant (MDR) tuberculosis (TB), an area where solutions for better diagnosis and treatment continually develop. Recent findings The prevalence of drug resistance has been constantly rising during the recent years. It has peaked in eastern European countries such as Belarus, where a record of 35.5% MDR-TB amongst new cases have been reported from Minsk. New diagnostic tools are becoming available. Xpert MTB/RIF is by far the most promising of these new techniques. Clinical management of drug-resistant TB is still cumbersome. However, after over 40 years of neglect, new drugs are becoming readily available: delamanid, bedaquiline, and PA-824 combined into innovative regimens raise hopes for substantially higher success rates. Summary The innovative diagnostic tools recently validated are changing the traditional paradigms of TB diagnosis, for too long based on sputum smear, culture, and drug susceptibility testing. New anti-TB compounds, which can be combined with several ‘old’ drugs with new indications, are gradually modifying the chances of cure for MDR-TB cases. Although initial evidence appears promising, the market use of new drugs must be accompanied by a serious public health approach aimed at preventing the development of further drug resistance.

Compliance to combination antiretroviral therapy in HIV-1 infected children

Adherence to antiretroviral therapy is considered one of the most important factors determining the success of treatment. Its crucial role in antiretroviral treatment has been proven in both adults and children [1–4]. Monitoring adherence to combination anti-HIV therapy is a crucial tool in improving compliance and consequently in obtaining a durable suppression of plasma viral load [5]. Many variables influence adherence to a single drug or to a more complex regimen: formulation of drugs, number of tablets, schedule of administration, taste, food interference with absorption, duration of treatment, adverse events (quality, quantity and frequency), clinical status and efficacy. Taste, palatability, liquid formulation, ease of administration, number of tablets and interactions with food are determinant features in the treatment of children. Such features can become great problems for their parents and their physicians if therapy is long term. Our cohort included 37 children with perinatally acquired HIV infection. Thirty four of them were on combination antiretroviral treatment at the time of the study. Twenty five consecutively treated children were enrolled in our study after written consent had been obtained from parents or guardians. A questionnaire was used to evaluate the degree of adherence to treatment and the main problems faced by people who had to give medicines to the children every day. Our form included a series of questions about antiretroviral treatment and was an adaptation of a similar one used in the USA in 1997–1998 [6]. Children of our cohort who were included in the study were mainly males (56%); their mean age was 8.2 years (median: 8 years). Each child took a mean of 7.36 tablets and/or syrup doses. Evaluation of the answers from the questionnaire gave the following results: 1. The mother was the main person giving medicines to the child (80%). 2. The father or grandmother were the other chief figures (16% each). 3. A written list of child’s medicines was kept by 24% of families and a full written schedule of the child’s treatment by 44% of families. 4. Twenty four percent of children had missed at least one dose in the 3 days before the visit and almost half the children (44%) had missed at least one dose since the last visit.