 Okay, good afternoon. Welcome back from the break. So we are continuing with the last session of today, which is the fourth session. And this is also a special session because this session will be live-streamed in the UK, in London. So what it means is that the people in the auditorium of the Royal Society of Madison in London will follow this session, but also online on the session will be live-streamed. So I would also like to welcome our audience in London and to the MSF Scientific Day in India. So the fourth session will start with introducing the Chair, who is Dr. Suman Rijal. So can I ask Dr. Suman Rijal with the presenters to come up to the stage, please? And I'll introduce him and then Suman will introduce the presenters. Suman Rijal joined DNDI in 2014 as the Managing Director of the Regional Office in India. Before joining DNDI, he was Professor of Internal Madame Chief Tropical and Infectious Diseases Centre at BP Corolla Institute of Health Sciences in Nepal, where he has been a faculty member since 1997. For the last 15 years, he has been working in the field of neglected tropical diseases, particularly Kalazar. He coordinated several collaborative research projects and participated in the development of guidelines for the control of Kalazar in the region. He undertook his medical training in Kolkata, India, and the United Kingdom and was awarded a PhD from the University of Ghent in Belgium. He's a member of several national and international committees, including the WHO Expert Panel on Parasitic Diseases, Lysmoniasis, Ingeniva, and the Regional Technical Advisory Group on VL Elimination at WHO SAE, that's Southeast Asia Regional Organization. So I welcome everybody and I wish you a good session. Thank you. Thank you Martin for the kind words and introduction. I welcome you all here in India and also in London and around the world who are watching this program to this final session of the scientific program, first scientific program day in India. I'm pleased to let you know that we have a panel of five speakers who are going to present to you on the different things related to Kalazar control. Just to briefly introduce to you, as many of you would be aware, but some of you may not be aware that India, Nepal, Bangladesh had started a Kalazar Elimination campaign in 2005 and with a target to reach this elimination target by the end of 2015 which has been agreed to be increased to 2018. There has been quite a remarkable achievements to attain this goal, but there are still some major issues remaining and the speakers today are going to discuss some of the ways to challenge some of these important issues which still are needed to be challenged. For example, how do we reach our patients early? How do we manage PKDL? How do we manage HIV VR co-infections? So I would like to start the session by introducing you to the first speaker who is Mani Moai Chakma, who is from MSF. He has been with MSF since April 2010. He's currently Outreach Supervisor in the post-Kalazar Dermal-Lishmanias' program in Miami-Sing District in Bangladesh. He holds an MBA in management and is studying for an MPH at the American International University in Bangladesh. So he's going to talk to us on the active and passive case detection strategies for control of VR in Bangladesh. Honorable Chair and distinguished guest, I thank you everyone and good afternoon as I am introduced. So I'm going to present today active and passive case detection strategies for control of VR-Lishmanias' in Bangladesh. As we know, Kalajor is a parasitic disease that kills if remains untreated. So in other words, it's a deadly disease also. More than 7,000 cases of Kalajor were reported particularly till 2007 in Bangladesh. And 5, 2007, around 200,000 and 500 to 3,000 patients were reported from specifically to Tishalopojela. First Kalajor Dermal-Lishmanias' develops in 10 to 15 percent. Piccadil patients serve as a source of infection if not treated. And Piccadil patients usually do not seek care by themselves. In the region, they are not aware about the disease, about the reservoir or parasites. And more importantly that they are not sick. They don't feel sick. So they just do whatever they do just like a normal person. Out of 64 districts of Bangladesh, 32 districts affected by Kalajor and 70 percent reported from myosin districts. In myosin districts, actually 5 upojela, so sub districts are endemic, Kalajor endemic, which are full barrier, Tishal, Muktagasa, Bhaluka and Gaffergaon. Full barrier and Tishal, which are hyper endemic for release many cases in Bangladesh contributed 50 percent case load. Why did MSF intervene? The conventional treatment was of Kalajor and Piccadil was long and not safe. The treatment was SSG and it was a painful injection Kalajor and also 120 days injection for Piccadil. Pacific case detection was missing a lot of patients in the community, especially Piccadil. As I said earlier that Piccadil patients usually do not seek care by themselves because they are unaware about the parasites. If Piccadil is not treated, then elimination of Kalajor will not be possible. Project location, this is the map of Bangladesh and this is myosin district. Full barrier upojela, Tishal upojela, full barrier and Tishal upojela, neighboring upojela. Objective of this study was to determine the yield of active case detection in terms of number of cases of BEL and Piccadil diagnosed and to compare it with that of diagnosed by Pacific case detection. Method, study design, this is descriptive study type. It was exceptional research, it was done in a program setting that's why data were collected retrospectively. Study population, all be sure less many assist in Piccadil patients diagnosed between April 2010 to December 2011 in MSF Kalajor treatment center and also health complex of Tishal. Ethical approval, we obtain ethical approval from MSF ethical review board. It was also approved by ethics advisory group of the International Union against tuberculosis and lung disease. Permission from the director of communicable disease control, Ministry of Health, Dhaka, Bangladesh