Prevention and Treatment of Vivax Malaria - Travel Medicine

Sept 2012 NZSTM: Malaria Prevention Slide 1

Malaria Prevention

Alan J. Magill MD, FACP, FIDSA, FASTMH

Emeritus, Division of Experimental Therapeutics

Walter Reed Army Institute of Research


Disclaimer

• The opinions presented in this lecture are

those of the author and do not reflect the

official views of WRAIR or the US

Department of Defense.

• COL Magill has no financial conflict of

interests to declare.

• Use of FDA approved drugs for a non

approved indication will be discussed:

– primaquine



The Pyramid of Prevention

B Bites: Personal Protection Measures

A Awareness: know the risk

C Compliance with Chemoprophylaxis

D Diagnosis: prompt Dx and early Rx


Freedman DO. Clinical practice. Malaria prevention in short-term travelers.

N Engl J Med. 2008 Aug 7;359(6):603-12


Freedman DO. Clinical practice. Malaria prevention in short-term travelers.

N Engl J Med. 2008 Aug 7;359(6):603-12


What is the best way to

prevent infection?

Don’t get bitten!!


Sept 2012 NZSTM: Malaria Prevention

The mercurial malariologist, Sir Ronald Ross:

“I myself have been

infected with malaria

only once in spite of

nineteen years service

in India and thirteen

subsequent malaria

expeditions to warm

climates; I attribute this

good fortune to my

scrupulous use of the

bed net”

Ross R. Memoirs with a full account of the great malaria problem and its

solution. London: Murray, 1923.

Slide 9


Chemoprophylaxis Choices 2012

• Approved indication for malaria prophylaxis, generally in use

– Mefloquine generics

– Atovaquone / proguanil (Malarone®)

– Chloroquine (Aralen®) + generics

– Doxycycline (Vibramycin®) + generics

• Available, not approved for malaria chemoprophylaxis indication

– Primaquine (Sanofi Winthrop Pharmaceuticals)

– Azithromycin (Zithromax®) + generics

• Not available in USA or FDA approved, used in other countries

– Proguanil (Paludrine®)

– Savarine® - fixed combination of CQ and proguanil used by the French

• Stand-by Emergency treatment (SBET), not FDA approved indication, occasional use recommended by CDC

– Artemether / lumefantrine (Coartem®)

– Atovaquone / proguanil (Malarone®)

Overall Principle of Chemoprophylaxis

• Prevent adverse clinical outcomes from

malaria with drugs

– Prevent infection = eliminate parasites in the

liver = prevent any blood stage infection

• Causal prophylaxis

– Prevent symptomatic illness = abort blood

stage infection

• Suppressive prophylaxis

– Prevent severe disease or death

• Stand By Emergency Treatment (SBET)



Causal Prophylaxis

• Causal drugs do not need to be given more than 7 days after last exposure

• Atovaquone-proguanil

• primaquine Atovaquone- Proguanil

Primaquine

Liver Schizont


P. falciparum mature trophozoites

Chloroquine

Mefloquine

Doxycycline

Atovaquone

Proguanil

Suppressive Chemoprophylaxis

Width of cytoplasm

Diameter of nucleus


Suppressive

Chemoprophylaxsis

• Doxy and mefloquine need to be

taken for 28 days after last exposure.

– 28 pills of doxy, once daily

– 4 pills of MQ once weekly

– Absent DOT, it won’t happen


-2 -1 +1 0 +2 +3 +4 weeks

42 doses of doxy, 100 mg daily

14 days of travel

-3 +5 +6

10 doses of mefloquine, 250 mg weekly

21 doses of primaquine, 30 mg daily

21 doses of Malarone, 1 tab daily

1st question: Does this traveler

need to take malaria prophylaxis?

• Yes or No

• Most of us default this

decision to “guidelines”

– CDC Yellow Book

– Commercial services (e.g.

