By Claude Kirimuhuzya Department of Pharmacology and Toxicology Faculty of Biomedical Sciences

1. Extensively Drug Resistant tuberculosis (XDR-TB): Is the World Losing the Battle against Tuberculosis? By Claude Kirimuhuzya Department of Pharmacology and Toxicology Faculty of Biomedical Sciences Kampala International University-Western Campus

2. Background Definition of XDR • Extensively drug-resistant tuberculosis (XDR TB) is a type of multidrug-resistant tuberculosis (MDR TB) that is resistant to two first-line drugs: isoniazid and rifampicin as well as to the second-line medications: fluoroquinolones and at least one of three injectable drugs (i.e., amikacin, kanamycin, or capreomycin) (World Health Organization [WHO] definition for cases detected on initial susceptibility testing) • XDR TB being resistant to the front-line drugs and two or more of the six classes of second-line drugs makes it virtually untreatable.

3. Background (cont’d) • HIV positive people particularly at a greater risk. • A recent survey of 18,000 TB samples by the US-based CDC and the WHO between Nov 2004 and Nov 2005 found 20% of them had MDRTB and a further 2% had XDR TB. • Further detailed analysis of several countries found the prevalence was in about 50 countries • In the US, 4% of all MDR TB cases met the criteria for XDR TB; in South Korea, the figure was 15%. • In Latvia, and other areas of the Baltics and the former Soviet Union, 19% of all MDRTB cases were XDR too. • Globally 6% of resistant TB cases are also resistant to second line drugs.

4. Background (cont’d) • In Kwazulu-Natal, in South Africa, 53 patients were found with XDR TB. Of these, 52 died within 25 days, and 44 of the 53 had been tested for HIV and were all found to be HIV positive. • XDR TB could have a bigger impact on developing nations, including Africa, because of the prevalence of HIV and lack of diagnostic tools to identify the disease. • Urgent need for new diagnostic tools, drugs and TB vaccines to be developed and $5bn is reqired to confront XDRTB.

5. Background(cont’d) Can XDR TB be treated and cured? • Yes, in some cases. • Some TB control programs have shown that cure is possible for an estimated 30% of affected people. • Successful outcomes depend greatly on the extent of the drug resistance, the severity of the disease, whether the patient’s immune system is weakened, and adherence to treatment.

6. Background(cont’d) What can health care providers do to prevent XDR TB? Health care providers can help prevent MDR and XDR TB by : • quickly diagnosing cases, • following recommended treatment guidelines, • monitoring patients’ response to treatment, and • making sure therapy is completed. • ensuring proper implementation of infection control procedures to prevent exposure to TB in hospitals or health-care settings where TB patients are likely to be seen.

7. Background(cont’d) WHO's seven-point Global Action Plan to Combat XDR TB, • conduct rapid surveys of XDR TB to determine the burden, • enhance laboratory capacity with an emphasis on rapid drug-sensitivity testing, • improve the technical capacity of clinical and public health practitioners to respond effectively to XDR TB outbreaks and manage patients, • implement infection-control precautions, • increase research support for TB drug development, • increase research support for rapid diagnostic test development, and • promote universal access to antiretroviral drugs under joint TB/HIV activities.

8. Challenges • Drug-susceptible (regular) TB and XDR TB are spread the same way • Final diagnosis for TB, and especially for XDR TB, may take from 6 to 16 weeks. • There are limited treatment options for XDR-TB which makes it virtually untreatable • The majority of patients infected with XDR-TB are co infected with HIV and this infection has been found to be virtually 100% fatal. • Transmission of XDR-TB is in clusters and follows similar transmission patterns as ordinary TB • The world is not responding fast and with enough resources as was the case with SARS, avian flu or swine flu

9. Challenges(cont’d) • Difficulty in identifying and locating the XDR-TB cases due to poor surveillance especially in the poor developing countries. • There have been no new diagnostic tests invented in the past 50 years ; the tests in place can take months. • TB affects mostly poor people who live in places where health care is not easily accessible where the patients have to pay for their own transportation. • The world’s only vaccine being 100 years old and only effective in children • High rates of failures of new drugs at clinical trials level • Clinical trials required to register a TB drug can take a minimum of 6 years, much longer than trials for other infectious diseases.