results. I'm showing the results by this bar diagram. Case diagnosed during April 2010 to December 2011. Be sure less many assist cases and the right side is the Piccadil cases. So be sure less many assist by the active case detection MSF diagnosed 1087 patients which was 59% of total patients and in detection area which is case where reported 756 which is 41% of total patients. And in case of Piccadil, MSF diagnosed by active case detection 1145 patients which is 97% of total patients and in Tishal active case detection area only 37 patients were reported which is only 3% of total patients. And by outreach MSF did the active case detection by a trained outreach worker team and in case of be sure less many assist outreach report 195 patients which is 18% of total patients but in case of Piccadil MSF report directly 667 patients which is almost 59% of total patients. So this is very clear that active case detection patients can be found more than the passive case detection. Conclusions. Successful active case finding strategy based on cluster approach. I should say something about the cluster approach. In the beginning of the MSF work we started our active case detection by the do-to-do approach but later on we had to switch cluster approach considering this and the research. So cluster we defined it as 20 hundred meters radius index case as a cluster. We visited almost every clusters more than three or four times. So an active case detection strategy at the sub-district level resulted in an increased yield of be sure less many assist and a much higher yield of Piccadil. Thank you. Thank you for a very nice presentation. I would like to open the floor for any clarifications on this presentation. Yes, please. Could you use the mic? Thank you for the very nice presentation. Active case detection by its very nature. It is definitely going to give increased yield. But to me one of the questions that lingers is what was the cost per patient identified? So would you be able to... Sorry, it's not clear actually. So what were you able to estimate the cost per case identified by the active case? So I said it was an operational reaches. So we did it in a program settings. As a program, MSF had owner staffs who used to go to the outreach. So it was part of the program. There is no actually specific cost related to it. Can I have one more question? Yes, please. So the second question is in the non-the government health program districts. Were these like... Was there a dedicated program and workers dedicated only for the control efforts? Like you know we have a dedicated tuberculosis program. Or was it part of the general health setting? It was actually specially for the Calajor. Because MSF started working there for Calajor. And before MSF started the Calajor condition in that area was very poor, very bad. So as I presented that why MSF did intervention. So MSN outreach staffs, outreach team who were dedicated to go to the community level and find the patients in the community. And we referred patients to the MSF Calajor treatment center. Thank you. Thank you. At the back there. Thank you for the nice presentation. My question is corrected to the earlier question but it's a bit different. My question is that what has been the sustainability strategy? Was there an effort to give the methodology to the government system to do the active case detection and whether the government bought this idea of active case detection in their program? That's question number one. Question number two is just clarification that I read through the document. What was the confirmatory test which was performed at the clinic? It says that the kit was used, ARCHITARTENAN kit was used at the community level. But what was the confirmatory test at the clinical level? So I would like you to answer the second question and the clarification. The first question is very important and we could take it up in the discussion. So ARCHITARTENAN test is also done in the community by the outreach team. But when patients were self-reported, they came by themselves, then in the clinic settings we had a laboratory there. They were tested. Okay. Thank you very much. Actually, as you know that we don't have any vaccine for prevention of Kalazar. And the only strategy we have is early detection and appropriate treatment along with vector control. So this is a very important demonstration that if you have a strategy of active case finding, you will not only be able to take the reservoir out of the community and decrease transmission, but it also has a benefit effect on the patient that they will also have a better outcome of treatment which has been well demonstrated. Thank you. So now I would like to invite the second speaker, Dr. Vishal Goyal. Vishal is a medical doctor specialized in anesthesia. Since January 2011, he has been working as a clinical manager at the DNDI initiative. He has global clinical trials, has a special interest in drug development, and is knowledgeable about the Indian health structure. He has implemented studies on VL involving government agencies and international partners at primary health center and district level in India and Bangladesh. Vishal is going to talk to you in the next 10 minutes on effectiveness of new treatment regimes for VL in Bangladesh and Nepal. Thank you, Dr. Soman. Good afternoon, everyone. I will talk on safety and effectiveness of new treatment regimes for VL in Bangladesh and India. Just to give you a background introduction. So in last decade, we have seen a development of new treatment regimes from existing liposomal lymphoterosine B, paramoysine, and myltofazine. So various new treatment regimes has been developed like combination of paramoysine and myltofazine, and myltofazine. So new treatment regimes that is combination of paramoysine and myltofazine, combination of ambisome and myltofazine, combination of ambisome and paramoysine. D&A has conducted phase three clinical trials completed in 2010 on these new treatment regimes which have been reviewed and then recommended by WHO expert committee and regional technical advisory group of WHO. So they