Tuberculosis. New TB diagnostics. New drugs.new vaccines. Dr: Hussein M. Jumaah CABM Mosul College of Medicine 23/12/2012

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1 Tuberculosis New TB diagnostics. New drugs.new vaccines Dr: Hussein M. Jumaah CABM Mosul College of Medicine 23/12/2012

2 Tuberculosis (TB )is a bacterial disease caused by Mycobacterium tuberculosis (occasionally by Mycobacterium bovis and africanum ). It ranks as the second leading cause of death from an infectious disease worldwide, after HIV. Without treatment, by the end of 5 years 50% of PTB patients will be dead. 25% will be healthy. 25% will remain ill with chronic infectious TB.

3 The global burden of TB remains enormous. TB remains a major global health problem. In 2011, there were an estimated 8.7 million new cases of TB (13% co-infected with HIV) and 1.4 million people died from TB, including almost one million deaths among HIVnegative individuals and among people who were HIV-positive.

4 HIV infection is by far the strongest risk factor for TB : it increases risk by about 100-fold. jejunal bypass surgery, increases risk by about 20-fold. Diabetes and smoking both increase risk by between two- and fivefold. Being tall and thin increases risk by about 1.3- to 1.5-fold. Chronic renal failure, silicosis increases the risk of developing active TB.

5 Diagnosis The most common method for diagnosing TB worldwide is sputum smear microscopy (developed more than 100 years ago). Interferon gamma release assay (IGRA)alone or a dual strategy (Mantoux test followed by IGRA test if Mantoux is positive (6 mm or greater)) is recommended as the first step in screening. Chest x ray was previously recommended as the first step. This is no longer the case.

6 After decades of stagnation, accelerated development of new TB diagnostics in the past decade presents real hope for the rapid diagnosis of TB and MDR-TB. Innovations in diagnostics are being implemented. In the past 5 years, WHO has endorsed several new tests and diagnostic approaches. These include: 1. liquid culture. 2. Molecular line probe assays. 3. light-emitting diode fluorescence microscopes for improved smear microscopy; and 4. Xpert MTB/RIF. a rapid molecular test that can diagnose TB and rifampicin resistance within 100 minutes

7 Bringing the Lab to the Patient: Developing Point-of-Care Diagnostic (POCTs) Easy-to-use, inexpensive POCTs to diagnose infectious diseases are urgently needed in resource-limited settings where laboratory capacity is limited. It requires coordinated efforts among the scientists and engineers designing the tests and the health care workers deploying them. The American Academy of Microbiology convened a colloquium in September 2011 to discuss how to develop POCTs to diagnose infectious diseases and other health concerns at the bedside, or point-of-care..

8 When is it mandatory to admit a TB patient to the ward? Admit your TB patient if he develops 1. Complications such as massive haemoptysis or pneumothorax. 2. If you suspect your patient will be noncompliant to treatment. 3. Poor family support or no proper home. 4. TB involving the vital organs such as the brain, heart, adrenal, kidneys, spine etc also.

9 Treatment According to randomised controlled trials treatment for six months is sufficient for TB at any site except the CNS ; is 12 months (2HREZ/10HR) and steroid. The WHO also recommend a six-month continuation phase of HR 1. If the patient is still culture positive after 2 months of treatment (approximately 15% of patients with fully sensitive TB) and 2. For those patients who have extensive bilateral cavitation at the start of treatment.

10 DOT should be considered for patients with active TB who have adverse factors on their risk assessment, in particular: 1. Street or shelter dwelling homeless people. 2. Patients with likely poor adherence, in particular those who have a history of nonadherence. 3. All prisoners with active or latent tuberculosis.

11 WHO s currently-recommended approach to TB care and control is the Stop TB Strategy, launched in The targets are that TB incidence should be falling by 2015, prevalence and death rates should be halved compared with their levels in The provision of diagnosis and treatment according to the DOTS/Stop TB Strategy has resulted in major achievements in TB care and control.

12 Drug-resistant tuberculosis Definitions Multi-drug resistant tuberculosis (MDR-TB) is defined as TB that is resistant at least to INH and RMP. Extensively drug-resistant tuberculosis" (XDR-TB) is defined as MDR-TB that is resistant to quinolones and also to any one of kanamycin, capreomycin, or amikacin.

13 The WHO extended the DOTS programme in 1998 to include the treatment of MDR-TB (called "DOTS-Plus"). Implementation of DOTS- Plus requires the capacity: To perform drug-susceptibility testing. and the availability of second-line agents, in addition to all the requirements for DOTS. Monthly surveillance until cultures convert to negative is recommended for DOTS-Plus.

