National Treatment Guidelines for Malaria in Cambodia

Transcription

1 Kingdom of Cambodia Nation Religion King National Treatment Guidelines for Malaria in Cambodia December 2014

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3 National Treatment Guidelines for Malaria in Cambodia i 1. PREFACE Malaria, which has plagued humankind since ancient times, continues to be one of the most important and devastating infectious diseases in the world. Half of the world s population, roughly 3.4 billion people, living in 104 countries are at risk of contracting the disease, with an estimated 207 million cases and 627,000 malaria deaths in 2012 (World Malaria Report, 2013). In Cambodia, despite the limited areas of the country where transmission occurs, an estimated 8.6 million people live in malaria endemic areas. In the past few years, we have made remarkable strides in controlling malaria. The number of recorded malaria deaths dropped from 93 in 2011 to 45 in 2012 and further to only 12 in Similarly the total number of malaria cases dropped from 62,690 in 2012 to 45,533 in However, Cambodia s gains in malaria control are threatened by the emergence and spread of artemisinin resistance, originally detected along the Thai-Cambodia border. Reduced efficacy of artemisinin combination therapies (ACTs) has now been documented in several additional provinces. To successfully implement the National Strategic Plan for Elimination of Malaria (NSPEM) by 2025 supported and approved by Samdech Akak Moha Sena Badei Techo HUN SEN, Prime Minister of Cambodia, it is imperative that every malaria control intervention be implemented with the highest degree of coverage and quality. Selection and spread of drug resistant malaria strains will occur more rapidly with inappropriate treatment regimens, inadequate patient adherence, and use of substandard quality pharmaceuticals. Accordingly, the Ministry of Health (MOH) is publishing this revised version of the National Treatment Guidelines for Malaria, incorporating updated information presented at National Malaria Drug Policy meetings held in December 2013 and January These meetings gathered experts and key stakeholders from the Ministry of Health, WHO, academic and international partners to consider the latest malaria surveillance and research findings including Therapeutic Efficacy Studies (TES) to refine and improve existing treatment guidelines. These guidelines are designed for doctors and staff at each level of the public health framework (referral hospital, health center and health post), the military, police, and private sectors as well as community level workers to provide uniform and quality malaria case management. The goals espoused in these guidelines are threefold. First, the MOH seeks to further aggressively reduce malaria morbidity and mortality as it approaches malaria

4 ii National Treatment Guidelines for Malaria in Cambodia pre-elimination. Second, by optimizing drug regimens and extending case management to follow up with patients in high risk areas to ensure successful cure, we aim to reduce the impact of resistant malaria strains and preserve our current arsenal of malaria treatments. Third, more comprehensive diagnostic testing is encouraged to accurately diagnose and treat a larger proportion of malaria cases. Achieving the triple aims of Test, Treat, and Track is critical as we execute Cambodia s National Malaria Elimination Strategy. In the 2014 version of the Malaria National Treatment Guidelines, the Ministry of Health now recommends the following changes to the existing national treatment guidelines: Substitution of artesunate-mefloquine for selected provinces where DHA-piperaquine is currently used and failing to achieve acceptable cure rates. Replacing co-blistered artesunate-mefloquine previously used in Cambodia with a fixed dose combination (FDC). Prioritize directly observed therapy (DOT) and documentation of cure as an essential part of case management. Enhancing timely surveillance to inform drug treatment policy. Reducing primaquine dosing to block P. falciparum malaria transmission to be consistent with the 2012 WHO guidelines on transmission and amending P. vivax radical cure. The main aim of this publication is to provide all those involved in the management of malaria in different sectors and levels with clear and practical guidelines for the early diagnosis and prompt and appropriate treatment of malaria. The Ministry of Health would like to recognize for strong effort being made by National Center for Parasitology Entomology and Malaria Control (CNM) and to thank President s Malaria Initiative (PMI), WHO and other stakeholders for their assistance in updating this new edition.