also recommended to do field implementation study at a primary health center level so that it can be adopted into the national program. D&A conducted two studies on new treatment regimes, one in Bangladesh, another in India. Phase three clinical trial was conducted in Bangladesh to assess the safety and efficacy, and pilot implementation study was done in India to assess the safety and effectiveness. The objective of these studies was to provide data to provide evidence, policy makers for replacing medicine monotherapy which has been given for 28 days with new treatment regimes and to be adopted into the national Kalazar elimination program. The rationale of this new treatment regime was to reduce the treatment depending on the type of treatment like single dose ambisome which is given for one day, medicine paramoysine treatment is given for 10 days. So from 28 days it will be reduced to 1 to 10 days. Improving the compliance and also preventing the emergence of resistant parasites. I'll start with a trial done at Bangladesh. Phase three open-label randomized non-inferty study was conducted in Bangladesh from 2010 to 2014. Treatment regimes were medicine and paramoysine combination for 10 days, ambisome and medicine combination for 8 days, ambisome and paramoysine combination for 11 days. They were compared with ambisome monotherapy. Their total dose was 15 milligram per kg. This study was conducted in two steps, step one and step two. So in step one, 120 patients they were enrolled and at medical college at Maiman Singh. All these patients they were hospitalized for 15 days and treatment provided. The primary purpose of step one was to assess the safety of new treatment regimes and then this data was reviewed by data safety monitoring board which gave a green signal to proceed to step two. In step two, three Uppsula health centers were identified, Trishal, Baluk and Gaffergaon where 482 patients were enrolled. Total of 602 patients were enrolled. Talking about their results, in ambisome group 158 patients were enrolled, ambisome, paramoysine group 159 patients were enrolled, ambisome, meltypsine group 148 patients were enrolled, paramoysine, meltypsine group 142 patients. Initial cure was assessed at day 45 and in all the treatment groups, except ambisome and meltypsine group, the cure rate was 98 percent but in the ambisome meltypsine group, the cure rate was 94 percent. Final cure was assessed at six months in which cure rate was 98 percent for all the treatment groups except ambisome and meltypsine in which cure rate was 94 percent. There was no relapse during the six month fall-up period and this is the conventional period for doing fall-up in VL studies but then when the sites were followed, it was observed that there were two to three patients that relapsed but that was between six to 12 months. There was no loss to fall-up in the study because we had a dedicated team of field workers who were employed for active case detection for all patients enrolled in the study. This slide talks about the adverse events. So approximately 60 to 64 percent of patients, one adverse event in each treatment arm. There were total 12 serious adverse events in this study. Four were drug-related and eight were, there were three deaths that were not related to the study drug and all essays whether related or not related, they were resolved. To conclude, all these new treatment regimes, they showed excellent safety and efficacy. Single-dose Mbisome has been already adopted in the national guideline of Bangladesh and combination treatment has been adopted as a second option for treatment of VL. These new treatments, they can be safely administered at primary health care level as treatment duration, more compliance and less side effects. So Mbisome treatment requires cold chain storage of between 2 to 25 degrees. So combination regime can be choice of treatment where cold chain cannot be employed. Now I'll talk about a study done in India. It was an open-label prospective, non-randomized, non-comparative, multi-center study done at public health sector from 2012 to 2015, still the follow-up is ongoing. The objective of this study was to evaluate the safety and effectiveness when conducted in actual real scenario field conditions within the routine program settings, further generating evidence for the policy makers to adopt the regimes in the national program. This study was done in collaboration with the State Health Society Bihar, Rajinder Memorial Research Institute of Medical Sciences based at Patna MSF. Here I'll mention that at all sites, patients were diagnosed, investigated, and treated by the government, doctors, health staff, except one site, Hazybo district hospital, where patients were treated by MSF team, where they have experience of treating VL patients since July 2007. In this study, it was conducted in two districts of Bihar, Vishali and Saran. In Vishali district, Vishali-Hazybo district hospital, single dose ambisome treatment was given, patients were hospitalized and treatment provided, and five PhDs of Vishali district, ambisome and medicine combination treatment was given for seven days on outpatient basis. In Saran district, at district hospital, as well as PhDs, combination of Miltusin and Parmoisen was given for ten days. At district hospital level, majority of patients were hospitalized and then treatment provided, but at the PhD level treatment was done on basis. RMRI was one of the sites where all the treatment were given, and mainly the complicated patient they were offered here. From each site, whether it's for Saran or Vishali at PhD or district hospital, all the six severely complicated patients they were referred to Hazybo district for receiving treatment, and then they received, majority of them received single dose ambisome. Total of 1,761 patients were treated in this study. Initial cure was assessed at day 10. Each arm had cure rate of around 99% at day 10. Till date, 1,591 patients have completed six month follow-up. Rest of patients follow-up is still ongoing. Final cure at six month was 93% cure rate in single dose ambisome arm, 89% in ambisome miltusin group, and 97% in miltusin and Parmoisen group. Relapse, there were 4.5% relapse in single dose ambisome group, 4.8% relapse in ambisome miltusin group, and 0.5% relapse in miltusin and Parmoisen group. Here we can see, like I mentioned earlier, complicated patients they were treated in single dose ambisome group. So, maybe having higher number of... So, the national program recommended to do 12 month follow-up of these patients to generate evidence on relapse. So, in January 2015, 12 month follow-up was started in this study. And till date, it further yielded six relapse in single dose ambisome arm, six relapse in ambisome miltusin arm, and five cases of PQDL in M plus B arm. Talking about adverse events, so there were around 13% of adverse events. 