14 The principles of treatment for MDR-TB and for XDR-TB are the same. WHO s guidelines recommend an intensive phase of 8 months and a total duration of 20 months with second-line drugs. Treatment must be done on the basis of sensitivity testing: the patient should be started on SHREZ+MXF+cycloserine pending the result of laboratory sensitivity testing. Modern surgical management confined to the management of multi-drug resistant TB. Lobectomy or pneumonectomy with the aim of cutting out the infected tissue.

15 Totally drug-resistant TB and developments in India in 2012 In December 2011, clinicians in Mumbai, India reported TB patients with what was termed total drug resistance. As a result of this episode, in March 2012 WHO convened 40 experts to discuss its implications.

16 The development of new drugs and new vaccines is also progressing. The anti-tb drugs used in first-line treatments are around 50 years old. The regimen that is currently recommended by WHO for new cases of drugsusceptible TB is highly efficacious, with cure rates of around 90% in HIV-negative patients. Nonetheless, it requires 6 months of treatment with first-line drugs. There are also interactions between anti-tb treatment and antiretroviral therapy (ART) for people living with HIV.

17 New drugs are required to shorten and simplify treatment, to improve the efficacy and tolerability of treatment for MDR-TB and to improve the treatment of TB among people living with HIV also help to treat latent TB infection.

18 The status of the pipeline for new anti-tb drugs in July 2012 is shown in Figure. Of the new TB drugs under clinical investigation, 4 are in Phase III (efficacy) trials and 7 are in Phase II trials. Two of the Phase III trials are evaluating 4- month combination regimens in which a fluoroquinolone (gatifloxacin or moxifloxacin) is substituted for either ethambutol or isoniazid; results are expected in 2013.

19 A third Phase III trial, rifamycin (longer half-life than rifampicin) as part of a 4-month regimen for the treatment of drug-susceptible TB. Since mid-2011, the delamanid, for the treatment of MDR-TB, has moved from a Phase II to a Phase III trial. Bedaquiline is expected to move to a Phase III trial before the end of The other six compounds in Phase II trials are linezolid, sutezolid analogue of linezolid; PA-824, a nitro-imidazole;rifapentine; and AZD- 5847, another oxazolidinone.

20 A study published on 23rd July 2012 presented at the XIX International AIDS Conference (AIDS 2012) reveal that a novel TB drug combination PaMZ (consisting of PA- 824, moxifloxacin and pyrazinamide) has shown the potential to dramatically shorten the length of multi drug resistant TB treatment by 80%, from the existing 24 months to 4 months raised hopes to make MDR-TB treatment shorter, simpler, safer, and more cost effective.

21 Rifampicin, the most important antituberculosis agent, reduces serum levels of many antiretrovirals. Latest data suggest that concurrent therapy of HIV and TB may have lower mortality than sequential treatment. Often treatment for tuberculosis alone will raise the CD4 lymphocyte count.

22 Eleven vaccines to prevent TB are moving through development stages. How effective is BCG vaccination in preventing TB? The BCG vaccine for the prevention of TB is almost 100 years old, protects against severe forms of TB in children (TB meningitis and miliary TB), but its efficacy in preventing pulmonary TB in adults is highly variable. BCG is not recommended for use in infants infected with HIV, due to the risk of disseminated BCG disease.

23 New vaccines to prevent TB Historic opportunities for developing new TB vaccines arose during the 1990s, following the development of techniques for genetic manipulation and completion of the genome sequence of M. tuberculosis.

24 Two different approaches are being used to develop TB vaccines for prevention of TB. The first approach is to develop vaccines that would do better than BCG and replace it such as an improved version of BCG or anew attenuated live M. tuberculosis vaccine. The second approach is to develop a primeboost strategy in which BCG continues to be given to neonates, since it prevents TB in infants and children, and give the new vaccine as a booster dose at a later stage.

25 The vaccine candidates currently under development could be used to prevent either infection (pre-exposure), or to prevent primary progression to disease or reactivation of latent TB (post-exposure). Work is also being carried out to develop vaccines that could be used as immunotherapeutic agents, i.e. to improve responsiveness to chemotherapy.

26 MVA-85A, (modified vaccinia Ankara 85A) in development by Oxford-Emergent Tuberculosis Consortium Ltd and the EU-funded research program TB-VAC, is a live attenuated viral vaccine expressing the immunodominant TB antigen 85A, and is intended for use in a heterologous primeboost strategy to prevent TB. Is highly immunogenic, eliciting strong polyfunctional CD4+ T-cell responses when administered as a boost following BCG vaccination or when administered to individuals previously exposed to TB.

27 The development pipeline for new TB drugs, July 2012

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