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Impact of HIV on Early MDR-TB Treatment Outcomes in

BotswanaJeffrey Hafkin MD

Botswana-UPenn PartnershipCenter for Clinical Epidemiology and Biostatistics

Infectious Disease Division, Department of MedicineUniversity of Pennsylvania School of Medicine

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Background: MDR-TB and HIV-infection

• In the pre-HAART era, MDR-TB with HIV infection had worse treatment response and higher mortality compared to HIV-uninfected MDR-TB

• Few studies of MDR-TB outcomes in HIV+ with access to HAART, particularly in sub-Saharan Africa

Seung et al. PloS One 2009Brust et al. PloS One 2011

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Background: Epidemiology of HIV and TB in Botswana

• Prevalence of HIV infection = 25% (UNAIDS 2009)

• Incidence of TB disease = 503 cases per 100,000 population (WHO 2010)

• Prevalence of MDR-TB during 1995-2008:– 0.2% to 3.4% (treatment naïve)– 6.1% to 13.1% (treatment experienced)

• Start of HAART roll-out in Botswana in 2003

Nelson et al. Lancet 2005WHO. M/XDR-TB: 2010 global report on surveillance and response

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Study Design• Cohort study

– MDR-TB patients receiving individualized, integrated, ambulatory care at a two public clinics in Botswana

• Exposure– HIV infection (two parallel HIV ELISA assays)

• Outcome– Sputum culture conversion (two consecutive

negative sputum cultures at least one month apart)

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Endpoints• Primary:

– Time to initial sputum culture clearance after starting MDR-TB treatment

– Proportion of patients converting sputum cultures

• Secondary:– Proportion of patients with ototoxicity,

peripheral neuropathy, and renal toxicity

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Data Collection• Subject population:

– All confirmed MDR-TB patients who were started on anti-MDR-TB treatment prior to September 2008

– Excluded from analysis if no quantifiable culture follow up time after start of treatment

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Statistical Analysis• Unadjusted Analysis:

– Time to culture conversion by HIV status • Log rank test and Kaplan-Meier curves

– Proportion of patients with sputum culture conversion by HIV status• Chi-Square test

• Adjusted Analysis:– Cox proportional hazard models controlling for

age, sex, number of active anti-TB agents and TB treatment history

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Baseline Characteristics• 74 patients with culture-confirmed

MDR-TB were identified– 4 were excluded

• no quantifiable culture f/u time after start of treatment

• 70 had complete data for analysis– 40 (57%) HIV-infected– 30 (43%) HIV-uninfected

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HIV-Related Characteristics• Baseline CD4+ count = 158 (IQR 88-347) 3m f/u CD4+ count = 262 (IQR 129-382)

• 28 (69%) on HAART prior to start of MDR-TB treatment and 36 (90%) during treatment

• Most regimens consisted of 2NRTI + NNRTI– 19 (53%) zidovudine/lamivudine– 8 (22%) stavudine/lamivudine– 8 (22%) tenofovir/lamivudine– 4 (11%) abacavir/lamivudine

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Baseline Characteristics by HIV Status

Characteristic HIV+N=40

HIV-N=30

P-value

Median Age (years, IQR) 39 (30-45) 33 (24-59) 0.4

Sex, n (%) Male Female

29 (73)11 (28)

22 (73)8 (27)

>0.5

TB Treatment History, n (%) Any 1st line therapy Any 2nd line (plus 1st line) Unknown

29 (73)7 (18)4 (10)

23 (77)3 (10)4 (13)

>0.5

Resistant Drugs at Baseline(median, IQR) 5 (4-5) 5 (5-5) >0.5

Number Active Drugs(median, IQR) 4 (4-4) 4 (4-4) >0.5

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1st Line Anti-TB Drug Resistance by HIV Status

Drug n (%)

HIV+N=40

HIV-N=30

P-value

Ethambutol Yes No Unknown

24 (60)16 (40)

0 (0)

23 (77)7 (23)0 (0)

0.14

Streptomycin Yes No Unknown

25 (63)13 (33)

2 (5)

19 (63)9 (30)2 (7)

>0.5

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2nd Line Anti-TB Drug Resistance by HIV Status

Drug n (%)

HIV+N=40

HIV-N=30

P-value

Kanamycin Yes No Unknown

1 (3)18 (45)21 (53)