13% of subjects had at least one adverse event in single dose ambisome arm, and 22 to 25% in other two arms. Total, there were five serious adverse events in this study, ambisome group. Two were drug related and three were non-drug related. So, they were all resolved. Talking about limitations of the study, it was a recommendation by DCJ regulators of India that children should be treated at district hospital level only. And so, children were, they were not treated at primary health center and they were treated at, only adults were treated at PHC level. And a higher number of severely complicated patients, they were treated in only one arm, that is single dose ambisome arm. To conclude, all treatments except ambisome miltusin group, which had cured of efficacy of 94%, they showed excellent safety and effectiveness when conducted within the public health sector, setting within the national program settings. Based on the data Indian national program, they revised the national policy for treatment of VL in last year and 14 in which single dose ambisome was considered as first option for management of VL patients and combination treatment has been adopted for treatment of VL patients. Combination regime can be choice of treatment at sites where cold chain cannot be deployed, maybe in the case of ambisome. There is need for establishment of active farm equivalent center, public health care facilities and systemally collection of the data at all the sites and integration with the national farm equivalent program. So lessons learned from both the studies is all these new treatment regimes and single dose ambisome, they are safe when conducted at public health sector level and it is very much feasible to implement these regimes at large scale in conventional doing follow up is six months and relapses continue to occur beyond six months so there is need to follow patients beyond six months maybe till 12 months to have more evidence. Cohort even monitoring should be strengthened at all sites in India and Bangladesh to document long term outcome data to generate evidence on relapse, PKDL and treatment failure. So important thing is there is need to have a great field workers like in these studies there were health educators which did detection and involved Asha workers from the field to do the ensuring less loss to follow up in the studies. So I will acknowledge all the collaborating partners and special thanks to all the doctors nurses, technicians all the staff involved in the study without whom the study would not have been possible. Thank you. Thank you Vishal. We have time for one or two questions for clarifications of the study. I have a question from the online audience. Having the single dose ambisome based treatment is already included in the guidelines in Bangladesh. Why should the MOH take up the proposed treatment of DNDI? This is someone called Ashish Kumar who is based in Bangladesh MSF. I think this question is for you. Single dose ambisome has been already adopted so we started this study in 2010. So in between this was changed and national policy was changed but we have to complete the study and then in the study there were other treatment regimes, combination treatments. So now recently it has been adopted treatment they have been adopted as second line option. Thank you sir. I am Ashish Kumar from Energy Media. My point is that I have no question of observation that in the context of safety, health and environment one issue is climate change and health care system that is called ecosystem. In this, the medicine is there but the ecological footprint decreases gel or water when the water is clean when the water is clean how to make the increase in the process of immunization of the body. Should the water be clean or the water is clean so the question is that prevention is better than cure. How to increase the ecological footprint of the areas. Thank you sir. We can consider this later on yes. One last question please. If you shall present this data very succinctly. Just one question. You said the combination was less superior as compared to the single dose. You have any good reason for it because two combinations you have used both appear to have inferior to a single drug ambizone. You used both amb and miltofousine and was it one randomized trial or how did you determine who is severe and who is not severe. So you are talking about Bangladesh study. I think other study also you used no. In Bangladesh it was only ambizone and I think it's a miltofousine group which had efficacy of 94. Rest all they were around 98% and there was a study conducted in 2010 so in which phase 3 clinical trial in which combination treatment was compared. And efficacy was also 97%. And then the ambizone monotherapy study was done with Dr. Shyam Sundar which had efficacy of around 95.6%. In this study in study being done in India over here so efficacy of 93, 94%. And ambizone miltofousine group it has efficacy of 89%. And parmoisen miltofousine has 97%. It's less though. Ambizone miltofousine it's less. Maybe sir ambizone miltofousine it's like dose of ambizone and single dose ambizone is 10 million and dose in ambizone it's 5 milligram per kg plus 7 days of miltofousine. Maybe the duration of miltofousine it has to be increased. Thank you sir. I think there is a lot to ask. I would