cotrimoxazole prophylaxis in hiv positive tb patients rhehab chimzizi anthony harries ministry of...
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Cotrimoxazole prophylaxis in HIV positive TB patients
Rhehab ChimziziAnthony Harries
Ministry of Health-Malawi
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What is known so far
• CTX is cheap, safe antibiotic with a broad spectrum action against several HIV related and non-related pathogens
• In developed countries CTX has been widely used as primary and secondary prophylaxis to prevent:– PCP– Toxoplasma gondii encephalitis
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CTX prophylaxis in subsaharan Africa may reduce mortality
By protection against: • PCP (uncommon)• Toxoplasmic encephalitis (uncommon)• Isospora diarrhoea (common)• Bacterial infections: pneumonia, meningitis, sepsis
(very common) • Malaria (very common)• CTX routine use in developing countries, particularly
sub-Saharan Africa has been minimal
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What is the evidence base for the use of cotrimoxazole prophylaxis in HIV positive patients with TB?
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Early RCT’s from Cote d’Ivoire late 1990’s in HIV-1 or HIV-1,2 patients
Author Pats CTX reduction of benefit mg morbidity mortality
Anglaret 1 stage 2 or 3 960 od 43% -** all CD4 strata (severe no PCP, few TE events*) mainly bacterial
infection, malaria, isosporiasis
Wiktor 2 sm+ve TB 960 od 43% 46% CD4<350 only (stage 3 or 4) admissions (58% of pats)
* death or hospital admission** not designed to demonstrate mortality benefit
1 Anglaret et al, Lancet, 19992 Wiktor et al, Lancet, 1999
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After Cote d’Ivoire studies
WHO / UNAIDS: • stopped all placebo controlled trials (Malawi, RSA, Senegal)
• provisional recommendation (2000): CTX prophylaxis (960 mg od) for HIV-infected adults
and children in Africa with WHO stage 2,3 or 4
or CD4 < 500/mm3
or TLC equivalent
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Concerns were raised - 1
Significant reduction in events / admissions
Anglaret: attributed to bacterial pneumonia malaria isosporiasis acute unexplained fever
Wiktor: attributed toenteritis (isospora and NTS)septicaemia (NTS)
Thus: CTX may be effective in areas where these infections are common causes of morbidity and mortality
Regional differences in spectrum of HIV disease?
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Concerns were raised - 2 Resistance to CTX
Non-Typhi Salmonellae Cote d’Ivoire (1995) : 14% Kenya (1993-94) : 46%Senegal (1996-98) : 57%Malawi (1998) : 83%
PneumococciCote d’Ivoire (1994-96) : 3%
South Africa (1999) : 10% Kenya (2000) : 54%
Malawi (1998) : 91%
Differences resistance patterns to CTX
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Concerns were raised - 3
Regarding treatment of malaria:
Cotrimoxazole : trimethoprim-sulfamethoxazole SP : sulfadoxine-pyrimethamine
Shared mechanisms of action:
• Pyrimethamine and trimethoprim – inhibit parasite dihydrofolate reductase (DHFR)
• Sulfadoxine and sulfamethoxazole– inhibit parasite dihydropteroate synthase (DHPS)
Will CTX prophylaxis lead to accelerated resistance of malaria to SP?
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Studies from Africa in areas with high rates of resistance to CTX
Senegal ( 2001)Design : RCT, CTX 480 mg vs. placebo Patients : n= 100; CD4 < 400; HIV-1 or HIV 1+2
Results:Mean follow-up: ~ 8 months Hazard ratio’s (95% CI)
survival 0.84 (0.36-1.94)severe event 1.10 (0.57-2.13)clinical event 1.19 (0.55-2.59)
Effect absent in all strata; CTX low dose well tolerated
Maynart et al. 2001, JAIDS
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Studies from Africa in areas with high rates of resistance to CTX
South Africa (2001)
Design: Observational cohort with 5-year follow-up: Pats:
HIV+ve adults in stage 2-4 or CD4 <500 CTX n =155 vs. no CTX n= 407
CTX regime:CTX 960 mg 3 x week; later 480 mg daily
Badri et al. AIDS 2001
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Studies from Africa in areas with high rates of resistance to CTX
South Africa (2001)
Outcome in those on CTX
Reduced mortality in stage 3 and 4 or CD4 < 200
HR 0.56 (95% CI 0.33-0.85)
Reduced incidence of HIV related illness
HR 0.52 (0.38-0.68)
No effect in stage 2 or CD4 200-500/mm3
CTX had a 53% improved survival rate
Methodological problems
Unclear starting rules
Badri et al. AIDS 2001
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Studies from Africa in areas with high rates of resistance to CTX
South Africa (2005)
Design: observational study with historical controls
Pats:
Intervention group (n=1321): all TB; irrespective of HIV status, CTX 960 mg
Historical controls (n=2004): all TB; irrespective of HIV status, no CTX
29% reduction of mortality In a cohort of adult TB patients taking CTX irrespective of HIV status
Grimwade et al. AIDS 2005
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Studies from Africa in areas with high rates of resistance to CTX
South Africa (2005) - ctd
Adherence• 58% at 3 months; 43% at 6 months• better in females• good adherence predictive of survival
deaths at 6 months:
1.8% (adherent) vs. 6% (non-adherent); p<0.001
Side-effects• 2 severe: 1 Stevens-Johnson syndrome; 1 exfoliative dermatitis• otherwise minor – no reason for stoppingGrimwade et al. AIDS 2005