Travex®)

– WHO green book

– CATMAT

• Guidelines differ! Sept 2012 NZSTM: Malaria Prevention Slide 16


Assessing the Risk:

The New Zealand - Liberia Spectrum

No risk “some” risk High risk


Worldmapper: The Human Anatomy of a Small Planet Dorling D PLoS Medicine Vol. 4, No. 1, e1 doi:10.1371/journal.pmed.0040001

Malaria


Malarious Places

• High risk, all or most of the time

– West Africa

• Seasonal risk

– Mali, Peru

• Very low risk, but not zero risk

– Latin America


Malarious Places

• Unpredictable, very focal risk

• Wide range of “data” and “facts”

• Non-expert cannot know what is

truth

• We default to recommending

prophylaxis because we cannot

assess individual risk


What is the risk of malaria for

the individual traveler?

Destination

Sleeping Activities

Behaviors


Endemic Populations and

Travelers Do Not Have Equal Risk

Duration of exposure

Sleeping conditions

Background immunity


Risk of Malaria in Travelers

Two surveillance

networks specifically

focused on travelers

http://www.tropnet.net/

http://www.istm.org/geosentinel/main.html


Leder K, Black J, O'Brien D, Greenwood Z, Kain KC, Schwartz E, Brown G, Torresi J. Malaria in travelers:

a review of the GeoSentinel surveillance network. Clin Infect Dis. 2004 Oct 15;39(8):1104-12.


http://www.tropnet.net/reports_friends/pdf_reports_friends/mar07_falcmal2006_friends.pdf

Imported malaria. Place of infection: geographic distribution similar

since 2002. West Africa leads the list

97% of falciparum

from SSA


Number of imported malaria cases

and estimated relative case rates*

among U.S. civilians, by country of

acquisition - United States, 2008.

Malaria surveillance - United States,

2005. MMWR Surveill Summ Vol 59,

SS-7. Jun 25 2010

*relative case rates = No. of

cases attributable to each

country / travel volume as

estimated by WTO


Chemoprophylaxis: The Big 3

Mefloquine Doxycycline Atovaquone-

proguanil


How do we choose

Chemoprophylaxis Drugs?

For CQ resistant P. falciparum destinations…

3 choices of: Malarone®, mefloquine and

doxycycline • Listed alphabetically • All considered efficacious • Choice based on tolerability


How do we choose

Chemoprophylaxis Drugs?

http://www.cdc.gov/travel/yb/ http://www.who.int/ith/en/


Remember!

Your patient is asymptomatic

This is a trip of a lifetime

They are spending a lot of money

When choosing a chemoprophylaxis drug…….


Mefloquine

• Lariam® is very efficacious

• Not tolerated by some

• Neurotoxicity concerns

• Screen patients

– Have taken MQ before w/o problems

– Careful education, consider options

• Risk / benefit

Mefloquine: facts and fiction


The Lariam® Controversy



Does MQ cause neuro-

psychiatric adverse events?

• Unknown biologic mechanism

• Women at higher risk

• Low body weight / BMI

• Polymorphisms in MDR1 / ABCB1

transporters in endothelial cells

• Active area of research needed


Neurotoxicity of Mefloquine

– An Overview

Presynaptic cell

Post-synaptic cells

Electrical

synapse

junction

Brain

Blood X

Blood

Brain

Barrier

PgP

M

PgP

M

M M

M

M

M

Chemical

synapse

CA++

CA++

CA++

CA++

CA++

CA++ CA++

CA++

X

X X

X

PgP

Miscellaneous

Neurological

Effects

Cell Death

Accumulation of

mefloquine or

xenobiotics

M

Severe

Depolarization

Gap

Junction

Channel

M

Mefloquine blocks

charge transfer

through gap junctions

Mefloquine modulates

neurotransmitter release

Modulation of ion

channels and second

messengers

Mefloquine inhibits

P -glycoproteins


Other Adverse Reactions with

MQ • Gastrointestinal - N/V/D/Abd pain

• Dizziness / vertigo

• Sleep disturbances – Intense and vivid dreams

– Insomnia

• May be difficult or impossible to distinguish mefloquine AEs from travel related symptoms of jet lag, new experiences, etc.


