Effects of daily trimethoprim-

Presentation on theme: "Effects of daily trimethoprim-"— Presentation transcript:

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