Tuberculosis and HIV

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Tuberculosis and HIV
K-RITH

• Prashini Moodley
• Medical Microbiology Research Laboratories
• KwaZulu-Natal Research Institute for TB and HIV
  (K-RITH)
• Nelson R Mandela School of Medicine

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Hippocrates
DO NOT VISIT CASES IN LATE STAGE OF DISEASE !!

• 460 BC
• most widespread disease (phthisis)
• almost always fatal
• warned medical colleagues

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Why the Warning?

• Phthisis was an untreatable, highly contagious
  disease
• survival based on intact immune system
• XDR TB
• untreatable, highly contagious disease
• HIV
• highly effective cause of immune-suppression

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Population in SA with widespread immune impairment
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TB HIV
Twin tornadoes in Elkhart, Indiana on April 11,
1965
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M.tuberculosis and HIV are independent pathogens
M. tuberculosis infected HIV uninfected
M. tuberculosis uninfected HIV infected
M. tuberculosis infected HIV infected

• infection with M. tuberculosis does not prevent
  the acquisition of a new infection
• infection with HIV does not prevent the
  acquisition of a new infection

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XDR Tuberculosis

• Isolated from all continents
• paucity of information from many countries
• In SA
• Gandhi et al, Lancet, 2006
• reported 53 cases of XDR TB from Tugela Ferry
• found throughout South Africa
• Pillay and Sturm, CID 2007
• present in KZN in 2001 or earlier

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(Pillay and Sturm, CID, Dec. 2007)
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The incidence of smear negative PTB increased 35
fold.
The incidence of smear positive PTB increased 6
fold.
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Assumptions

• Each patient with PTB has 5 ml infected material
  in the lungs
• Each patient with smear positive PTB caries 105
  bacteria/ml
• Each patient with smear negative PTB caries 102
  bacteria/ml

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Mutation rates in resistance conferring genes

• Rifampicin 1108
• Isoniazid 1106
• Ethambutol 1106
• Streptomycin 1106
• Kanamycin 1106
• Cycloserine 1103
• Capreomycin 1103

In Schaaf and Zumla (2009)
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Assumptions

• Each patient with PTB has 5 mL infected material
  in the lungs
• Each patient with smear positive PTB caries 105
  bacteria/mL
• Each patient with smear negative PTB caries 102
  bacteria/mL
• Generation time of M.tuberculosis 24 hrs
• Mutation rate 1/1.000.000

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(Pillay and Sturm, CID, Dec. 2007)
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Over the last 2 decades

• increase in immune impaired hosts and TB
  transmitters
• total number of bacterial cells in the population
  increased over time
• increased number of mutational events
• creation of resistant bacterial cells to every
  available drug
• initiation of treatment without knowledge of
  susceptibility pattern
• selection of resistant organisms
• reactivation disease with MDR/XDR organisms
• new infection with MDR/XDR

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Diversity of M. tuberculosis strains

• Strains differ in their ability to spread in a
  population
• Two dominating families of strains in
  KwaZulu-Natal
• Beijing
• F15/LAM4/KZN

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F15/LAM4/KZN dominates among resistant isolates

• 28 of all MDR cases fingerprinted between 1994
  and 2002 (Pillay and Sturm, 2008)
• 70 of fingerprinted XDR and MDR isolates from
  Tugela Ferry since 2005 (to be published)

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Transmission in health care facilities

• M. vaccae immunization trial (1994-96)
• 14 (4 ) of 347 patients during 2 months of
  hospitalisation
• 4/14 were MDR F15/LAM4/KZN isolates
• Tugela Ferry XDR outbreak
• 2/3 possibly hospital acquired
• Many other reports of hospital acquired MDR
  tuberculosis

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Mathematical modellingbased on the Tugela Ferry
data (Basu et al, 2008)

• By the end of 2012
• 1300 cases of XDR in the Msinga district
• approximately 50 due to nosocomial infection

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Reactivation versus new infection

• Wilkinson et al (1997)
• 29 43 new infections in rural KwaZulu-Natal
  (Hlabisa) before the HIV epidemic turned into an
  AIDS epidemic
• Bandera et al (2001)
• 16 new infections in patients in Italy, a
  country with low prevalence
• Charalambous et al (2008)
• 69 new infections in mine-workers in South
  Africa
• Andrews et al (2008)
• 100 new infections in MDR/XDR patients in rural
  KwaZulu-Natal (Tugela Ferry)

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Reactivation versus new infection

• (Re)infection with a new strain plays an
  important role in the current tuberculosis
  epidemic
• Van Helden (IAS, 2009)
• extensive transmission of MDR
• very little transmission of XDR

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Genome sequencing of 13 F15/LAM4/KZN

• 1 susceptible
• 1 MDR
• 1 MDR
• 10 XDR

XDR-TB is transmissible
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INH prophylaxis

• INH prophylaxis prevents reactivation disease
  with INH susceptible organisms
• can result in selection of resistance in patients
  with undiagnosed/sub-clinical disease
• In KZN
• 28 MTB isolates are INH resistant
  (mono-resistant/combinations)
• likelihood of contact with someone that transmits
  INH resistant organisms are high

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INH Prophylaxis and the Acquisition of New
Infections

• long term antimicrobial prophylaxis
• preferential spread of resistant organisms
• will INH prophylaxis change the epidemic?
• ? decrease TB incidence in HIV infected
  individuals
• ? from predominantly drug susceptible
  tuberculosis into drug resistant tuberculosis

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What fuels the current TB epidemic in South
Africa ?

• High HIV prevalence with many cases progressing
  to AIDS
• Increased incidence of smear positive as well as
  smear negative cases of PTB
• High prevalence of MDR/XDR TB
• Delayed commencement of treatment of MDR/XDR
  cases
• ineffective laboratory support
• Nosocomial transmission
• The presence of highly successful strains

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Possible solutions

• Rapid diagnostic test for PTB
• for diagnosis
• for susceptibility testing
• These tests must detect smear negative PTB as
  well

undiagnosed smear negatives will eventually
become smear positives !
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• A test must identify within 1 to 2 hours whether
  a patient has TB and whether it is Susceptible,
  MDR or XDR TB
• immediate appropriate treatment
• isolation/cohort nursing during hospitalisation

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• 2. Anti-retrovirals
• accelerate roll out
• start much earlier than 200 CD4 cells/mm3
• 3. Infection prevention measures
• in outpatient facilities
• in hospital wards

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Acknowledgement

• K-RITH
• Wim Sturm
• Cookie Pillay
• Bill Jacobs
• Africa Centre
• Marie-Louise Newell
• Richard Lessels
• Graham Cooke

• TF CaRes
• Gerald Frieland
• Neel Gandhi
• Sarita Shah
• Tony Moll