like to request if you could keep your questions for the last half an hour which we'll have for the discussions if you don't mind. So I would like to move on to the next presenter and it is Dr. Temi Sunyoto. Temi is a doctor currently working with MSF as a medical coordinator in Delhi. She holds a MPH from the Institute of Tropical Medicine in Antwerp and completed a medical training at University of Indonesia in Jakarta. She has previously worked for the WHO and worked for MSF since 2005 in numerous countries and settings. She has a special interest in epidemiology and neglected disease and has published on VL. So Temi I invite you to present on a combination treatment for VL patients who are infected with. Good afternoon everyone. Thank you very much. So this afternoon as you know it's a session on lesmaniasis. I would like to bring your attention to one subgroup of the fissure lesmaniasis patients or KALASA which are co-infected with the human HIV virus in Bihar, India which we have treated with the combination treatment. So I will not repeat what has been said before by many more that VL or KALASA is a neglected disease meaning it has a very limited treatment option. It affects the poorest of the poor in the rural areas and the elimination goal that is in the Indian subcontinent for India, Bangladesh and Nepal is because actually we found that only one parasite is causing it, the lesmania donovani and it's transmitted by the bite of a female sandfly. So as you know I mean VL in general world is between 3 to 5 lakh cases per year but 90% are happening only in 6 countries which is India, Bangladesh, Sudan, South Sudan, Ethiopia and Brazil. However we know that even in India itself not everyone knows about KALASA because there's only 4 states that are endemic for the disease. Bihar is actually one of the epicenter you know Bihar is one of the massive state in India with population more than 100 million people and it contributes to more than 50% of the global burden of VL. So if you look at the number that is reported by national factor born disease control program of India which range between 40,000 in 2011 more close to 80% are only reported from Bihar. The other state like Jharkhand, West Bengal and Uttar Pradesh are contributing very small proportion. However I would like to note as well that this elimination also we know that in the last year we have seen a declining trend in the epidemiology that we see the number from 2011 if you see it was 33,000 reported cases of India and then it goes down to 20,000 in 2012 and last year was less than 10,000 patients are reported. Now to bring to the other side which is the HIV burden in Bihar itself as I said before has a massive population and it's also out migration a lot of people from Bihar are working in other states the prevalence generally is considered as low 0.2% However it's one of the few states in Bihar with the prevalence are increasing and these are the statistics that are officially from NACO that this number of people of living with HIV AIDS are served with only 14 ART centers and also they're probably reporting around there's between 100 to 300,000 people HIV AIDS in the state my apology that actually the first line treatment that are now being used as a NACO guidelines is as we know before it was Zidoo Fudin and TDF, let me food in and if you're up in Afafir and so this is not correct. Now we'd like to bring on attention why this co-infection is important. So first of all we don't know really the magnitude of the problem so there is limited evidence on the prevalence of HIV as sensitive and as well they have a typical presentation because normally Calazares have a prolonged fever sprenomegalia and all that which is not always the clinical manifesting subgroup and also it has been very well established in the evidence that they have a worse treatment response with the treatment that are available so they have higher risk of mortality so they die much more and they relapse much more meaning they have repeated episode of feel throughout their life let's say. So there is a recent study I will come back to that later that when you compare to the HIV negative patient for sure the rate of mortality and really much higher and until recently there also is a high risk group of HIV meaning the voluntary counseling and testing are not routinely offered to them and as I have mentioned before as well actually in India since October 2014 the single dose ambisome has also been adopted as first line treatment for primary Calazares. However this regimen is not suitable for this co-infected group because it's kind of low dose. So for the moment in India there is no national guidance available they they were given the same regimen which is 20 to 25 milligram per body weight. So the combination treatment that I'm going to speak here is actually a combination between 30 milligram of ambisome so it's divided in six dose and plus 14 days of 100 milligram of metafocine. So the objective is to determine the long-term outcome because this is the evidence that I'm missing what are the outcome in the longer term for this particular subgroup. So this is an observational study retrospectively analyzing routine program data. We are diagnosed field using the RK-39 and whenever feasible we do the spleen and bone marrow aspiration and we do a monthly follow-up of the patients. So this study fulfilled the criteria of exemption of MSF ethical review board and as well this the use of the combination treatment itself has been approved by in compensation at use based on expert opinion and as well by Arimara institutional committee. So when we look at the results here we saw that okay throughout from July 2012 until September 2014 we have 102 patients majority are males and we see that quite high proportion they seek treatment beyond four weeks almost half of them already has previously treated with FL with various regimen they have concurrent TB and and almost half of them they know that they were HIV before meaning they were actually already somehow managed in the ART center and they were referred to us for the FL