Cotrimoxazole prophylaxis in HIV positive TB patients Rhehab Chimzizi Anthony Harries Ministry of Health-Malawi

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

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

What is the evidence base for the use of cotrimoxazole prophylaxis in HIV positive patients with TB?

Early RCTs from Cote dIvoire late 1990s in HIV-1 or HIV-1,2 patients AuthorPatsCTX reduction of benefit mgmorbidity mortality Anglaret 1 stage 2 or od 43% -** all CD4 strata (severe no PCP, few TE events*) mainly bacterial infection, malaria, isosporiasis Wiktor 2 sm+ve TB960 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, Wiktor et al, Lancet, 1999

After Cote dIvoire 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/mm 3 or TLC equivalent

Concerns were raised - 1 Significant reduction in events / admissions Anglaret: attributed to bacterial pneumonia malaria isosporiasis acute unexplained fever Wiktor: attributed to enteritis (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?

Concerns were raised - 2 Resistance to CTX Non-Typhi Salmonellae Cote dIvoire (1995): 14% Kenya ( ): 46% Senegal ( ): 57% Malawi (1998): 83% Pneumococci Cote dIvoire ( ): 3% South Africa (1999): 10% Kenya (2000): 54% Malawi (1998): 91% Differences resistance patterns to CTX

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?

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 ratios (95% CI) survival0.84 ( ) severe event1.10 ( ) clinical event 1.19 ( ) Effect absent in all strata; CTX low dose well tolerated Maynart et al. 2001, JAIDS

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

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 ) Reduced incidence of HIV related illness HR 0.52 ( ) No effect in stage 2 or CD /mm 3 CTX had a 53% improved survival rate Methodological problems Unclear starting rules Badri et al. AIDS 2001

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

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 stopping Grimwade et al. AIDS 2005

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

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

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/mm 3 ; p<0.0001) lower annual mean rate of increase in viral load (0.08 vs log 10 copies/mL; p=0.01)

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%

Studies done in Malawi (all in HIV +ve patients with tuberculosis ) Location Design CTX Mortality reductionp Karonga cases: all TB 960 mg odsm+ve33 to 11%0.01 (2004) controls: historicalsm-ve 50 to 39%ns EPTB50 to 12 %0.06 Thyolo cases: all TB 480 mg bdsm+ve 22 to 20%ns (2003) controls: historical sm-ve 49 to 37%<0.01 EPTB40 to 33%0.05 Blantyre RCT 480 or % (2005) (sm+ve only) mg od %ns cases (480/960 combined) 14.7% controls (NTP) 21% p<0.001

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 Results Thyolo: Uptake VCT 97%; 69% started CTX ThyoloMulanje TB treatment success 75%61%p<0.001 Deaths21%25%p< Chimzizi et al. IJTLD 2004

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 sensspecppv Verbal verification Pill count Both Zachariah, IJTBLD 2001

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 ( ) 45 Very low compliance (< 0.6) 14 * Mermin, Lancet 2004 ** Boeree et al, TMIH, in press

Feasibility Malawi, 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

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)

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

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

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

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