10. Challenges(cont’d) • Stop TB estimates, that through 2015, it will take about $2.4 billion for further discovery and early-stage development work and another $2.4 billion for clinical trials for new anti TB drugs. • Current resources are believed to total about $600 million, leaving a substantial funding gap. • Drug-drug interactions are a serious complicating factor in finding treatments for people co infected with TB and HIV eg rifampicin, which inhibits RNA polymerase, interacts with P450 and causes some HIV drugs to be cleared too quickly.

11. Challenges(cont’d) • Many clinicians, laboratorians, health-care professionals, public health officials, and policy makers do not possess up-to-date knowledge of what constitutes appropriate laboratory capabilities and capacities. • Many laboratories have limited capacity to respond to XDR TB. • The lack of guidelines for the use of conventional and rapid culture-based or molecular methods for detection of M. tuberculosis and drug resistance impedes the widespread use of these tests. • The laboratory confirmation of TB in HIV-infected persons is difficult and time consuming because of the need for highly sensitive, sophisticated and technically challenging diagnostic tests that are not universally available in all settings with a high burden of HIV and TB.

12. Current drugs used for XDR TB treatment • Some TB control programs have shown that cure is possible for an estimated 30% of affected people. • Successful outcomes depend greatly on the extent of the drug resistance, the severity of the disease, whether the patient’s immune system is weakened, and adherence to treatment • There are no newly approved drugs specifically for the treatment of XDR-TB • Researchers have shown that a cure is possible with a combination of at least five drugs, (The Lancet).

13. Current drugs used for XDR TB treatment(cont’d) Tailored treatment in 600 patients in Russia with at least five drugs showed that almost half of XDR-TB patients had treatment cure on completion of the course. • Study leader Dr Salmaan Keshavjee, from Harvard Medical School in the US, said: "Aggressive management of this infectious disease is feasible and can prevent high mortality rates and further transmission of drug-resistant strains of TB." • However, "This treatment is extremely labour and resource intensive and has to be done within extremely well structured TB programmes.

14. Ongoing research • Clinical trials in various phases for new anti TB drugs • Clinical trials in various phases for new TB vaccines • Research to identify biomarkers for drug efficacy in the treatment of tuberculosis (TB). It is believed that the identification of biomarkers could streamline and accelerate the process of developing new TB drugs. • Research to identify the genes responsible for extensive drug resistance

15. Ongoing research (cont’d) • The researchers found that the combination of meropenem and clavulanate had potent activity against drug-susceptible laboratory strains of M tuberculosis and also inhibited the growth of 13 strains of XDR-TB in the laboratory. • Clinical trials are now being planned by the US researchers. Science 2009 ; 323:1215–8). • An antibiotic discovered by the Johnson & Johnson Pharmaceutical team belonging to a family of drugs called the diarylquinolines or DARQs is one of a number of hopeful candidates.

16. New Diagnostic tests • Scientists in the UK say they have devised a new ultra-sensitive test which can diagnose the presence of the tuberculosis bacterium in one hour using the PCR technique (Health Protection Agency ,HPA). • The HPA test comes just weeks after details of a rival project were published in the New England Journal of Medicine. • A rival test called "Xpert MTB/RIF" has also been developed and its developers claim it can deliver a diagnosis in less than two hours. • Such a test would allow earlier diagnosis and treatment of the lung disease, potentially saving many lives. ,( BBC News 15 September 2010 )

17. Drugs in the pipeline • About 30 compounds identified for potential development of new anti TB drugs • Treatment for XDR TB expected to be available not earlier than 2012. • Drugs in the pipeline include: • Moxifloxacin , a fluoroquinolone (from Bayer and TB Alliance) – being looked at as a substitute for isoniazid or ethambutol and is now going for Phase III clinical trials. • Gatfloxacin , also a fluoroquinolone ( from OFLOTUB) – going for Phase III clinical trials to replace ethambutol. • LL3858 (from Lopin) in Phase I clinical trials. • Rifabutin (related to rifampicin) (from Pfizer) – under study to replace rifampicin. Work continues on rifapentine, which was approved in 1998. • PA-824, a nitroimidazole, (from Chiron –part of Norvatis) – under Phase II. • OPC-67683, a nitrodihydroimidazo-oxazole derivative (from Japan’s Otsuk Pharmaceuticals)- in Phase II trials for treatment of MDR TB.

