sulfamethoxazole prophylaxis on long term clinical impact of malaria infection among HIV infected adults on successful ART in Blantyre Malawi Felix Mkandawire Randy G Mungwira Titus H Divala ID: 641270
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Slide1
Effects of daily trimethoprim-sulfamethoxazole prophylaxis on long term clinical impact of malaria infection among HIV infected adults on successful ART in Blantyre, Malawi
Felix Mkandawire
,
Randy G.
Mungwira
,
Titus H. Divala
,
Osward
M.
Nyirenda
, Maxwell
Kanjala
,
Lufina
Tsirizani
,
Francis
Muwalo,
Nicaise
Ndembi
,
Terrie E. Taylor, Jane
Mallewa
, Joep
J. van Oosterhout
, Matthew B. Laurens, Miriam K. LauferSlide2
Malaria and HIVCombined 2 million deaths annually Highest
burdens
overlap
in sub-Saharan Africa Proportion of global incidence 88% of malaria cases and 90% of malaria deathsHIV 70% Geographical overlap: high risk of coinfection
1. WHO Annual report - 2008
, 2. UNAIDS report –
2010, 3. WHO- 2015Slide3
Malaria and HIV immunosuppressionRisk of malaria disease increases slightly with immunosuppressionCotrimoxazole preventive therapy
(CPT)
p
revents OI’sreduces the risk of malaria4 Laufer et al. - 2006, 5 WHO guidelines – 2006, 6.
Polyak
et al. – 2016,
7.
Kasirye
et al. – 2016Slide4
Role of CPT after ARTAntiretroviral therapy (ART) now widely available in sub-Saharan AfricaHighly effective in leading to immune recoveryAfter immune reconstitution, is CPT still beneficial?
Why consider CPT discontinuation?
Side effects, pill burden,
cost, antimicrobial resistanceSlide5
With ART success, can CPT be discontinued?What we know about CPT discontinuation Two clinical trials:
Most significant morbidity was increased malaria infection
Also increase in diarrhea
No increased risk of other OIsWhat is unknownMechanism of clinical malaria susceptibility Impact on asymptomatic malaria
1.
Polyak
et al 2016, 2.
Kasirye
et al. 2016Slide6
Goals of this studyWhat is the impact of discontinuing CPT on Clinical susceptibility to malaria infectionAsymptomatic malaria infectionUsing data from an on-going clinical trialSlide7
Study site and settingNdirande Health Centre, Blantyre, MalawiParticipants selected from:
A
randomized, open-label controlled trial of daily
cotrimoxazole or weekly chloroquine among adults on ART Small subgroup selected for immunology sub-studySlide8
Cohort selection from TSCQParticipants from the CPT and No CPT arm
Non-pregnant adults aged ≥18 years
≥6 months on ART and CPT
Clinically stable: no acute illnessEvidence of successful ART and immune recoveryHIV viral load <400 copies/ml, CD4 count >250 cells/mm3Slide9
Study proceduresFollow up: every 4 weeks for 6 monthsAlso evaluated when sickData collectedHistory: Malaria symptoms or signs,
b
ednet use
Examination: malaria signs Diagnostic specimensBlood smear if symptoms of malaria were presentDried blood spots on filter paper for qPCR at every visitSlide10
Molecular detection of malariaQiagen extraction of dried blood spots on Whatman 3M filter paperReal-time PCR detection of P. falciparum 18s rRNA geneStandard curves evaluated for each runSlide11
Outcome definitionsClinical malariaMalaria symptoms plus positive blood smearAsymptomatic malariaNo malaria-like symptoms plus positive Real-time PCRSlide12
Baseline characteristics were similar between groups
Characteristics
CPT
No CPT
Total enrolled
34
27
Proportion
Male (%)
15
19
Mean
age (
Yrs
)
41
40
Median
CD4 (cel
ls/mm3)
494
519
Mean
Hemoglobin (g/
dL
)
13
13
Bed
net
use (%)
85
85Slide13
Study profileEnrolled: 61
No CPT:
27
CPT:
34
31 completed
f/up
Accrued: 17 PYO
# F/paper analyzed
239
Exposure
Outcome
22 completed
f/up
Accrued: 14 PYO
Clinical:
4 cases
Asymptomatic: 0
Follow up
Clinical: 1 case
Asymptomatic: 0
# F/paper analyzed
225Slide14
Clinical and asymptomatic malariaClinical malaria6/100 PYO (CPT) vs 29/100
PYO
(No
CPT)Incidence rate ratio 5.0 [95%-CI 0.5 to 246.4]No episodes of asymptomatic malaria detected in either groupSlide15
Discussion: Clinical malariaMore episodes of clinical malaria in the “no CPT” group Difference not statistically significant Small sample size
Results of clinical disease incidence confirm previous findingsSlide16
Discussion: Asymptomatic malariaNo episode of asymptomatic malaria detectedAll infections manifested clinicallyUnusual in BlantyreRecent adult population survey
in Blantyre
5
% (120/2613) parasitaemia prevalence by qPCRAll most all were asymptomatic5 Walldorf et al. - 2015Slide17
Does CPT impact malaria immunity?CPT successfully prevented most Malaria infectionsWe expected to find some degree of asymptomatic malaria Demonstrated by surveillance studies in same areaHowever, all malaria infection → symptomatic disease
By preventing malaria, CPT may have impacted immunity to malaria disease.
Rebound effect described in some but not all previous prophylaxis studiesSlide18
Strengths and limitationsStrengthsDetailed clinical and laboratory data from RCT settingGood active and passive malaria surveillance
Limitations
Power
Sample sizeLow transmission areaDid not measure malaria immunitySlide19
ConclusionCPT discontinuation after long term useAssociated with increased risk of clinical malariaNo infections were asymptomatic
Suggests loss
of malaria
immunityFinal analysisHigher power with inclusion of more TSCQ study participantsExplore impact on malaria immunityPlan to evaluate serological responseSlide20
Acknowledgements
Ndirande Health Center
Study
participantsBlantyre Malaria Project Study nurses led by M. Funsani Study clinicians led L. KhondeLaboratory led by R.
Masonga
Data team led E.
Huwa
Funding
NIH U01AI089342