3 (10)12 (40)15 (50)

0.4

Ofloxacin Yes No Unknown

2 (5)16 (40)22 (55)

3 (10)10 (33)17 (57)

>0.5

Ethionamide Yes No Unknown

7 (18)12 (30)21 (53)

6 (20)9 (30)

15 (50)

>0.5

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Anti-TB Drugs Used by HIV StatusDrug, n (%) HIV+ (n=40) HIV- (n=30) P valueEthambutol 12 (30%) 8 (27%) >0.5Pyrazinamide 38 (95%) 29 (97%) >0.5Ciprofloxacin 37 (93%) 27 (90%) >0.5Ofloxacin 0 (0%) 1 (3%) 0.4Moxifloxacin 2 (5%) 3 (10%) 0.4Streptomycin 2 (5 %) 1 (3%) >0.5Amikacin 35 (88%) 20 (83%) >0.5Capreomycin 2 (5%) 3 (10%) 0.4Cycloserine 27 (67%) 20 (67%) >0.5Terizidone 0 (0%) 1 (3%) 0.4PAS 2 (5%) 3 (10%) 0.4Amox/Clav 2 (5%) 6 (20%) 0.05Clarithromycin 3 (8%) 1 (3%) 0.5

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Follow-up• Median on treatment follow up time:

– 82 days (IQR 52-133)

• Median duration aminoglycoside: – 8 mos (no difference by HIV status, p=0.48)

• Sputum culture conversion:– Overall: 59 of 70 (84%)– HIV-infected: 34 of 40 (85%)– HIV-uninfected: 25 of 30 (83%)(p>0.5)

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Follow-up• 4 patients died following enrollment:

– 2 following sputum culture conversion (both HIV-infected)

– 2 prior to culture conversion (both HIV-uninfected)

• 2 patients identified with XDR TB during follow-up (one HIV+, one HIV-)

• No patients defaulted from care during the study period

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Time to Sputum Culture Conversion

• Median time to sputum culture conversion: – 78 days (IQR 42-186) for HIV-infected– 95 days (IQR 70-133) for HIV-uninfected

• (log rank p >0.5)

• Unadjusted HR = 0.9 (95% CI: 0.5 to 1.5)

• Adjusted HR = 0.8 (95% CI: 0.4 to 1.4)– adjusting for age, gender, TB treatment history,

and number of active agents

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HIV neg

HIV pos Logrank Test, p>0.5

0.00

0.25

0.50

0.75

1.00

Pro

porti

on w

ith C

ultu

re C

lear

ance

40 24 14 10 8 4 3HIV = Pos30 23 11 3 2 1 1HIV = Neg

Number at risk

0 60 120 180 240 300 360

Analysis Time (Days)

Kaplan-Meier Clearance Estimates

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ToxicityType of toxicity

HIV positiven (%)

HIV negativen (%)

P-value

Neuropathy 16 (40) 3 (10) p<0.01

Nephropathy 10 (25) 2 (7) p=0.04

Ototoxicity 21 (53) 21 (70) p=0.14

Neuro-psychiatric

3 (8) 3 (10) p>0.5

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Limitations• Sample size• Generalizability:

– Botswana vs. Sub-Saharan Africa• Selection bias:

– Specialist care in a referral center– Missing culture/DST data

• Misclassification bias:– Characterization of toxicity

• Unmeasured confounding

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Conclusions• HIV infection did not impact time to culture

conversion in cohort of adults with MDR-TB from Botswana

• Suggests that in resource-limited settings with broad access to ART and individualized MDR-TB care, short term microbiologic outcomes may be comparable in HIV-infected and uninfected patients

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Conclusions• Furthermore, high rates of drug toxicity

overall and more likely to be associated with co-infection

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Acknowledgements• Univ of Pennsylvania

– Chawanga Modongo– Lephata Molopisi– Craig Newcomb– Elizabeth Lowenthal– Andrew Steinhoff– Rob Roy MacGregor– Harvey Friedman– Gregory Bisson

• Botswana NTP– Tore Steen, Howard

Moffet

• Botswana TB Reference Lab– Koobiditse Radisowa– Valentina Anisimova

• CDC-Atlanta– Victoria Gammino

• CDC-Botswana– Robert Makombe

• Funding Support:– NIH T32AI055435– Penn CFAR NIH P30AI045008