management. So when we look at the mortality analysis we saw among the 102 patients we have 16 deaths maybe just to say that the mortality at 6 months is quite high at 11 percent at 12 months is 14.5 and 18 months at 16.6 percent if you see from the graph you saw that actually there is quite high risk of early mortality 6 months although later on it rich kind of plateau. He's webbed by our institutional ethical committee though in the past 7 years these are their admission rate 4459 HIV patient 408 BL patients and 24 BL HIV the BL patients diagnosed with HIV infected after admission and almost majority of the patients at previous relapses most probably 5 5 had 5 had 2 relapses 7 had multiple relapses look from 2010 the HIV is gradually blue is the HIV HIV is gradually steadily decreasing BL is strictly decreasing whereas HIV BL from 2000 steadily increasing and now has reached a plateau if you compare the best characteristics of HIV BL and the mono infected BL I have collected data of a historical cohort of 120 BL patients compared to the HIV BL the significant difference you look at the age whereas in BL 18 years and HIV BL 30 and in this means hemoglobin 7.1 hemoglobin is low in comparison to significantly low in HIV BL and other features like hepatomegaly, liver size etc K39 positivity in serum 90% and with RK39 positivity with testing with urine you all know that it can be tested also with urine it is more 23 was positive with 24 C4 count was 1 less than 200 CT4 as in 87.5% and 3 patients presented with artificial features the predominant clinical picture was diarrhea and 2 and cop with respiratory trouble in 1 and diarrhea not controlled with antipotozoal antibiotic and ultimately antillismenial drug given to control treatment outcome amphotericin B was given a total 20mg per kg 14% life 10% liposomal end of treatment cured at 96% 1% diet while on treatment HIV hurts completion of total dose it is our policy to give after completion after control the infection and then another factor is that we are giving tenopovir for HIV and amphotericin B is nephrotoxic tenopovir is also nephrotoxic and look that is one 2 patients with respiratory involvement GI involvement you give heart immunity will be raised and theoretical chance of IRIS so our policy is to complete the treatment of VL it is easy to initial cure the patient then start HIV and if CD4 rise then relapse rate will be low we have given secondary prophylaxis to 12% 52% with 1mg per kg monthly amphotericin B and the result is spectacular in the secondary prophylaxis group no relapse no death whereas in the no secondary prophylaxis group 8% relapse over 1 year 5% died over 1 year the difference is highly significant so our 23 patients 1 patient died before treatment secondary prophylaxis given in 12 at that time the mean CD4 count was 122 no prophylaxis group 11 mean CD4 count was 126 6 months cure rate that is end of treatment and follow up for 6 months here it is in the secondary prophylaxis 12 after CD4 steadily increased from 122 to 180 and what is the problem and in 1 year and 2 years follow up CD4 then 378 after 2 years after 1 year and no patient relapse no prophylaxis group 6 months cure rate 8% relapse at least 1 6 months and within 1 year multiple relapses in 5 patients and they died amongst them 2 stopped ART and we could not follow up 3% we are lost to follow up in Kaplan-Mayer analysis you can easily you can see the graph there is definite survival advantage for the secondary prophylaxis group and with the cox regression analysis of the multiple variables we found secondary prophylaxis the most robust important factor to prevent relapse and death baseline CD4 is also important if you look at the picture no prophylaxis group CD4 was when those patients were not on secondary prophylaxis but CD4 rose after after ART the CD4 175 they did not relapse though this sample size is very low but those where CD4 steadily CD4 steadily decreased from 126 to 108 and then no result their relapse and death were high so limitation our limitation is that our data was not computerized detailed clinical laboratory data of every patient were not available some data hands with some data had to be eliminated from the analysis and very few data were available prospective analysis very small cohort size some of secondary prophylaxis may be due to other associated infection because of declining CD4 count detailed investigations were not always available and Burjai et al they have studied with most probably Sunito presented it 159 patients you have already seen it so what we learn from my experience increasing it is deadly if not deadly R then VL at least early initiation of ART appears to be promising tool along with the secondary prophylaxis against VL needs to be considered with seriousness and generation of evidences against opposition of eminences those of the eminent physicians those thing secondary prophylaxis may give rise to resistance because of giving lower dose but we need larger studies to establish our hypothesis that is a very important tool personally as a clinician I think giving secondary prophylaxis giving life to the HIV VL patients thank you for your patience thank you Dr. Goswami now I open the floor for any clarifications so thank you sir that was a very good presentation and it's really a issue treating the relapse again and again and it's quite inspiring about the secondary prophylaxis but you've not mentioned like how long did you go with this secondary prophylaxis secondary prophylaxis is usually given till CD4 rises above 200 to 250 and it is sustained and maintained over 200 for 6 months at least then we have stopped secondary prophylaxis that is the reason actually so we have to continue ampere dressing B monthly for one year to one and a half year at least to get CD4 above 200 that was also the reason why we go on giving 5 milligram per kg life as well ampere dressing B monthly then the cumulative toxicity will give rise to permanent renal injury thank you sir thank you very much now I would like to invite the last speaker of this session Dr. Sakeeb Burza Sakeeb has been