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Studies from Africa in areas with high rates of resistance to CTX
Uganda study (2004)
Design: prospective cohort
Pats:• HIV+ve (all stages; n=509; median age 34 years)
• After 5 months follow-up HIV+ves given CTX 960 mg od; followed for another 1.5 years
• HIV-ve household members (n=1522; median age 10 years)
Mermin et al. Lancet 2004
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Studies from Africa in areas with high rates of resistance to CTX
Uganda study (2004) – ctd
CTX in HIV positive persons was associated with a:• In HIV +ve before vs. after CTX
Reduction in– mortality : 46% (only in CD4 < 200 or WHO 3 or 4)– malaria rate : 72% (all ages and all CD4 counts)– diarrhoea rate : 35% (age > 5 yrs, CD4 > 200– hosp. admission :15-30% (all patients)
Mermin et al. Lancet 2004
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Studies from Africa in areas with high rates of resistance to CTX
Uganda study (2004) - ctd
Other outcomes
While on CTX• lower annual mean rate of decline in CD4 count
(77 vs. 203 cells/mm3; p<0.0001)
• lower annual mean rate of increase in viral load
(0.08 vs. 0.90 log10 copies/mL; p=0.01)
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Studies from Africa in areas with high rates of resistance to CTX
Uganda study (2004) - ctd
Other outcomes• Resistance of bacterial isolates to CTX
before CTX 76%after CTX 83%
• Compliance excellent>75% of CTX was taken by 90% (self-report) and by
96% (pill count)
• Adverse reactions: 2%
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Studies done in Malawi (all in HIV +ve patients with tuberculosis)
Location Design CTX Mortality reduction p
Karonga cases: all TB 960 mg od sm+ve 33 to 11% 0.01(2004) controls: historical sm-ve 50 to 39% ns
EPTB 50 to 12 % 0.06
Thyolo cases: all TB 480 mg bd sm+ve 22 to 20% ns(2003) controls: historical sm-ve 49 to 37% <0.01
EPTB 40 to 33% 0.05
Blantyre RCT 480 or 960 480 15.4% (2005) (sm+ve only) mg od 960 14.0% ns
cases (480/960 combined) 14.7% controls (NTP) 21% p<0.001
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Studies after CTX implementation
Malawi: Thyolo (2004)
Objective Evaluation of VCT+CTX package (Thyolo) and no
package (Mulanje)Design: cohort study using routine NTP data
ResultsThyolo: Uptake VCT 97%; 69% started CTX
ThyoloMulanje
TB treatment success 75% 61% p<0.001Deaths 21% 25% p< 0.026
Chimzizi et al. IJTLD 2004
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Compliance
Malawi:Thyolo
Pats: n=87 with HIV/TB who started CTX
• Trimethoprim levels in urine as gold standard• Detected in 94%• Verbal verification and pill counts
sens spec ppvVerbal verification 100 40 96.5Pill count 91.5 60 97.4Both 100 60 97.6
Zachariah, IJTBLD 2001
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Compliance
Uganda study 2004*• Compliance excellent:
– took at least 75%: 90% by self-report; 96% by pill count
Blantyre study**• N=579• Compliant/over compliant 520• Low compliance (0.6-0.8) 45• Very low compliance (< 0.6) 14
* Mermin, Lancet 2004** Boeree et al, TMIH, in press
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FeasibilityMalawi, 15 hospitals (2003)
Objective: to study implementation of VCT and CTX for TB pats
Time: June –Sept 2003
Place: 15 hospitals visited
Results: • VCT accepted by 59%• HIV positive 68%• of those HIV+ve: 97% started CTX
Chimzizi et al. IJTLD 2004
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High dose vs. low dose CTX
In Caucasians, for PCP prophylaxis
Schneider et al. NEJM 1992: • 480 mg had equal efficacy; delayed onset of adverse reactions
Ioannidis et al. Arch Intern Med 1996• meta-analysis: CTX 480 mg: 43% decrease in severe side-
effects prompting discontinuation of CTX
In Africans• Boeree et al. TMIH (in press): 480 vs. 960 mg: no differences in
mortality or side-effects (but not powered to detect)
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High dose vs. low dose CTX
Cost
At IDA for a container of:
1000 caps 480 mg: Euro 4.30 (0.004 ct. per tab)
500 caps 960 mg: Euro 4.95 (0.01 ct. per tab)
In uganda the cost of treating one person with CTX annaully was USD6
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Conclusions -1
• Accumulating evidence that CTX is beneficial in stage 2, 3 or 4 or if CD4 <200– reduction of morbidity and mortality– slows HIV disease progression
• Also in areas with high CTX resistance
• CTX resistance in the lab may not exclude efficacy of CTX as a prophylactic agent
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What do we need to know?
Efficacy and cost-effectiveness of CTX• Stage 1, (2): no evidence of benefit but several studies lacked power
• Stage 1 and 2: benefit of CTX while not on HAART yet?
• How long will CTX be effective (increasing resistance)?
• How long if on ART? Until CD4 >200 x 3 months?
• Effect on efficacy of SP for malaria?
• Safety and efficacy of CTX in HIV positive pregnant women
• What is most appropriate dose?• Best delivery sites for CTX (TB, VCT, ART, PMTCT clinics
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What has to be done to fill the knowledge gap
• Given the established benefits of CTX, further randomized controlled trials on efficiency and cost-effectiveness will be difficult with CTX given as single intervention
• However, in conjunction with ARV therapy a randomized controlled with or without CTX will probably be the only to way answer the question about added efficacy