5 National Treatment Guidelines for Malaria in Cambodia iii 2. GOALS AND OBJECTIVES OF THE NATIONAL MALARIA CONTROL PROGRAMME Goal: To move towards pre-elimination of malaria across Cambodia with special efforts to contain artemisinin resistant P.falciparum malaria. Objectives: 1. To improve access to early malaria diagnosis and treatment services. 2. To decrease drug pressure for selection of artemisinin resistant malaria parasites. 3. To improve access to preventive measures and specifically prevent transmission of artemisinin resistant malaria parasites. 4. To increase community awareness and behavior change among the population at risk. 5. To provide effective management (including information systems and surveillance) and coordination. Broad Aims of Malaria Case Management To cure infection and reduce morbidity and mortality To reduce the infectious reservoir Specific Objectives of Malaria Case Management Early detection and prompt effective treatment to cure the infection and prevent progression to severe disease Proper management of severe disease to prevent death Prevent drug resistance Reduce malaria transmission Components of Malaria Case Management Prompt parasitological diagnosis Treatment with effective drugs Referral (and pre-referral treatment when indicated) Counseling and Follow up of patient Issues related to diagnosis: policy and quality assurance Drugs: supply and management; safety (pharmacovigilance), quality (regulation issues) and therapeutic efficacy

6 iv National Treatment Guidelines for Malaria in Cambodia 3. TABLE OF CONTENTS 1 PREFACE...i 2 GOALS AND OBJECTIVES OF THE NATIONAL MALARIA... CONTROL PROGRAMME...iii 3 TABLE OF CONTENTS...iv 4 ABBREVIATIONS AND ACRONYMS...viii 5 GLOSSARY...ix 6 INTRODUCTION COMPARISON BETWEEN 2012 and 2014 CAMBODIA NATIONAL MALARIA TREATMENT GUIDELINES Recommendations changed from the 2012 Cambodia National Treatment Guidelines Recommendations unchanged from the 2012 Cambodia National Malaria. Treatment Guidelines EVALUATION OF PATIENTS WITH POSSIBLE MALARIA Taking a patient history Malaria Diagnosis: When to perform a diagnostic test? Malaria diagnosis: rapid diagnostic tests vs. microscopy Evaluating for uncomplicated vs. severe malaria REFERRAL OF MALARIA PATIENTS Rectal artesunate pre-referral treatment for severe malaria TREATMENT OF UNCOMPLICATED MALARIA Principles First Line Treatment for Uncomplicated P. falciparum, vivax, ovale and... malariae species DHA+PPQ dosing Artesunate + mefloquine FDC dosing Mefloquine adverse effects and contraindications Second-line treatment for uncomplicated P. falciparum malaria Use of Malarone in Cambodia for use in special situations...15

7 National Treatment Guidelines for Malaria in Cambodia v 10.8 Additional considerations for treating uncomplicated malaria Drug resistance, treatment failures, and strategies to reduce transmission of resistant parasites How to manage potential treatment failure Follow up of uncomplicated P. Falciparum malaria Primaquine indications Primaquine dosing (low dose) Primaquine dosing (standard dose) Uses of primaquine by species Primaquine safety and other considerations TREATMENT OF UNCOMPLICATED MALARIA IN INFANTS... AND CHILDREN TREATMENT OF UNCOMPLICATED MALARIA IN PREGNANT. WOMEN First line treatment Lactating women TREATMENT OF SEVERE MALARIA Treatment objectives Clinical assessment Differential diagnosis of severe malaria Urgent initial treatment steps First line treatment of severe malaria in adults and children Preparation of artesunate for IV or IM administration Alternative first line treatment: IM artemether Recommended dosing for IM artemether in adults and children Second line treatment for severe malaria Pre-referral treatment for severe malaria with rectal artesunate Dosing of pre-referral AS suppositories General management of severe malaria Clinical and adjunctive treatment for severe malaria Parasitological monitoring in severe malaria...33

8 vi National Treatment Guidelines for Malaria in Cambodia 14.2 Treatment of severe malaria in pregnant women MALARIA DIAGNOSIS AND TREATMENT IN COMMUNITY... (VMW/MMW) AND PRIVATE SECTOR Village Malaria Worker (VMW)/Mobile Malaria Worker (MMW) PRIVATE SECTOR DIRECLY OBSERVED THERAPY (DOT) QUALITY OF ANTIMALARIAL MEDICINES SCREENING OF PREGNANT WOMEN CHEMOPROPHYLAXIS REFERENCES Annex A...38

9 National Treatment Guidelines for Malaria in Cambodia vii DHA-piperaquine cure rates by provinces in Cambodia Location Year Cure rate DP (%) Oddar Meanchey N Ref Location Year Cure rate DP (%) Preah Vihear N Ref Location Year Cure rate DP (%) Ratanakiri N Ref Location Year Cure rate DP (%) Pailin N Ref Location Year Cure rate DP (%) N Ref Battambang Location Year Cure rate DP (%) Pursat Location Year Cure rate DP (%) Kampong Thom N Ref N Ref Location Year Cure rate DP (%) Kampong Speu N Ref Location Year Cure rate DP (%) Snoul (Kratie) N Ref Notes (Ref.) 1. Not PCR corrected 2. Lon C., et a l ASMTH abstract 13-L-B-3664, presented at November 2013 ASMTH, Wash DC. ACP R 59% based on ITT analysis 3. Leang R, Efficacy of DHA-PIP for the treatment of Uncomplicated PF Malaria in Cambodia, WHO/CNM 5. Fairhurst, US NIH, unpublished data 6. Malaria J Sep 23;12:343