Lariam Medication Guide


MQ resistant P. falciparum

• Areas on Thai-Cambodian and Thai - Burmese borders

• Sporadic elsewhere

– Does not influence prescribing practice o/s SE Asia


Taken MQ before Tolerated well Longer term travel Aware of controversy

Taken MQ before +/- tolerate well Shorter term travel Aware of controversy

+ / - taken MQ before Did not tolerate at all Very aware of controversy


Malarone®

• Well tolerated combination

• Very efficacious combination

• Causal activity

– 7 days post-travel

• No geographic considerations for resistance (yet)

• Optimal choice for short term (2-3 weeks) travel


• Fixed combination tabs – 100 mg PRO + 250 mg

ATQ (adult)

– 25 mg PRO + 62.5 mg ATQ (peds)

– 4 tabs once daily X 3 days

• > 98% efficacious in licensure trials – Semi-immunes in

Thailand, Gabon, Peru, Philippines

Am J Trop Med Hyg 1999 Apr;60(4):533-41


Adverse Events with Malarone ®

• Both components of combination have very good safety records

• Gastrointestinal symptoms uncommon with prophylaxis daily dose

• Few drug-related adverse events when used for prophylaxis

• Occasional dermatological SAEs – Stevens Johnsons syndrome

• Better tolerated in RDBPC trials when compared to MQ, doxy, CQ/proguanil


What Malarone® does not do

• Does not prevent hypnozoite relapse

in relapsing malarias (vivax and

ovale)

• Expensive, cost prevents use in

longer term travel for many

• Daily administration not ideal for

some

Primaquine for Prophylaxis

• In 2012 CDC

Yellow Book

primaquine is

recommended for

destinations in

Latin America with

> 90-95% vivax

malaria


Primaquine for Prophylaxis

• 30 mg (base) daily starting a day

before travel, daily during travel, and

7 days after return

• G6PD normal

• Take with food

• Do not use for Sub-Saharan Africa

• Limited data to support indication



Why do travelers get malaria?

• Do not use any PPMs

• Do not take any prophylaxis

• Do not take the correct drugs

• Do not adhere prescribed regimens


Outstanding Issues in Malaria

Chemoprophylaxis • Long stay traveler

– Safety of long term drug use

– Pre-Iicensure trials won’t include long durations

• Short stay, frequent visits, low risk (airline

personnel, oil field workers)

• New drug development

– No big pharma involvement

• Novel systems / delivery

– IM injection

– New way of using drugs we have: e.g. pre-exposure

prophylaxis


Outstanding Issues in Malaria

Chemoprophylaxis • Drug – drug interactions

• Dueling guidelines and different

recommendations leading to traveler confusion

• Do we really know the right dose and regimen for

doxycycline?

• Current malaria control activities are making big

changes in the epidemiology of falciparum

malaria in Sub-Saharan Africa – when will our

recommendations change?


Malaria Chemoprophylaxis: Decision Matrix

Drug

Criteria

Mefloquine Doxycycline

hyclate*

Malarone™

(atovaquone+proguanil)

Importance

1 COST 1

1.2 Cost per pill $2.90 (generic) $0.05 (generic) $3.00

2 EFFICACY 3

2.1 Prevention of falciparum

malaria

> 95% > 95% > 95%

2

2.2 Prevention of vivax malaria > 95% > 95% 84% - 100% 2

2.3 Prevention of Pv / Po relapse None None None 2

2.4 Resistance limiting use of drug

in geographic areas?

Thai-Cambodia and

Thai-Burmese

borders

No No 2

*There are two salts of doxycycline commercially available, doxycycline hyclate and doxycycline monohydrate.