involved with MSF since 2003 originally trained as an anesthetist he now works in public health and community medicine he has previously worked in Sudan, Gambia, Palestine Uzbekistan, Afghanistan and India he is currently completing a PhD and VL at the Institute of Tropical Medicine at Antwerp while researching the economics of NDD and neglected infectious disease we will talk on PKDL treated with LTCNB thank you so much first of all thank you all for staying I was expecting most of the people to disappear by now so well done for sticking it out I'm going to talk today it kind of fits nicely with the other presentations that we've had this is one of the sub-sectors, sub-sections of visceral life moniesis that's not very well known about to the general public as Temi saying even VL isn't particularly well known throughout India let alone the world it's one of those things that you sort of remember from medical school but not really much about it it's something to do with the sand fly and this is something that's even smaller so to speak than that so PKDL post-calizard dermal life moniesis it's essentially a complication related to visceral infection with visceral life moniesis it's common in areas endemic for VL caused by Eldonavani and it's characterised by skin rash after an episode of VL although there is some evidence of it it can happen concurrently as well however it poses quite an interesting dilemma for us because the patients are typically not ill it's not a fatal disease and the main issue is that of aesthetics however at the same time it's based on existing evidence it's a substantial public health problem because it's a major reservoir of Eldonavani so when we talk about elimination which is something that my colleagues have mentioned a few times in VL that basically means reducing the incidence of disease to less than 1 in 10,000 not to be confused with interruption and transmission but elimination is a public health problem however once we get the numbers down sustain that level at a low level for the next 5 to 10, 20, 30 years if you have this major reservoir remaining then of course that's going to be very difficult to do so from the public health perspective imperative that we treat these patients however at the same time it's not considering the patients from the aesthetics aren't actually ill there's a burden upon the healthcare provider to make sure that whatever treatment is provided is a safe treatment with minimal side effects or compromise for the patient themselves now unlike in Africa in South Asia PKDL isn't thought to self heal in Africa what we see the same parasite but we see that about 50% of cases do tend to self heal by 6 months after the onset say in South Asia if we're looking at interruption transmission then we do need to focus on treating PKDL and just numbers wise about 5 to 10% of VL cases are thought to go on to develop PKDL depending partly on the treatment used giving us an incidence of about 4.8 per thousand with an interval of between 0 and 3 years after suffering the initial VL infection as I was saying it's really a neglected disease within a neglected disease we don't really know very much about this condition we don't know really why it happens we have some ideas some immunological factors that are being looked at closer and closer we don't really know what the pathogenesis really know what the risk factors are there have been some studies but primarily based on the very small sample sizes it's very difficult to establish any patterns or causality to pick up on I think one of the questions from Vigoss which was about diagnosis accurate diagnosis is really a challenge presently we don't really have any very sensitive and specific tests normally PKDL is diagnosed by the use of the RK39 serological test however this is a test that any patient who has VL will test positive for different periods of time following the infection so if a patient presents with what a lesion that may look like PKDL but they've had a previous history of VL their RK39 test may be positive and that doesn't really help you with regards to diagnosis pathological visualization so basically sampling the lesions and looking at the lesions looking at the sample under a microscope is the gold standard test however for the majority of lesions which are macular lesions basically I'll show you some pictures in a minute the sensitivity is very low 30-50% and most importantly it requires experience and skilled human resources available in the majority of the sites and certainly not in the public at the primary healthcare level secondary to this there is very little evidence on management we don't really have any idea about how well the current drugs used for visceral isomalysis of which there are very few how well do they penetrate the skin so when it comes to estimating doses duration of treatment it's really just guesswork how much does a drug injected intravenously does it access the epidermis the same thing goes for oral drugs topical drugs as well there's also no evidence on the end point of treatment we don't know when to stop treatment we know that after some time usually between one to three months there is a response following treatment but obviously for complete clearance of all the lesions do you wait for partial clearance to show no parasite we don't really know some pictures here about just to kind of show you what Picardia looks like this is the macular form basically look very easily confused with vitiligo can be confused with leprosy as well the difference being that you have some sensation we have popular lesions here slightly raised lesions which are more disfiguring tumourous lesions here if you actually look at the back of the very back page of the scientific day guide you can see a nice picture of a lady who pre and post treatment and this here is the same patient that you can see how once lesion resolves how it looks so what is the I'm going to focus now on the existing evidence for PKDL what is the existing evidence essentially in South Asia there's only one trial to date comparing oral milteficin 100mg for 8 