18. Drugs in the pipeline (cont’d) • TMC-207 an ATP synthase inhibitor, selective for MTB (from (Johnson & Johnson) – under development at Tibotec for MDRTB and being considered as substitute for rifampicin and isoniazid to shorten the dosage period for MDR TB • FAS20013, a sulfonyl tridecamide (from FASgen)- being developed against MDR TB. It interferes with MTB cell wall synthesis and is expected to be effective against dormant bacteria. • SQ109, a 1,2-ethylene diamine (from Sequella)- inhibits cell wall synthesis and has shown synergistic effect with rifampicin and isoniazid and is effective against MDR and latent forms. • SQ609, dipiperidine (from Sequella but got from Sankyo, Japan), an inhibitor of translocase I involved in cell wall synthesis, is in pre-clinical studies.

19. New Tuberculosis Vaccines in pipeline • Existing BCG (Bacille Calmette Guerin) vaccine which came into the market in 1921, has limited effectiveness in preventing people from TB. • BCG vaccine which is used to prevent childhood TB may not be safe for children living with HIV.  • Aeras Global TB Vaccine Foundation and other agencies including Bill & Melinda Gates Foundation are pushing hard to accelerate research and development of safe and effective TB vaccines.

20. New TB Vaccines in pipeline (cont’d) • For the first time in 80 years, very promising live and attenuated tuberculosis vaccines have reached the clinical trial stages in various countries. • Currently there are seven vaccine candidate products in different stages of the research pipeline around the world. • AERAS has six vaccine candidate products" shares Peg Willingham • Five boosters and one improved BCG vaccine candidate products in the research pipeline, adds Peg. • One vaccine candidate is being developed to replace the existing BCG vaccine with a better, modern and more effective alternative. This candidate is expected to start phase-I clinical trial later this year.

21. TB Vaccines in pipeline (cont’d) • One phase-III clinical trial in Tanzania which was sponsored by a US University, studied adults who were living with HIV, gave promising results which were announced in October 2008; findings from the Tanzanian trial showed that TB infection in HIV-positive patients was reduced by 39 percent. (11 February 2010 • "With sufficient resources, a new TB vaccine could be ready by 2020" says Peg Willingham..

22. TB Vaccines in pipeline (cont’d) High hopes for TB vaccine By Fergus Walsh, Medical correspondent, BBC News • Trials in children of a new TB vaccine are underway in South Africa. • The experimental jab was developed by scientists at Oxford University, and I travelled to witness the trial first hand in Worcester, north of Cape Town. • In a large garden outside a small vaccine clinic, a group of boisterous two, three and four-year-olds is playing. Their mothers sit in the shade watching. • All these children are taking part in a vital stage of a vaccine trial. • They will be among the first children in the world to receive an experimental vaccine known as MVA85A. • There is already one TB vaccine - BCG. It is no longer routinely used in the UK, but is given at birth throughout the developing world. • The problem is that BCG is not very effective - a fact made plain when you consider that more than 1.5m people a year die still die from TB. • The aim of the new vaccine is that it should be used as a booster, in addition to BCG.

