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 RCT’s from Cote d’Ivoire late 1990’s
in HIV-1 or HIV-1,2 patients
Author
Pats
CTX
mg
reduction of
morbidity mortality
Anglaret 1
stage 2 or 3
960 od
43%
(severe
events*)
Wiktor 2
sm+ve TB
(stage 3 or 4)
960 od
43%
46%
admissions
* death or hospital admission
** not designed to demonstrate mortality benefit
1
Anglaret et al, Lancet, 1999
2 Wiktor et al, Lancet, 1999
-**
benefit
all CD4 strata
no PCP, few TE
mainly bacterial
infection, malaria,
isosporiasis
CD4<350 only
(58% of pats)
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 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 d’Ivoire (1995)
Kenya (1993-94)
Senegal (1996-98)
Malawi (1998)
: 14%
: 46%
: 57%
: 83%
Pneumococci
Cote d’Ivoire (1994-96)
South Africa (1999)
Kenya (2000)
Malawi (1998)
: 3%
: 10%
: 54%
: 91%
Differences resistance patterns to CTX
Concerns were raised - 3
Regarding treatment of malaria:
Cotrimoxazole
SP
: trimethoprim-sulfamethoxazole
: 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 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/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
(2004)
controls: historical
960 mg od
sm+ve 33 to 11%
sm-ve 50 to 39%
EPTB 50 to 12 %
0.01
ns
0.06
Thyolo
(2003)
cases: all TB
controls: historical
480 mg bd
sm+ve 22 to 20%
sm-ve 49 to 37%
EPTB 40 to 33%
ns
<0.01
0.05
Blantyre
(2005)
RCT
(sm+ve only)
480 or 960
mg od
480
960
ns
cases (480/960 combined)
controls (NTP)
15.4%
14.0%
14.7%
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
TB treatment success
Deaths
Chimzizi et al. IJTLD 2004
Thyolo
75%
21%
Mulanje
61%
25%
p<0.001
p< 0.026
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 ppv
Verbal verification 100 40
96.5
Pill count
91.5 60
97.4
Both
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
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 sideeffects 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 costeffectiveness 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