The emerging threat of multidrug resistant TB: Global and local challenges and solutions

Summary of IOM-ASSAf Workshop on: The emerging threat of multidrug resistant TB: Global and local challenges and solutions Salim S. Abdool Karim Pretoria - March, 2010

Why this workshop? Why is it on MDR / XDR TB? Lethal condition a Threat Difficult-to-treat disease Spreading in the community with global potential Exacerbated by toxic mix with HIV Man-made problem We still have an opportunity to chose a different future thro action now to avert worsening of the crisis

Reminder: Goals of this workshop? The emerging threat of multidrug resistant TB: Global and local challenges and solutions

What have we learnt here? 1. How to detect M/X/TDR TB? 2. What is the scale of the problem? Is it getting worse? 3. How and why is it spreading? 4. What treatment works? 5. What prevention works? What are the implications?

Prevailing situation: Don t look Don t find!!

Fig 1. Resistance development in the KZN family of strains of Mycobacterium tuberculosis from 1994 till 2006 Resistance found for the first time in: Resistance to: 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 none IE IS ISE IR IRE IRET IREEtT IRS IRSE IRSEEtT IRSETCa IRSEEtTK IRSEEtFq IRSEEtKFq IRSEKFq I isoniazid; S streptomycin; E ethambutol; Et ethionamide; R rifampicin; T thiacetazone Ca capreomycin; K kanamycin/amikacin; Fq fluoroquinolones (Pillay and Sturm, CID, Dec. 2007)

DST Among XDR TB Cases All XDR TB isolates resistant to at least 6 drugs: H, R, E, S, OFL, KAN 2 (11%) 6-drug resistance only 6-drug + CAP + ETHIO resistance 13 (68%) 4 (21%) 6-drug + CAP resistance 8-drug resistance Gandhi, 2010

The key problem: Delays Infection Symptoms Clinic Diagnosis Start Px Convert Cure t1 t2 t3 t4 t5 t6 Progression of TB patient. In order to decrease transmission, we need to reduce time for each interval. Some of these are programme problems, some are drug response, while others are diagnostic. All the above apply to antibiotic sensitive and resistant M tb. Px for drug sensitive cases is 6-9 months, while for drug resistant cases may be 18 months or more. Diagnostics can address primarily t3, but also can be used in a comprehensive programme to address t1, t2, t3 and t5 and perhaps reduce t5 and t6 Van Helden, 2010

Delays in diagnosis of MDR & XDR TB kills need rapid reliable diagnostics 1.00 0.75 HIV co-infection 90% Median CD4: 87 cells/mm 0.50 MDR TB 0.25 0.00 HIV co-infection 98% Median CD4: 66 cells/mm XDR TB 0 50 100 150 200 250 300 350 400 29 days SURV1YR Survival in days STRATA: TYPE=MDR Censored TYPE=MDR TYPE=XDR Censored TYPE=XDR 60 days Gandhi et al AJRCCM 2010

The challenge of TB & DS diagnostics Smear, culture & DST need safe labs Symptoms & signs cough Future Antigen, antibody and molecular detection? Host based? Phage assay? Urgent: Point -of-care TB diagnostic ( + DST) Van Helden, 2010

TB Incidence in Africa, 1990 and 2005 Chaisson and Martinson, N Engl J Med 2008;358:1089

The March of Resistance Drug susceptible TB* MDR- TB 1990 XDR-TB 2006 Total DR? *or limited resistance manageable with 4 drug regimen -DOTS Resistance to H&R Treatable with 2 nd line drugs Resistance to 2 nd line drugs treatment options seriously restricted Resistance to all available drugs no treatment options Treatment outcomes worse with HIV infection

DST Results of XDR TB : 2005 2007 100% 80% Percentage 60% 40% 20% 4-drug: HROflKm 5-drug: HREOflKm, HRSOflKm 6-drug: HRESOflKm 0% Jul-Dec 05 Jan-Jun 06 Jul-Dec 06 Jan-Jun 07 Months Moll A, et al. 38th Union World Conference on Lung Health, Cape Town, 2007

Estimated MDR-TB No estimate 0-400 401 1,200 1,201 3,600 3,601 15,914 Over 75,000 MDR-TB cases estimated to have emerged in AFR in 2010 60% of whom would be sputum smear positive Friedland, 2010

Epidemic spread of HIV-Associated XDR TB in Tugela Ferry 1.1 1.0.9.8 Proportion Surviving.7.6.5.4.3.2 N = 53.1 0.0 -.1 0 30 16 days 60 90 120 150 180 Days since Sputum Collected 210 240 Gandhi et al. Lancet 2006

Tugela Ferry December 2005 Moodley, 2010

Use of antibiotics and resistance Van der Walt 2010 Emerg Infect Dis.; 2005; 10(3):514 7

Transmission Where were your last 100 cases of TB acquired? Household Health Care Setting How many cases are evolved resistance within individuals vs externally acquired resistant strains? -Adherence & case-holding -Infection control to prevent both nosocomial and community spread Community Reactivation Friedland- Adapted from Peter Godfrey- Faussett, Capetown, 2009

How resistant is XDR M.tuberculosis in KZN? Most isolates are resistant to: 1. isoniazid 2. rifampicin 3. ethambutol 4. pyrazinamide 5. streptomycin 6. kanamycin 7. amikacin 8. capreomycin 9. ofloxacin 10.ethionamide Sturm, 2010

When choosing between Amikacin, Streptomycin, Capremycin and Moxi the sequence in which they are used is important to avoid class level resistance noting that cost is an issue in choice of drugs Clifton Barry, 2010

Adult MDR TB Treatment Outcomes 2000-20032003 (n= 1209) James C.M. Brust Int J Tub in press KGV MDR TB Treatment Outcomes 2000-2003 (n=1209) Defaulted 21% Cure 41% Died 18% Failed 17% Completed 3%

11-month-old Morning tablets MDR-TB Rx Difficult to accurately break tablets to correct dosage. Also receives an injectable

Increasing Access to MDR TB Treatment 45 40 35 30 25 20 15 10 5 0 40 projects and 26,000 patients provided with 2 nd -line drugs over 6 years 2000 2001 2002 2003 2004 2005 2006 Number of MDR TB Treatment Projects Friedland, 2010

A map of KwaZulu-Natal showing the location of KGV and the decentralised MDR-TB treatment sites

Community based care Tugela Ferry Photos: Gerald Friedland

While TB drug choice is strongly evidence based, MDR-TB treatment has very little evidence to define optimal treatment regimens Richard Chaisson, 2010

EARLY DIAGNOSIS MDR AND Rx Good DOTS to stop MDR-TB ART Intensified case finding Lawn, 2010 Infection Control Preventive Rx -IPT

Contact tracing in community LEGEND Marra, 2010

Infection Control in HIV Clinics Environmental Infrastructure 4 (27%) had ultra-violet (UV) light; none had a UV maintenance plan; 4 (27%) had windows opened appropriately; 7 (47%) had outdoor covered waiting areas; 3 (20%) had operational extraction fans. Personal Protective infrastructure 10 (67%) had N-95 respirators, none offered fit testing; 3 (30%) had respirators in use at the time of visit. Farley, 2010

Implication 1 Urgent Action i. Reverse the ostrich approach: ii. iii. iv. Not thro hype or exaggeration but rather thro Evidence for action A new partnership with community and patient advocates Simple and rationale explanation of the potential scale of the problem Clear articulation of evidence-based actions needed for control v. A plan (with costs) on how to move forward to tackling the problem vi. The health service needs to be able to rise to this challenge with priority actions for implementation

Implication 2 More evidence We know we have a problem with MDR/XDR TB but we don t know How big is this hidden problem? What is the current extent of TDR-TB? How much spread is person-to-person - in hospitals? in the community? What is the best treatment regimen? How to address sub-optimal adherence? How to enhance HCW protection? What is the cure rate?

Implication 3 A broader approach for social mobilisation TB is more than a medical problem Recall that Europe was already bringing TB under control even before effective drugs were available Many of the challenges in TB are about social organization eg. migrant labour, over-crowding, etc The solutions are not only about new diagnostics, new vaccines and new treatments: it is also about patient and HCW behaviour, about health systems and about political commitment and social mobilisation

Wood, 2010