A Randomized Controlled Double Blind Trial of Ciclosporin versus Prednisolone in the Management of Leprosy Patients with New Type 1 Reaction, in Ethiopia.

BACKGROUND: Leprosy Type 1 (T1R) reactions are immune-mediated events leading to nerve damage and preventable disability affecting hands, feet and eyes. Type 1 Reactions are treated with oral corticosteroids. There is little evidence on alternative treatments for patients who do not respond to steroids or experience steroid adverse effects. We report the results of a randomized controlled trial testing the efficacy and adverse effect profile of ciclosporin and prednisolone (CnP) in comparison to prednisolone only (P) in patients with new T1R in Ethiopia. Ciclosporin is a potent immunosuppressant. Outcomes were measured using a clinical severity score, recurrence rate, adverse events and quality of life. RESULTS: Seventy three patients with new T1R were randomized to receive CnP or P for 20 weeks. Recovery rates in skin signs was similar in both groups (91% vs 88%). Improvements in nerve function both, new and old, sensory (66% vs 49%) and motor (75% vs 74%) loss were higher (but not significantly so) in the patients on CnP. Recurrences rates of T1R (85%) were high in both groups, and recurrences occurred significantly earlier (8 weeks) in patients CnP, who needed 10% more additional prednisolone. Serious major and minor adverse events rates were similar in patients in the two treatment arms of the study. Both groups had a significant improvement in their quality of life after the study, measured by the SF-36. CONCLUSIONS: This is the first double-blind RCT assessing ciclosporin, in the management of T1R in Africa. Ciclosporin could be a safe alternative second-line drug for patients with T1R who are not improving with prednisolone or are experiencing adverse events related to prednisolone. This study illustrates the difficulty in switching off leprosy inflammation. Better treatment agents for leprosy patients with reactions and nerve damage are needed

Novel approaches toward the development of an oral post-exposure DNA vaccine for latent tuberculosis using Salmonella typhimurium ΔaroA vector

Tuberculosis remains one of the major causes of global public health problems. There is no effective vaccine for the disease until now. Many reports show that DNA vaccines are promising to induce protection against Mycobacterium tuberculosis (M. tb); however, the efficiency of DNA vaccine is limited due to inadequate delivery systems. Among others, live attenuated bacterial vectors such as Salmonella enterica typhimurium (S. typhimurium) have significant promise as efficient mucosal delivery vehicles for DNA vaccines. In this study, we constructed recombinant attenuated S. typhimurium DNA vaccines carrying genes encoding resuscitation promoting factor (Rpf)-like proteins of M. tb on eukaryotic expression plasmid agianst latent tuberculosis and evaluated the plasmid stability and growth curve assays of the recombinant Salmonella vaccine constructs in vitro. Four Rpf gene fragments (RpfB, RpfC, RpfD, RpfE) associated with latency were amplified from genomic DNA of the H37Rv strain of M. tb, cloned into eukaryotic expression plasmid (pVR1020) and verified by sequencing. In later studies, we will demonstrate the potential use of the Salmonella-mediated DNA constructs as candidate post-exposure vaccines against tuberculosis through testing their immunogenicity and effectiveness for oral delivery in eukaryotic systems.Key words: Latent tuberculosis, resuscitation promoting factor (Rpf), DNA vaccine, recombinant Salmonella typhimurium

Comparison of Efficacy and Safety of Ciclosporin to Prednisolone in the Treatment of Erythema Nodosum Leprosum: Two Randomised, Double Blind, Controlled Pilot Studies in Ethiopia.

BACKGROUND: Erythema Nodosum Leprosum (ENL) is a serious complication of leprosy. It is normally treated with high dose steroids, but its recurrent nature leads to prolonged steroid usage and associated side effects. There is little evidence on the efficacy of alternative treatments for ENL, especially for patients who have become steroid resistant or have steroid side effects. These two pilot studies compare the efficacy and side effect profile of ciclosporin plus prednisolone against prednisolone alone in the treatment of patients with either new ENL or chronic and recurrent ENL. METHODS AND RESULTS: Thirteen patients with new ENL and twenty patients with chronic ENL were recruited into two double-blinded randomised controlled trials. Patients were randomised to receive ciclosporin and prednisolone or prednisolone treatment only. Patients with acute ENL had a delay of 16 weeks in the occurrence of ENL flare-up episode, with less severe flare-ups and decreased requirements for additional prednisolone. Patients with chronic ENL on ciclosporin had the first episode of ENL flare-up 4 weeks earlier than those on prednisolone, as well as more severe ENL flare-ups requiring 2.5 times more additional prednisolone. Adverse events attributable to prednisolone were more common that those attributable to ciclosporin. CONCLUSIONS: This is the first clinical trial on ENL management set in the African context, and also the first trial in leprosy to use patients' assessment of outcomes. Patients on ciclosporin showed promising results in the management of acute ENL in this small pilot study. But ciclosporin, did not appear to have a significant steroid-sparing effects in patients with chronic ENL, which may have been due to the prolonged use of steroids in these patients in combination with a too rapid decrease of steroids in patients given ciclosporin. Further research is needed to determine whether the promising results of ciclosporin in acute ENL can be reproduced on a larger scale

Anti-Tuberculosis Therapy-Induced Hepatotoxicity among Ethiopian HIV-Positive and Negative Patients

Background: To assess and compare the prevalence, severity and prognosis of anti-TB drug induced hepatotoxicity (DIH) in HIV positive and HIV negative tuberculosis (TB) patients in Ethiopia. Methodology/Principal Findings: In this study, 103 HIV positive and 94 HIV negative TB patients were enrolled. All patients were evaluated for different risk factors and monitored biochemically and clinically for development of DIH. Sub-clinical hepatotoxicity was observed in 17.3 % of the patients and 8 out of the 197 (4.1%) developed clinical hepatotoxicity. Seven of the 8 were HIV positive and 2 were positive for HBsAg. Conclusions/Significance: Sub-clinical hepatotoxicity was significantly associated with HIV co-infection (p = 0.002), concomitant drug intake (p = 0.008), and decrease in CD4 count (p = 0.001). Stepwise restarting of anti TB treatment was also successful in almost all the patients who developed clinical DIH. We therefore conclude that anti-TB DIH is a major problem in HIV-associated TB with a decline in immune status and that there is a need for a regular biochemical and clinical follow up for those patients who are at risk

Duration and severity of T1R in study participants.

<p>Duration and severity of T1R in study participants.</p

Sensory function change in nerves with new loss of sensation.

<p>Sensory function change in nerves with new loss of sensation.</p

Weekly mean prednisolone per patient by treatment arm.

<p>Weekly mean prednisolone per patient by treatment arm.</p

Number of T1R recurrence episodes by Clinical Severity Score.

<p>Number of T1R recurrence episodes by Clinical Severity Score.</p

Number of patients experiencing minor and major adverse events per study arm (related to ciclosporin and/ or prednisolone).

<p>Number of patients experiencing minor and major adverse events per study arm (related to ciclosporin and/ or prednisolone).</p

Median and inter-quartile ranges in Clinical Severity Scores.

<p>Median and inter-quartile ranges in Clinical Severity Scores.</p