weeks compared to 12 weeks the result was that it was a 93% curate at 12 months however this was based on a sample size of 15 cases no children were treated no macular PKDL which forms the vast majority of cases and there was no safety data post 4 weeks in addition to this considering it being a very aesthetic condition a lot of the people who self present for treatment are females and in women of reproductive age to have this treatment safely you need to ensure contraception for above 7 months and of course for any treatment that you're giving an oral treatment for 12 many of us take treatment complete a course of antibiotics taking oral treatment for 12 weeks is also a major issue and it may lead to resistance essentially the regimen poses high direct and indirect costs both the patient so what was MSF's approach it's really started in the use of ambison in PKDL started in Bangladesh the diagnosis was clinical so we weren't doing samples and microscopy as a standard essentially clinical symptoms i.e. the rash or the lesions a history of VL and a positive RK39 test treatment was given with 30mg total low ambison that's 6 doses of 5mg twice a week in an ambulatory fashion initially given in Bangladesh they treated I think 2,500 patients and then started in India after a WHO consultative meeting in 2012 recommended it as a treatment option however subsequently the treatment in Bangladesh was reduced to 15mg based on some safety concerns which we'll talk about in a minute as I say it was an ambulatory treatment so patients could go home and come back in to receive their treatment and the end points were at 12 months whereby photographs of the patients and the lesions pre and post treatment were taken and then assisted in validating the scoring from the clinicians themselves in particular safety data was monitored closely particularly hypochlemia because of reports of rabdomyosis from the larger cohort that was initially treated in Bangladesh just to give you some examples of some details on the types of patients that we saw as you can see it's quite interesting we have 97% of patients in Bangladesh presenting with macula that's the vitiligo type condition equal spread between males and females and to the patients had ambison as a previous treatment for their VL prior to developing the condition the average onset of symptoms the medium was 6 with a mean of 15 months in India it was quite different we had a lower prevalence of macular PKDL with much more mixed morphology the average age was younger we did see a higher number of females and the treatment of choice the historical treatment for VL was SSG above all of the other treatments and the median time was slightly shorter to presentation looking at effectiveness and safety outcomes at 12 months so far 50 patients have completed the 12 month follow up of these 84% 42 patients showed substantial complete cure in Bangladesh of the 88 patients completing 12 months follow up 80% showed substantial or complete cure in Bangladesh now we're not really sure why but they weren't seen in India but they were seen in Bangladesh there was a concerning incidence of severe hypokalemia in the Bangladeshi cohort that we didn't see in India the same thing went for mild and moderate as well fortunately none of these patients had any other sequelae none of them developed rabdomyosis and all of the hypokalemia resolved without incidence however reflecting the safety concerns in Bangladesh the treatment was switched to 15mg per kilo so this was a prospective observational study the primary objective of which was to evaluate the effectiveness of the new regimen at 12 months 3mg per kilo given in 5 doses over 2-3 weeks with a particular focus on safety specifically looking at hypokalemia and looking at which point in time did lesions start to respond to treatment a good sample size and here are the results so far as of March 2015 we don't have the 12 month results yet that data collection has just started but 73% of patients showed a substantial or complete improvement by 6 months definition of substantial is between 80% and 99% improvement and complete of course is 100% complete clearance of lesions excellent safety data and the results are no severe adverse events or severe hypokalemia there were some adverse events which are quite common to ambiosomes such as lower back pain and shivering but nothing all of which resolved by themselves as I say 12 month data collection has already started number of limitations with the studies it's very difficult to standardize assessment of improvement patients have lesions on their hands their arms, their legs, their faces each part of the body resolves at different speeds in addition to that some people some clinicians choose to feel that the classification of complete cure should be when you have complete repigmentation of the lesions where others feel that actually when you show a substantial amount of resolution of the lesion with no parasite on biopsy that can be defined as a cross checking of the clinicians decision making there was some regularity in the quality of the photographs in the PQDL group however this was improved in the 15 and of course finally the inclusion was clinical assessment based so if you did come in to have your parasite if you did have a skin biopsy and there was no parasite it did not preclude inclusion so there is a possibility that a number of the patients didn't actually have PQDL and had other conditions so in conclusion 13 milligrams per kilo appears effective in the treatment of PQDL seems to be safe in India and has shown safety concerns in Bangladesh however 15 milligrams per kilo appears safe tolerable and showed good adherence for these patients the effectiveness appears to be similar to the higher dose pending the 12 months results becoming available and essentially there is an urgent need for of course treatment options for PQDL and some can be treated can be considered an option in this case with a caveat that it still requires the more difficult treatment being given for a conditionale runs at risk of developing resistance and that's it