23. Summary of TB vaccines in pipeline • Vaccine candidate: VPM 1002 Prime rBCG ∆ureC::hly::hyg; Being developed by Vakzine Projekt Management GmbH has reached Phase II trials • Vaccine candidate: AERAS 402 / Crucell Ad35 Boost; Live recombinant serotype 35 replication deficient adenovirus vector expressing a fusion protein of three Mycobacteriumtuberculosis antigens (Ag 85A, 85B and new TB 10.4).Being developed by: Aeras / Crucell.Currently in: Phase 2

24. TB Vaccines in pipeline (cont’d) Vaccine candidate: HyVac4/AERAS-404 Boosting vaccine for prevention of new TB in BCG vaccinated infants.Recombinant protein (Ag85B plus TB10.4) fusion molecule with adjuvant (IC31). Being developed by SSI/Aeras/Sanofi Pasteur.Currently inPhase 1 Vaccine candidate: SSI Hybrid 1 (H1) Boost;Recombinant protein (Ag85B plus ESAT 6) fusion molecule with adjuvant (IC31).Being developed by SS. Currently inPhase I/II Vaccine candidate: GSK M72 Boost.Recombinant subunit protein vaccine with adjuvant. Being developed by GSK, in partnership with Aeras and others. Currently in: Phase: 2

25. TB Vaccines in pipeline (cont’d) Vaccine candidate: RUTI Targets subjects with latent new TB infection (LTBI).Based on detoxified cellular fragments of M. tuberculosis.Being developed by Germans Trias i Pujol Health Science Research. Currently in: Phase 1 Vaccine candidate: M. vaccae Booster to BCG, for HIV infected. Investigational heat-killed preparation derived from rough variant of an environmental isolate.Being developed by Immodulon (with Aeras). Currently in Phase III • Vaccine candidate: AdAg85 • Being developed by McMaster University In Canada. Currently in  Phase I

26. Existing gaps in research on XDRTB • In areas where XDR TB has been identified, the actual prevalence of resistance to first- and second-line drugs among TB cases is unknown. • The risk factors for and transmission dynamics of XDR TB in domestic and international settings are not completely understood. • The survival rates among patients with XDRTB have not been adequately analyzed, and • Host/pathogen determinants of survival, including the effect of co-morbidities, remain to be elucidated.

27. Existing gaps in research on XDR TB • Methods for detecting and documenting outbreaks of XDR TB both domestically and internationally are not currently optimized to allow a rapid response. • Effective and safe treatment regimens for XDR TB have not been established • The quality of currently available services and treatment for XDR TB patients has not been monitored or evaluated sufficiently.

28. Existing gaps in research on XDR TB • Safe, effective treatment regimens and appropriate follow-up procedures for managing contacts of XDR TB patients have not been established. . • Well-validated surrogate markers do not existto rapidly assess clinical efficacy of new chemotherapeutic agents and regimens against XDR TB.; identification of biomarkers could streamline and accelerate the process of developing new TB drugs • Effective treatments for latent MDR/XDR TBM infection have not been established. • Pharmacology of existing and new TB drugs, including interactions with antiretroviral medications commonly used among at-risk populations, has not been adequately assessed.

29. Existing gaps in research on XDR TB • Efficacy, safety and pharmacology of TB chemotherapeutics are not well characterized in special populations such as children, injection drug users, persons with HIV/AIDS, and others. • The characteristics of M. tuberculosis (e.g., growth, physiology, biochemistry, genetics, and molecular biology) are incompletely understood

30. Existing gaps in research on XDR TB • Rapid, point-of-care identification of drug-sensitive and drug-resistant pulmonary and extrapulmonary TB among HIV-negative and HIV-positive adults and pediatric populations ands reliable early identification of latent M. tuberculosis infection are not yet possible . • A comprehensive and up-to-date estimate of the costs of diagnosing, treating, and managing XDR TB is not available. • Cost-effective strategies to prevent XDR TB remain to be established.

31. 7-point Action Plan, Johannesburg, September, 2006 • Conduct rapid surveys of XDR-TB; • Enhance laboratory capacity; • Improve technical capacity of clinical and public health managers to effectively respond to XDR-TB outbreaks; • Implement infection control precautions; • Increase research support for anti-TB drug development; • Increase research support for rapid diagnostic test development; • Promote universal access to ARVs under joint TB/HIV activities.