Importance:

3 = high, affects all travel

2 = moderate, affects most travel

1 = minor, affects some persons or minimal impact

Legend:

Favorable

Inferior

No difference



Drug

Criteria

Mefloquine Doxycycline

hyclate

Malarone™

Atovaquone+proguanil

Importance

3 EFFECTIVENESS 3

3.1 Ease of Directly Observed

Therapy

Weekly = ++ Daily = + Daily = + 3

3.2 Risk of malaria with delayed /

missed dose

+ ++ + 1

3.3 Post travel regimen 4 weeks = 4 pills 28 days = 28

pills

7 days = 7 pills 3

3.4 Public perception / media adverse

publicity

Yes No No 2

3.5 Risk of adverse publicity High Low Low 1

3.6 Successful prior use with drug persons that have significant positive experience with a particular

agent may wish to continue with the same agent

2

Legend:

Favorable

Inferior

No difference

Importance:






Drug

Criteria

Mefloquine Doxycycline hyclate Malarone™

Atovaquone+proguanil

Importance

4 SAFETY 3

4.1 Safety (Drug related serious

adverse events)

Rare, case reports Rare, case reports Rare, case reports 1

4.2 Uncommon serious side

effects

Psychosis

seizures

Esophageal

ulceration w/o food

Erythema multiforme /

Stephens Johnson

syndrome

1

4.2 1st trimester of pregnancy Limited data

FDA category C

CDC recommends

Contraindicated

FDA category D

CDC does not

recommend

Limited data

FDA category C

CDC does not

recommend

1

4.3 Relevant drug-drug

interactions

Erythromycin, quinine,

and quinidine relatively

contraindicated

Cations (Mg++ and

Ca++) interfere with GI

tract absorption.

Antacids, milk cannot

be given at same time

tetraycyclines 2

Legend:

Favorable

Inferior

No difference

Importance:






Drug

Criteria


atovaquone+proguanil

Importance

5 Tolerability 3

5.1 (%) discontinuing drug in

randomized controlled trials

5%

Higher in open label

studies

5%

Higher if taken w/o

food

1% 2

5.2 Common side effects Vivid dreams

Gastrointestinal

upset

Gastrointestinal upset

w/o food and water

Photosensitivity

Few described 2

5.3 Gender related side effects Increased in women No difference No difference 1

Legend:

Favorable

Inferior

No difference

Importance:






Drug

Criteria


atovaquone+proguanil

Importance

6 Other operationally

important criteria

6.1 Prevents leptospirosis and

rickettsial infections

No Yes No 2

Legend:

Favorable

Inferior

No difference

Importance:





Chemoprophylaxis !!!

• Malaria prophylaxis

with quinine first

used by British

Royal Navy

• The bitter taste of

quinine was

masked by gin

• Tonic water today

still has quinine!


• In the United States, the Food and Drug

Administration limits the quinine content in

tonic water to 83 ppm (83 mg per liter)

• 500 – 1000 ml of tonic water (58.3 mg / l)

ingested in 15 minutes by N = 6 volunteers

• Mean quinine plasma levels of 0.62 mg/l

(0.4 – 0.77 mg/l) at 1-32 hours after ingestion

• At low end of quinine MICs

• Meyer CG, Marks F, May J.Editorial: Gin tonic

revisited. Trop Med Int Health. 2004 Dec;9(12):1239-40

• At a 1 part gin / 2 parts tonic mix, it may

require up to 1 - 2 liters of gin and tonic to

have sufficient levels of quinine.

•More research is clearly needed!!


The Pyramid of Prevention

Bites: Personal Protection Measures

Awareness: know the risk

Compliance with Chemoprophylaxis

Diagnosis: prompt Dx and early Rx


Alan J. Magill MD, MACP, FIDSA, FASTMH

COL / MC US Army (retired)

Emeritus, WRAIR

Associate Professor, Uniformed Services

University of the Health Sciences

[email protected]

[email protected]

Thank you!

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Prevention and Treatment of Vivax Malaria - Travel Medicine