1. 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. Laufer

2. Malaria and HIV Combined 2 million deaths annually
Highest burdens overlap in sub-Saharan Africa
Proportion of global incidence
88% of malaria cases and 90% of malaria deaths
HIV 70%
Geographical overlap: high risk of coinfection
1. WHO Annual report , 2. UNAIDS report – 2010, 3. WHO- 2015

3. Malaria and HIV immunosuppression
Risk of malaria disease increases slightly with immunosuppression
Cotrimoxazole preventive therapy (CPT)
prevents OI’s
reduces the risk of malaria
4 Laufer et al , 5 WHO guidelines – 2006, 6. Polyak et al. – 2016, 7. Kasirye et al. – 2016

4. Role of CPT after ART
Antiretroviral therapy (ART) now widely available in sub-Saharan Africa
Highly effective in leading to immune recovery
After immune reconstitution, is CPT still beneficial?
Why consider CPT discontinuation?
Side effects, pill burden, cost, antimicrobial resistance

5. 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 OIs
What is unknown
Mechanism of clinical malaria susceptibility
Impact on asymptomatic malaria
1. Polyak et al 2016, 2. Kasirye et al. 2016

6. Goals of this study What is the impact of discontinuing CPT on
Clinical susceptibility to malaria infection
Asymptomatic malaria infection
Using data from an on-going clinical trial

7. Study site and setting Ndirande Health Centre, Blantyre, Malawi
Participants selected from:
A randomized, open-label controlled trial of daily cotrimoxazole or weekly chloroquine among adults on ART
Small subgroup selected for immunology sub-study

8. Cohort selection from TSCQ
Participants from the CPT and No CPT arm
Non-pregnant adults aged ≥18 years
≥6 months on ART and CPT
Clinically stable: no acute illness
Evidence of successful ART and immune recovery
HIV viral load <400 copies/ml,
CD4 count >250 cells/mm3

9. Study procedures Follow up: every 4 weeks for 6 months
Also evaluated when sick
Data collected
History: Malaria symptoms or signs, bednet use
Examination: malaria signs
Diagnostic specimens
Blood smear if symptoms of malaria were present
Dried blood spots on filter paper for qPCR at every visit

10. Molecular detection of malaria
Qiagen extraction of dried blood spots on Whatman 3M filter paper
Real-time PCR detection of P. falciparum 18s rRNA gene
Standard curves evaluated for each run

11. Outcome definitions Clinical malaria
Malaria symptoms plus positive blood smear
Asymptomatic malaria
No malaria-like symptoms plus positive Real-time PCR

12. Baseline characteristics were similar between groups
CPT
No CPT
Total enrolled 34 27
Proportion Male (%) 15 19
Mean age (Yrs) 41 40
Median CD4 (cells/mm3)
494
519
Mean Hemoglobin (g/dL) 13
Bed net use (%) 85

13. Study profile Enrolled: 61 CPT: No CPT: Exposure 34 27
22 completed f/up
Accrued: 14 PYO
31 completed f/up
Accrued: 17 PYO
Follow up
# F/paper analyzed
225
# F/paper analyzed
239
Clinical: 4 cases
Asymptomatic: 0
Outcome
Clinical: 1 case
Asymptomatic: 0

14. Clinical and asymptomatic malaria
Clinical malaria
6/100 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 group

15. Discussion: Clinical malaria
More episodes of clinical malaria in the “no CPT” group
Difference not statistically significant
Small sample size
Results of clinical disease incidence confirm previous findings

16. Discussion: Asymptomatic malaria
No episode of asymptomatic malaria detected
All infections manifested clinically
Unusual in Blantyre
Recent adult population survey in Blantyre
5% (120/2613) parasitaemia prevalence by qPCR
All most all were asymptomatic
5 Walldorf et al

17. Does CPT impact malaria immunity?
CPT successfully prevented most Malaria infections
We expected to find some degree of asymptomatic malaria
Demonstrated by surveillance studies in same area
However, 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 studies

18. Strengths and limitations
Detailed clinical and laboratory data from RCT setting
Good active and passive malaria surveillance
Limitations
Power
Sample size
Low transmission area
Did not measure malaria immunity

19. Conclusion CPT discontinuation after long term use
Associated with increased risk of clinical malaria
No infections were asymptomatic
Suggests loss of malaria immunity
Final analysis
Higher power with inclusion of more TSCQ study participants
Explore impact on malaria immunity
Plan to evaluate serological response

20. Acknowledgements
Ndirande Health Center
Laboratory led by R. Masonga
Study participants
Data team led E. Huwa
Blantyre Malaria Project
Funding
Study nurses led by M. Funsani
NIH U01AI089342
Study clinicians led L. Khonde