Malaria 2010 The Good The Bad And the Ugly?

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1 Malaria 2010 The Good The Bad And the Ugly? Kevin Kain MD Director, Global Health Program, McLaughlin Centre for Molecular Medicine, Professor of Medicine The University of Toronto

2 Malaria Global M and M Snow et al. Nature. March 10, billion at risk = 1 in 3 Leading single agent cause of death of children Typical village of % will have malaria/yr (25-33% of income of $ /yr) 515 million clinical cases/yr (50% higher in Africa and 200% higher outside Africa than WHO estimates) 25% of Pf outside Africa Malaria robs African economies of $USD12B/yr

3 Malaria 2010 Attaran A. Nature 2004; 430:932..RBM pledged to halve malaria deaths by Today RBM is at the halfway point and deaths have actually increased RBM is not just a failure but a fatal betrayal by the United Nations.

4 Malaria 2010 Attaran et al. Lancet 2006; 430:932 The World Bank, False Financial Accounts and Medical Malpractice in Malaria Programs 100s of millions pledged for malaria never delivered claimed success using false statistics approved obsolete treatments akin to malpractice

5 Malaria 2010 There is today more attention and financing for malaria than in the past 4 decades...yet no real change. R. Feachem et al. JAMA 2007;297:2281

6 EID May 2009

7 Geosentinel: Malaria in Travellers Leder et al CID 2004;39:1104 Elliot et al. JTM 2004;11:213 WTO visits Risk/10M RR Caribbean North Africa South America SE Asia Central America South Asia Oceania Sub-Saharan Africa

8 Geosentinel: Malaria in Travellers Leder et al CID 2004;39:1104 Elliot et al. JTM 2004;11:213 N=1140 malaria cases in travellers 60% PF = 90% SSA (33 SM = 3 deaths) 24% PV = 30% acquired in SSA! 5% of cases with trips <1 week! (34 d) 97% developed symptoms after travel Illness onset <4 wks = 80% Pf, 40% Pv RISK: VFRs (only 15% pre-travel advice) RISK: Missionary group: 73% had Pre travel advice!!!!

9 VFRs: high risk travelers Leder et al. CID 2006 Geosentinel database, n=2241 Compared to tourist travellers VFRs sig. more likely to present with: Malaria OR 5.0 ( ) Typhoid OR 4.3 ( ) Tb OR 77 (28-209) STDs OR 10.2 (6-17) VFRs sig. less pretravel advice (19% versus 59%)

10 HIV and malaria Kublin et al. Lancet 2005;365:233 Prospective cohort Malawi n=367 HIV-1+ adults 148 had +Pf in follow up Overall HIV-1 RNA doubled with Pf (96,000 to 169,000 copies/ml) (0.25 log increase) If Pf >2000/uL and CD4> log Returned to ~baseline by 8-9 wks Malaria-induced increases in HIV viral load may increase transmission (1 log=doubles transmission) and disease progression

11 HIV increases risk of severe malaria in non-immunes Cohen et al. Clin Infect Dis. Dec 2005;41:1631 Prospective cohort RSA n=336 with 10% with severe malaria Risk factors for severe malaria HIV +, CD4 >200, higher parasitemia HIV+ non-immunes 4.2x more likely to develop severe malaria than HIV- HIV-1+ non-immunes at increased risk of severe malaria

12 HIV and malaria Abu-Raddad et al. Science Dec ;1603 Mathematical Modeling applied to Kisumu, Kenya Malaria HIV inc. by 8% HIV malaria inc. by 13% In a population of 200,000 Inc. of 8500 AIDS cases Inc. of 1,000,000 malaria cases

13 Keen J et al. PLoS Med 2007

14 Need PCR to detect Congenital malaria (>20%) Risk for congenital malaria (cord blood +) HIV+ OR 5.4 (2-15) Placental monocytes OR 48 (5-505)

15 US Malaria fatalities Newman et al. AIM 2004;141:547 >30,000 travellers/yr acquire malaria 185 deaths 93% Pf Largest risk group to die = VFRs CFR 1.3% Pf (0-4.4%).06% Pv 18% diagnosed at autopsy 1 in 100 with malaria die 86% of deaths Preventable

16 Who dies from malaria? Tan KR et al. ASTMH 2009 VFRs=33%, Missionaries=27%, tourists=13% USA (n=34 deaths ) Total No or wrong chemo. 100% Missed by MD 62% Lab misdiagnosis/delays 44% Inappropriate treatment 41% Diagnosis at autopsy 27%

17 Real time PCR for the detection of drug-resistant malaria in travellers Farcas and Kain JCM 2004 and 2007 Farcas and Kain CID 2006 Prospective blinded evaluation of real time detection of malaria and genetic markers of drug-resistance N = 260 febrile returned travellers Assay time = 25 minutes Sensitivity: 100% vs nested PCR Specificity: 100% vs nested PCR

18 Return of CQ-sensitive malaria in Africa? Kublin J et al JID 2003 & NEJM Malawi Hypothesis: replaced CQ with SP withdrawal of CQ CQ sensitivity pfcrt K76T % % In vivo: CQ cleared 100% of 63 infections In vitro: No resistance

19 Long lasting insecticidal nets (LLIN) Lindblade KA et al. TMIH Nov 2005;10:1141 Randomized evaluation of 6 nets, western Kenya Survival analysis comparing time to net failure conventional vs LLINs (Bioassay <50% mortality) N = 314 net to 177 households x 2 years Controlled for # of washes Of 2 LLINs (Olyset, Permanet) and 2 candidate LLINs: Insector TM had significantly higher failure rate ONLY Permanet TM performed significantly better than conventional nets (should be used in control programs)

20 Declining malaria in Africa Cessay S et al. Lancet Nov 2008;372:1545 O Meara W et al. Lancet Nov 2008;372:1555 ProMED Dec 22, 2008; Jan Retrospective analysis in Gambia and Kenya 5 sites Gambia, one in Kenya Gambia: smear+ cases dec. by 50-85% hospitalizations by 27-74% and deaths by 90% Kenya: 80% dec. in malaria admissions NB: cerebral malaria cases increased! NB: Travellers from Europe (64 cases and 3 deaths) USA (7 cases, 2 in ICU) from Gambia

21 N = 894 RCT RTSS (with new adjuvant ASO1E) vs Rabies vaccine ITT PE against clinical malaria 49% (95% CI 26-65%) Well tolerated

22 Choices for chloroquine- resistant regions: 2010 ATQ/Proguanil doxycycline mefloquine (primaquine)

23 Lariam : Label revisions 2008 New precautions New warnings Medication guide for travelers da/index.cfm?fuseaction=search.label_approvalhi story Google Drugs@FDA Feb 2010 CME at Sea: Malaria Prevention Slide 28 of 73

24 New MFQ Warnings / Precautions Adverse Reactions / Post marketing Pneumonitis, possible allergic In a small number of patients, dizziness and loss of balance have been reported to continue for months after mefloquine has been stopped Medication Guide updated Feb 2010 CME at Sea: Malaria Prevention Slide 29 of 73

25 Post market Safety Review: Pneumonitis 13 cases of pneumonitis or eosinophilic pneumonia with prophylactic (N = 6) and therapeutic (use (N= 5) of MFQ Onset of fever, chills, HA, myalgias, SOB, dyspnea, non-productive cough, abnl CXR, elevated WBC All hospitalized, 5 rec d steroids, 1 patient died FDA Drug Safety Newsletter: volume 1, (No. 4) Summer ucm htm Feb 2010 CME at Sea: Malaria Prevention Slide 30 of 73

26 MFQ Misconceptions Chen L et al. JAMA 2008;297:2251 Jacquerioz Fet al. Cochrane Database Syst Rev 2009 Meta-analysis of 8 RCTs n=4240 participants Underpowered to detect differences in safety and efficacy Withdrawal and overall incidence of AEs not higher with MFQ than comparator drugs Low-quality evidence that ATQ/Pro and doxy better tolerated WRT neuropsych and GI Women at greater risk of neuropsych AEs

27 Mefloquine for whom? No one? Still consider MFQ for: Previous users without AE and C/I Long term high risk travel, esp. tight budget Pregnant women who cannot defer travel Children: wkly dose registered for >5kg Document: you advised client of risks!

28 Doxycycline The Good Broad spectrum activity: rickettsia, lepto, bacteria mycoplasma, chlamydia No resistance reported Generics are inexpensive No dose change with renal failure No interactions with food

29 Doxycycline the Bad Drug interactions Tooth enamel discoloration?? No use in children < 8 yo, nursing moms & pregnancy Daily dosing Don t miss a dose! GI upset Pill esophagitis & esophageal ulceration Photosensitivity Vaginal yeast infxn Not causal, 28 days after return

30 Doxy: Drug Interactions Decrease doxy serum levels Antacids containing cations (Ca, Al, Mg) bind doxy Oral iron, bismuth, laxatives (contain Mg) Barbs, phenytoin, carbamazepine induce hepatic microsomal activity Do not take within 3 hours of doxy Increase doxy serum levels Warfarin OCPs - no proven or accepted interactions

31 What we don t know about doxy How photosensitive is doxycycline? Is there an increase in vaginal yeast infections in women using doxy as compared to other chemoprophylaxis drugs? Does doxycycline discolor teeth when used as chemoprophylaxis? Is the monohydrate salt better tolerated than the hyclate salt?

32 Doxycyline and Pregnancy Hellgren et al. J Trav Med 2010;7:1195 Spon. miscarriage rate 15-20% Cong. malformation rate ~5-6% (2-3% apparent at birth) Crude data rate of malformation same with/without malaria chemoprophylaxis Tetracyclines in preg stain primary teeth (not permanent) >4 months Doxy no tooth staining documented (only C/I >4 months) Swedes added doxy to drug choices for early pregnancy (at least as safe as MFQ)

33 Atovaquone/Proguanil P. vivax Soto J et al. AJTMH 2006;75:430 Randomized DBPC trial, Colombia N = 180 males (24 unevaluable) Randomized to AP versus placebo Malaria cases 28 d cure AP (n=97) 1 Pv 96% (69-100%) Placebo (n=46) 11 Pv 2 Pf ITT analysis PE = 87% 1 failure low drug levels

34 ATQ/Pro DRESS syndrome: (also Stephen Johnson Syndrome) drug eruption, eosinophilia and systemic symptoms

35 ATQ/Pro Resistance Just how common is it? AP~30 million tabs sold (>1.5 M travellers) Prophylaxis failures with molecular confirmation None documented Treatment failures with AP with genetic confirmation ~15 published cases of AP resistance plus several probable cases Boggild A et al AJTMH 2007

36 ATQ/Pro Treatment failures Boggild et al. AJTMH 2007 Age/travel Pro Para Failed Cyt b 45 WAF No 1.5% d28 Y268N 28 WAF?? d28 Y268S 45 WAF? 1.0% d21 Y268S 4 WAF CP 0.5% d28 Y268S 24 EAF No 3.0% d30 Y268S 3.5 WAF No 1.5% d30 Y268S 25 WAF P 1.5% d28 Y268S 28 WAF CP 1.5% d28 Y268S 32 WAF pyr? d17/d15 Y268S 38 CAF C 0.1% d16???

37 ATQ/Pro: What s new? Boggild A et al. AJTMH 2007 Patel S et al. AJTMH 2007 Uses: Rx Pf (cure >95%) Rx MDR Pf (cure >95%) NOT for Pv Rx alone Prophylaxis Pf (>90%) and Pv (>80%) Dose: Can use AP to Rx and prevent malaria in children down to 5 kgs

38 Atovaquone + proguanil Efficacy: PF non-immunes ~98% PV non-immunes 84 (45-95%) Tolerance: good in all ages (2-85 yrs) RCT better than MFQ, CQ/Pro, better or equal to doxy, rare skin AEs, SJS Caution: CI - CrCl < 30 ml/min Convenience: daily Causal: yes Cost: expensive Boggild A et al AJTMH 2007

39 ATQ has causal activity Shapiro T et al. AJTMH 1999;60:831 RDBPC volunteer challenge study (n=16) ATQ (750 mg) or placebo D1-D8 ATQ (250 mg) on D1 ONLY infected mosquito challenge D2 4/4 placebo 0/12 AP +Pf smear/pcr/culture +Pf by smear/pcr

40 14 days of travel weeks 42 doses of doxy, 100 mg daily 21 doses of ATQ/Pro, 1 tab daily 21 doses of primaquine, 30 Theoretical, mg daily not proven! 10 doses of mefloquine, 250 mg weekly 3 doses of ATQ/Pro, Pre-exposure? 3 weekly doses of ATQ/Pro?

41 Malaria: Risk Strategies Schlagenhauf P et al. Clin Micro Rev 2008;21: cases/10 3 /yr local pop n ~1 death/10 5 travellers/2 wk trip 100 cases/10 3 /yr local pop n ~8 death/10 5 travellers/2 wk trip ~ close to annual death rate MVA = 1 death/11,500 inhabitants/yr Authors no routine chemopro. for risks <10 cases/10 3 /yr local pop n (SBET = ATQ/Pro or Co-art)

42 Pregnancy and kids: HIGH risk of CRPF Don t go (defer travel if possible) extreme attention to PPM seek MD attention ASAP if fever chemosuppression MFQ (after 1st trimester) CQ/Pro (safe but efficacy) ATQ/Pro (ATQ: class C; Pro: class B) (CQ+Azi IPTp. NOT FDA-approved) CQ/PRO (MFQ) < 5 kg MFQ, ATQ/Pro > 5 kg

43 Chemosuppression Summary ATQ/Pro, doxy, MFQ (PQ): best choice for your client HIGH RISK ~ 0.2-6% A/E D/C MFQ & pregnancy MFQ & kids high risk high risk > 5 kg ATQ/Pro: short term, high risk

44 All travelers to malarious areas MUST: Understand malaria is a serious disease Know how to prevent it (PPM and drugs) Seek medical attention urgently if they develop fever

45 Fever From The Tropics Ryan, Wilson, Kain KC. NEJM 2002;347: malaria 2. malaria 3. malaria Traveller hepatitis typhoid dengue/rickettsia Immigrant TB TB TB

46 MALARIA:take home points Ryan, Wilson, Kain KC. NEJM 2002;347:505 Malaria deaths are preventable Fever from the tropics - malaria UPO (until proven otherwise) Malaria EMERGENCY STAT smears Rx all Pf malaria drug resistant

48 Pregnancy Treatment of MDR malaria RCT artemether-lumefantrine x3d (n=125) vs Artesunate x7d (n=128) Open label Pregnant women 2/3 rd trimester ITT Cure rate (day 42): AL: 82% (75-89) AS: 89.2% (82-96) No difference in birth outcomes McGready R et al. PLoS Med Dec 2008;5:e253

49 Mosquito receptors for human sweat Hallem et al. Nature 2004;427:212 From the Anopheles genome identified a female specific odorant receptor (AgOr1) Expressed it in a fruit fly neuron Measured neuron response to single odors 4-methylphenol in human sweat AgOr1 only expressed in female olfactory tissue and is decreased with a blood meal Activate or block receptor to trap or repel

50 Gin and Tonic? Effectiveness Meyer CG et al, TMIH 2004;9:1239 Q; How much do I have to drink to prevent P. falciparum malaria? A; 20 G & Ts at 50:50 mix (my normal intake)(100 mls each) Provides 58.3 mg/l provides ~peak [0.62 mg/l] Q, approaches the lower limit of therapeutic efficacy for Pf

51 Long Term Travellers Checkley A et al. Trends Para 2007;23:462 Inform: fever urgent Dx & treatment Identify: access to qualified medical triage/care before ill Discuss alternatives to continuous prophylaxis e.g. seasonal PPM ITNs 50%+ protection Discuss SBET and follow up (different from that used as prophylaxis) Discuss risk of fake drugs (bring your own from home) RDTs consider for some (needs training!)

52 Thai Cambodian border ACT = mefloquine + ART Initial efficacy (1993) = 99% Current efficacy with DOT = 79% inc. pfmdr1 copy number and delayed parasite clearance times

53 NW Thailand vs Cambodia (n=40/site) RCT Art 2MK x 7 d vs ART+MFQ Cambodia Thailand PCT 84 h 48h (P<.001) Rx failure 30% 10% Rx failure did not correlate with MIC or copy #/mutations in Pfmdr or Pfserca (ATPase 6)

54 Monkey malaria in Humans Singh B et al. Lancet 2004;363:1017 Cox-Singh. CID 2008; 46:165. Ng EID May 2008 N = 208 malaria cases in Borneo ~1/2 thought to be P. malariae BUT: neg for PM DNA and ++ symptoms 24 hr replication high parasitemia and severe and fatal outcomes 58% of 208 cases subsequently shown to be P. knowlesi A natural parasite of long-tailed macaques Now Singapore, Malaysia, Philippines, Thailand NB: 1 st human Pk infection found in a US traveller returned from Malaysia in 1965

56 Monkey malaria in Humans Singh B et al. Lancet 2004;363:1017 Cox-Singh. CID 2008; 46:165. Ng EID May 2008 Diagnosis: PCR Rapid tests mixed Pf+Pv or neg Treatment of P. knowlesi CQ alone (no PQ) Quinine IV if severe

57 Bonobo apes new Plasmodium falciparum and 1 related to P. malariae source of Pf in humans (not P. reichenowi ) Chimps 2 new Plasmodium sp. related to P. falciparum and 1 new one related to P. vivax Implications: new human zoonotic malaria infections in humans malaria eradication efforts

58 Severe P. vivax Malaria Tjitra et al. PLoS Medicine 2008;5:e128 Genton et al. PLoS Medicine 2008;5:e M cases of P. vivax/yr (50% of malaria) Severe malaria at 2 sites in Oceania Similar rates: Pf (12-30%) CFR 2.2% Pv (9-30%) CFR 1.6% Pv: 20% of SM in Papua respiratory distress 60% neuro 25%

59 Severe P. vivax Malaria Anstey et al. Trends in Para 2009;25:220 Is this just a Papua problem? What is the mechanism? Pathobiology Pv Pf Biomass - ++ Inflam response ++ + Cytoadherence +/- +++ Rosetting +/- + RBC fragility ++ (32) + (8) EC activation + +++

60 Severe P. vivax Malaria Anstey et al. Trends in Para 2009;25:220 Pathogenesis SMA CRPV inc. recrudescence PRPV inc. relapses ARDS [lung]& cap. perm. ALI Coma? PM maternal anemia LBW CRPV vs PRPV? Re-Rx ACT+PQ or MFQ+PQ

61 Take Home Points New ACTs decreasing malaria cases increasing CM? Drug resistance major threat Severe malaria host driven new Rx Malaria deaths preventable early Dx and Rx Fever emergency malaria UPO stat Dx and urgent Rx

Scenario#1 Fever from Kenya. New Drugs for Malaria

Scenario#1 Fever from Kenya. New Drugs for Malaria New Drugs for Malaria This talk may be politically incorrect or in bad 1 taste.viewer discretion is advised 2 Scenario#1 Fever from Kenya A 37 year old traveller returns from a one month vacation in rural