Incidence of malarial episodes in a cohort of West African HIV-1 infected adults exposed or not to cotrimoxazole chemoprophylaxy MALHIV STUDY Abidjan-Bamako-Bobo-Dioulasso-Dakar

F.Ello2 , S.P. Eholié 2, M.Ouiminga 2,I.S.Ouattara 2, L. Denoeud 3, T.C.Adjé2, ,A.Sawadogo 1, H.A Traoré 4, M.Soumaré 5,, E.Bissagnene 2

1 .Hôpital Sourou Sanon, Bobo-Dioulasso, Burkina Faso 2. SMIT, CHU de Treichville, Abidjan, Cote d’Ivoire 3. Hôpital Saint – Antoine , Paris France 4. SMIT, CHU Point G, 5. SMIT,CHU de Dakar, Sénégal

Presented at the 4th INTEREST Workshop 25-28 May 2010, Maputo Mozambique INTRODUCTION

* Malaria and HIV are the most frequent infectious diseases in Subsaharan Africa

* Numerous issues on the impact of both diseases in aeras where they overlap - malaria: rural aeras, pregnant women and children - VIH: urban aeras, town young adults citizens - co-morbidity HIV-malaria spread of both diseases in SubSaharan Africa (Abu-Raddad LJ, Science 2006)*

* Study conducted to assess the impact of cotrimoxazole chemoprohyalxy in Malaria in West Africa.

Presented at the 4th INTEREST Workshop 25-28 May 2010, Maputo Mozambique OBJECTIVES

* Principal objective : Describe the natural history of malaria in HIV-1 infected patient exposed or not to cotrimoxazole chemoprophylaxy (960 mg/j).

* Secondary objective : - Describe CD4 and viral load modifications in case of malarial episodes; - Assess efficacy and tolerance of artemisin combination

therapy(ACT)

Presented at the 4th INTEREST Workshop 25-28 May 2010, Maputo Mozambique METHODOLOGY

* Multicenter, prospective, longitudinal, comparative study;

* Duration : 30 months, inclusion period 12 months and 18 months follow-up;

* Comparative study on malarials episodes’ incidences in patients exposed to CTX ([CTX + CD4 < 350 cell/ml] vs patients not exposed [CTX – CD4 ≥ 350 cell/ml])

* Inclusion criteria: Age >18 years, cotrimoxazole and ARVs naive,

Karnofsky ≥70%, living in malaria endemic aera.

Presented at the 4th INTEREST Workshop 25-28 May 2010, Maputo Mozambique METHODOLOGY

• Inclusion visit : clinical examination ( weight, temperature, blood pressure, pulse, Karnofsky, CDC stage 1993 ), thick film j0 et PCR j0; clinical examination every 3 months • Biological follow up every 6 months: thick film, blood count, creatinine, ALT, AST, CD4,VL

• Malaria episodes: clinical parameters, thick film D0, D1, D3, D7, D14, D21, D28

- blood count , ALT/AST, Creatinine, PCR Pf (D0, D14 et D28) ;

- CD4, VL (D0, D28) • Primary endpoint: incidence of malaria episodes (number of cases/100PY) • Secondary endpoints: antimalarial drugs’ efficacy antimalarial drugs tolerance (ACT) grade 3-4

Presented at the 4th INTEREST Workshop 25-28 May 2010, Maputo Mozambique METHODOLOGY

Definitions:

* Acute uncomplicated malaria : fever ≥ 37°5 C, body trembling, chills, pain, headache, evidence of P falciparum parasitaemia (asexual forms)

* Severe malaria: fever ≥ 37°5 C with clinical and biological severe symptoms [WHO 2003], evidence of P falciparum parasitaemia (asexual forms);

Presented at the 4th INTEREST Workshop 25-28 May 2010, Maputo Mozambique ResultsResults

642 pre-include

94 not included 548 Included F (364 [66.5%])

380 Cotrimo (+) 168 Cotrimo(-)

325 ARVs+ (59.3%)

268 ARVs + (70.5%) 57 ARVs + (33.4%)

Presented at the 4th INTEREST Workshop 25-28 May 2010, Maputo Mozambique Patients recruitement/site

Abidjan Dakar Bamako Bobo Dioulasso

Inclusion 165 (30.1%) 76 (13.9%) 100 (18.2%) 207 (37.8%)

Cotrimo+ 111 (67.2%) 51 (67.1%) 60 (60%) 158 (76.3%)

Cotrimo- 54 (32.8%) 25 (32.9%) 40 (40%) 49 (23.7%)

ARVs+ 113 12 63 137

Presented at the 4th INTEREST Workshop 25-28 May 2010, Maputo Mozambique GeneralGeneral characteristicscharacteristics ofof studystudy populationpopulation

Cotrimo (+) Cotrimo (-) P Effectif N = 380 N =168

Mean age 35.5 32.1 0.05 Ratio H/F 0.38 0.28 - Mean weight 59.9 62.6 0.09 Asymptomatic parasitaemia ARVs+ 268 57 0.05 Mean CD4 171 534 0.00 Mean viral load 325035 112913 0.14