10 viii National Treatment Guidelines for Malaria in Cambodia 4. ABBREVIATIONS AND ACRONYMS ACT Artemisinin-based Combination Therapy AS Artesunate AS+MQ FDC Artesunate plus Mefloquine Fixed-Dose Combination BW Body Weight CNM National Center for Parasitology, Entomology and Malaria Control CQ Chloroquine DHA+PPQ Dihydroartemisinin plus Piperaquine FDH Former District Hospital G6PD Glucose-6-Phosphate Dehydrogenase HC Health Center HP Health Post HRP2 Histidine-Rich Protein 2 IC50 Concentration Providing 50% Inhibition IV Intravenous IM Intramuscular MIC Minimum Inhibitory Concentration MMW Mobile Malaria Worker MQ Mefloquine OD Operational District PCR Polymerase Chain Reaction PMI President s Malaria Initiative PQ Primaquine RCT Randomized Controlled Trial RDT Rapid Diagnostic Test RH Referral Hospital VMW Village Malaria Worker WHO World Health Organization dl Deciliter h Hour µl Microliter kg Kilogram mg Milligram ml Milliliter mmol Milimol mm Hg Millimeter of mercury

11 National Treatment Guidelines for Malaria in Cambodia ix 5. GLOSSARY Artemisinin-based Combination Therapy (ACT): A combination of artemisinin or one of its derivatives with an antimalarial or antimalarials of a different class. Asexual cycle: The life-cycle of the malaria parasite in host from merozoite invasion of red blood cells to schizont rupture (merozoite ring stage trophozoite schizont merozoites). Duration approximately 48 h in Plasmodium falciparum, P. ovale and P. vivax; 72 h in P. malariae. Asexual parasitemia: The presence in host red blood cells of asexual parasites. The level of asexual parasitemia can be expressed in several different ways: the percentage of infected red blood cells, the number of infected cells per unit volume of blood, the number of parasites seen in one microscopic field in a high-power examination of a thick blood film, or the number of parasites seen per white blood cells in a high power examination of a thick blood film. Cerebral malaria: Severe P. falciparum malaria with cerebral manifestations, usually including coma (Glasgow coma scale < 11, Blantyre coma scale < 3). Malaria with coma persisting for > 30 min after a seizure is considered to be cerebral malaria. Combination treatment (CT): A combination of two or more different classes of antimalarial medicines with unrelated mechanisms of action. Cure: Elimination of the symptoms and asexual blood stages of the malaria parasite that caused the patient or caregiver to seek treatment. Drug resistance: The World Health Organization (WHO) defines resistance to antimalarials as the ability of a parasite strain to survive and/or to multiply despite the administration and absorption of a medicine given in doses equal to or higher than those usually recommended but within the tolerance of the subject, provided drug exposure at the site of action is adequate. Resistance to antimalarials arises because of the selection of parasites with genetic mutations or gene amplifications that confer reduced susceptibility. Gametocytes: Sexual stages of malaria parasites present in the host red blood cells. Hypnozoites: Persistent liver stages of P. vivax and P. ovale malaria that remain dormant in host hepatocytes for an interval (most often 3 45 weeks) before maturing to

12 x National Treatment Guidelines for Malaria in Cambodia hepatic schizonts. These then burst and release merozoites, which infect red blood cells. Hypnozoites are the source of relapses. Mass drug administration (MDA): The practice of treating a whole population within a given geographical area, irrespective of the presence of symptoms and withoutdiagnostic testing. Monotherapy: Antimalarial treatment with a single medicine (either a single active compound or a synergistic combination of two compounds with related mechanism of action). Plasmodium: A genus of protozoan vertebrate blood parasites that includes the causal agents of malaria. Plasmodium falciparum, P. malariae, P. ovale and P. vivax cause malaria in humans. Human infections with the monkey malaria parasite, P. knowlesi have also been reported from forested regions of South-East Asia. Pre-erythrocytic development: The life-cycle of the malaria parasite when it first enters the host. Following inoculation into a human by the female anopheline mosquito, sporozoites invade parenchyma cells in the host liver and multiply within the hepatocytes for 5 12 days, forming hepatic schizonts. These then burst liberating merozoites into the bloodstream, which subsequently invade red blood cells. