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MDR-TB and HIV: how big is the problem and what are we going to do about it

MDR-TB and HIV: how big is the problem and what are we going to do about it. Matteo Zignol, Abigail Wright, Brian Williams Stop TB Department World Health Organization - Geneva TB/HIV Research Priorities in Resource-Limited Settings 14 February 2005 Geneva. MDR-TB and HIV. What do we know

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MDR-TB and HIV: how big is the problem and what are we going to do about it

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  1. MDR-TB and HIV: how big is the problem and what are we going to do about it Matteo Zignol, Abigail Wright, Brian Williams Stop TB Department World Health Organization - Geneva TB/HIV Research Priorities in Resource-Limited Settings 14 February 2005 Geneva

  2. MDR-TB and HIV • What do we know • What do we need to know • What has to be done in order to fill the knowledge gap • What to do in the meantime

  3. Epidemiology in institutions • Majority of the studies reviewed describe institutional outbreaks • Both in developing and industrialized countries • Probably underestimated number of institutional outbreaks • Basic institutional infection control sufficient to contain transmission in institutions

  4. Epidemiology in the general population • Patients Place Association between tested for HIV status and any R HIV and DR • Chum, 1996 1164 Tanzania No association • Kenyon, 1999 240 Botswana No association • Churchyard, 2000 1913 South Africa No association • Warndorff, 2000 836 Malawi No association • Espinal, 2001 463 Multicenter No association • Mac-Arthur, 2001 709 Mozambique Association with HS • Weyer, not published 762 South AfricaNo association • Association with MDR among retreatments

  5. Epidemiology in the general population Generally no association between HIV status and DR, but: • Majority of the studies in high HIV low MDR prevalence settings • Lack of statistical power in some studies • Methodologies difficult to compare • In some studies association might be confounded by: • history of previous treatment • history of hospital stay

  6. The case of Botswana • From the Global Project on Anti-TB Drug Resistance

  7. The case of Botswana • From the Global Project on Anti-TB Drug Resistance

  8. Acquired Rifamycin resistance in previously susceptible HIV (+) patients • No of Patients Potential Factors • Dylewski, 1990 1 HIV • Small, 1991 1 HIV and poor compliance • Small, 1993 3 HIV, drug / alcohol use, poor comp • Godfrey-Faussett, 1993 1 HIV, mutations population bacilli • Nolan, 1995 3 HIV, rpoB gene mutations • Lutfey, 1996 6 HIV, rpoB gene mutations, poor compliance • March, 1997 3 HIV, rpoB gene mutation (1), AZT fluconazole (1), • Munsiff, 1997 29 HIV, sputum smear (+), advanced immunosupp, and poor comp • Vernon, 1999 4 HIV, younger age, advanced immunosupp, extrap TB, and antifungal agents • Jenny-Avital, 2002 1 HIV, antiretroviral therapy

  9. Acquired Rifamycin resistance in previously susceptible HIV (+) patients 2002: CDC suspended enrolment in Study 23 (single-arm trial of twice-weekly rifabutin based therapy for treatment of HIV-TB) because of the occurrence of five cases of acquired rifamycin resistance: Features: • very low CD4 cell count (<60 /mm3) at diagnosis • twice-weekly therapy in the continuation phase in developing and industrialized countries • relation appears to exist between the frequency of dosing and the risk of acquired resistance

  10. Acquired Rifamycin Resistance Potential Mechanisms • Limited effect of highly intermittent regimens (continuation phase) on the mycobacterial replication which appear to be prolonged in advanced AIDS due host immunity • Functional monotherapy during sterilisation of bacillary populations (shorter half-life of INH, malabsorption of INH -- ?) • Inhibition of the p450 enzyme system by antifungal drugs • Gene mutations • Non-compliance with treatment

  11. What do we need to know Does HIV epidemic fuel MDR-TB epidemic? No evidence Dye C et al. Science. 2002;295(5562):2042-6 • Reasons why DR should be found more often among HIV infected TB patients • Reasons why MDR-TB/HIV co-infected patients are less likely to transmit resistant strains

  12. Reasons why DR prevalence could be higher among HIV infected TB patients • Immunosuppression and drug pressure affect fitness Ordway DJ et al. Infect Immun. 1995;63(2):741-3 • PLWH have higher risk of MDR TB because of hospitalization/institutionalization, IDU 3. Acquisition of Rifamycin resistance in previously susceptible HIV (+) patients Vernon A et al. Lancet 1999; 353(9167): 1843-7

  13. Reasons why MDR-TB/HIV co-infected patients are less likely to transmit resistant strains • HIV pos patients with TB are less likely than HIV neg patients with TB to transmit Mtb. Espinal MA et al. Lancet. 2000;22;355(9200):275-80 • Higher mortality in MDR-TB/HIV patients (due to poorer treatment outcomes of MDR-TB)

  14. What has to be donein order to fill the knowledge gap Conduct dual HIV and anti-TB drug resistance surveillance in 3 priority settings: • high HIV prevalence setting • assess acquisition of RMP resistance during treatment • high MDR prevalence settings • high risk populations (hospitals, institutions, IDU) Variables to be studied at a minimum: • age • sex • history of TB treatment (therapy and prophylaxis) • history of hospitalization or imprisonment • infectiousness (smear positives vs. smear negatives) • intravenous drug use

  15. What has to be donein order to fill the knowledge gap Modeling exercises Influence of HIV infection on MDR-TB not discussed by recent papers (Blower SM et al. Nat Med. 2004;10(10):1111-6 and Cohen T et al. Nat Med. 2004;10(10):1117-21) Need of good data!

  16. What to do in the meantimeInfection control • Encourage hospitals and institutions to monitor and document acquisition of (M)DR TB in TB/HIV co-infected patients • Advocate for implementation of measures of infection control in institutions

  17. What to do in the meantimePopulation studies • Expand dual HIV and anti-TB drug resistance surveillance • Ongoing projects: Botswana, Brazil, South Africa • Determine new pilot sites: • Sub-Saharan countries (Malawi) • Former Soviet Union countries (Baltic countries, Kyrgyzstan) • Studies in high risk populations (Baltic countries)

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