Presented at the 4th INTEREST Workshop 25-28 May 2010, Maputo Mozambique Incidences of febrile episodes and acute uncomplicated malaria episodes

Total CTX + CTX – RR P N = 548 N= 380 N = 168

Febrile 203 (37%) 134 (35.3%) 69 (41.1%) 0.68 0.19 episodes CI= [0.86 – 1.08] 6.75/100PY 9.3/100PY 24.4/100PY

Acute uncomplicated 35 (6.4%) 5 (1.3%) 30 (17.8%) 0.03 <0.05 malaria CI= [0.07 - 0.19] 1.17/100PY 0.34/100 PY 10.6/100PY

All malaria cases in stable malaria transmission aera

Presented at the 4th INTEREST Workshop 25-28 May 2010, Maputo Mozambique Incidences of febrile episodes and acute uncomplicated malaria in stable malaria transmission aera

Total CTX + CTX – RR P N = 364 N= 263 N = 101

Febrile 165 (45%) 105 (39.9%) 60 (59.4%) 0.80 0.0008 episodes CI= [0.7 - 0.92] 27.3/100PY 15.2/100PY 58.8/100PY Acute Uncomplicated 35 (9.6%) 5 (1.9%) 30 (29.7%) 0.28 <0.05 malaria CI= [0.16 - 0.49] 2.6/100PY 0.72/100 PY 29.4/100PY

(Abidjan n= 13 [11 CTX -, 2 CTX+), Bobo-Dioulasso n=22 [19 CTX-, 3 CTX+] )

Presented at the 4th INTEREST Workshop 25-28 May 2010, Maputo Mozambique CD4 modifications during malaria episodes

Total patients

600 475 492 442 500 361 400 Total patients 300 200 N=35 Malaria episodes 100

0

inclus ion PréAP J0 J28

Presented at the 4th INTEREST Workshop 25-28 May 2010, Maputo Mozambique Variation of viral load during malaria episodes

Presented at the 4th INTEREST Workshop 25-28 May 2010, Maputo Mozambique Preliminaries results of drugs resistance mutations MALHIV Cohort Study

Presented at the 4th INTEREST Workshop 25-28 May 2010, Maputo Mozambique Prevalence of mutations conferring resistance to chloroquine and sulfadoxine-pyrimthamine in Plasmodium falciparum isolates from MALHIV cohort study - JO

Genes locus Mutations N Mutations(%)

pfcrt K76T 75 13 (17.33%)

pfmdr N86Y 75 14 (18.66%)

pfdhfr N51I 75 12 (16%)

pfdhfr C59R 75 12 (16%)

pfdhfr S108N 75 1 (1.33%)

pfdhps A437G 75 27 (36%)

pfdhps K540E 451 75 (16.6%)

Presented at the 4th INTEREST Workshop 25-28 May 2010, Maputo Mozambique Prevalence of mutations conferring resistance to chloroquine and sulfadoxine-pyrimthamine in Plasmodium falciparum isolates from MALHIV cohort study – M6

Genes locus Mutations N Mutations(%)

pfcrt K76T 40 9 (22.5%)

pfmdr N86Y 40 2 (5%)

pfdhfr N51I 40 _

pfdhfr C59R 40 11 (27.5%)

pfdhfr S108N 40 1 (2.5%)

pfdhps A437G 40 14 (35%)

pfdhps K540E 143 40 (28%)

Presented at the 4th INTEREST Workshop 25-28 May 2010, Maputo Mozambique Efficacy and tolerance of antimalarial drugs n=35

* Efficacy AS/AQ

Mean fever clearance: 24h

Control Day 3: 98% patients negative parasitaemia

* Tolerance (side effects Grade 3):

07 épisodes (20%), CTX + (4[80%]), CTX – (3[10%])

Hématologicals +++, none hepatitis side effect

Anaemia 2 cases (8.6%), CTX + (2[40%])

Neutropenia 5 cases (14.3%), CTX + (2[40%]), CTX –(3[10%])

Presented at the 4th INTEREST Workshop 25-28 May 2010, Maputo Mozambique Conclusion

* Préliminaries results on the value of CTX in stable malaria transmission aera;

* Advocacy to start CTX prophylaxis in PLWH with CD4 < 500 cell counts in aeras where malaria and opportunistic infections are common (WHO 2006)

Presented at the 4th INTEREST Workshop 25-28 May 2010, Maputo Mozambique Aknowledgement Programm SLF Fondation BMS

Investigators Scientific committee Adrien Sawadogo Pr Papa Salif Sow Hamar Alassane Traoré Pr Pierre-Marie Girard Masserigne Soumaré Emmanuel Bissagnéné

Evaluation of study Pr Eric Delaporte

Presented at the 4th INTEREST Workshop 25-28 May 2010, Maputo Mozambique