32. XDR Action Plan 2006 General Recommendations • Immediate strengthening of TB control in countries, • Scaling up of universal access to HIV treatment and care, • Mobilization of teams of experts • The Global Plan to Stop TB, 2006-2015 revised • Reflect the threat of XDR-TB • Expand the laboratory strengthening component, • Scale up of MDR-TB treatment • Include Infection control • Revise budget

33. XDR Action Plan 2006 Specific Recommendations • Management of XDR-TB suspects in high and low HIV prevalence settings: • Complete and disseminate algorithm (CDC and WHO) • Access to rapid tests for rifampicin resistance (WHO and FIND) • Programme management of XDR-TB and treatment design in HIV negative and positive people • Implement WHO guidelines for the programmatic management of drug resistant TB • Update parts of the guidelines to address the XDR-TB threat (WHO to coordinate) • Specific guidelines for the treatment of known and suspected XDR-TB • Facilitate access to high-quality second-line anti-TB drugs • Disseminate the legal and ethical global guidelines that address compulsory medical treatment and isolation (WHO)

34. XDR Action Plan 2006 Laboratory capacity building • Enlarged, accelerated budgeted plan for national lab capacity building (hardware, including rapid diagnostic tests, software, personnel, policy guidance, training, technical assistance, and resource mobilization • Needs to address basic capacity as well as MDR and XDR specific concerns • Ensure improved coordination across technical and financial partners and other laboratory networks beyond TB • Strong public statement on lab strengthening as prerequisite for XDR-TB response • Support and expansion for SRL network • Ultimately, access to timely, quality-assured TB laboratory services, including AFB microscopy, culture, and DST for all patients

35. XDR Action Plan 2006 Infection control and protection of health care workers • • Rapid implementation of infection control (IC) measures in health care settings and other risk areas, including prisons • • CDC to update the WHO IC guidelines and • WHO to publish addendum, "Tuberculosis infection control in the era of expanding HIV care and treatment" • • Sub working group (SWG) on infection control should be established within the Stop TB Partnership. (WHO will establish a provisional secretariat) • – Urgent plan for supporting implementation of the infection control guidelines at country level • Expand pool of consultants

36. XDR Action Plan 2006 Immediate XDR-TB surveillance activities and needs • XDR-TB surveillance embedded in existing drug resistance surveillance systems • Including 2nd line drug susceptibility testing (task force of members of the surveillance group + WHO) • A generic protocol to determine rapidly the geographical distribution and size of XDR-TB, its association with HIV, and its genetic origins. • Future anti-TB drug resistance surveillance should always include HIV testing, and surveillance specifically of XDR-TB should incorporate rapid rifampicin testing.

37. XDR Action Plan 2006 Advocacy, communication and social mobilization • XDR ACSM Task Force within existing structures (Stop TB • Partnership) • Information-sharing strategies that promote effective prevention, treatment, and control of XDR-TB • Proactive media approach, • Place affected people at the heart of the response, • Mobilise existing supportive networks (eg the HIV community), • Provide clear information on the XDR-TB situation, • Promote public debate and develop a space for people to tell their stories, • Strategy for increasing ACSM capacities and strengthening communications channels at global and country level. • All Stop TB partners should actively promote the International • Standards of TB Care and the Patients' Charter

38. XDR Action Plan 2006 Resource Mobilization • Global level budget and plan for raising the resources required to address XDR-TB (Stop TB Partnership) • Costed plans for countries immediate needs, technical assistance, surveillance and global policy and coordination (Countries and WHO) • Rapid briefing of development partners and agencies • Short- and medium-term needs

39. Conclusion In order to Combat XDR TB there is need for public health authorities to : 1) conduct rapid surveys of XDR TB to determine the burden, 2) enhance laboratory capacity with an emphasis on rapid drug sensitivity testing, 3) improve technical capacity of clinical and public health practitioners to respond effectively to XDR TB outbreaks and manage patients, 4) implement infection-control precautions, 5) increase research support for TB drug and vaccine development, 6) increase research support for rapid diagnostic test development, and 7) promote universal access to antiretroviral drugs under joint TB/HIV activities Question: Are these requirements being globally addressed adequately and fast enough?

40. THANK YOU

41. Courtesy of MMWR Weekly March 24, 2006 / 55(11);301-305

42. Courtesy of MMWR Weekly March 24, 2006 / 55(11);301-305