Cotrimoxazole prophylaxis in HIV positive TB patients

Rhehab ChimziziAnthony 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 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

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

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?

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

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 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

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 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

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 stoppingGrimwade 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/mm3; p<0.0001)

• lower annual mean rate of increase in viral load

(0.08 vs. 0.90 log10 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 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

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

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

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

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

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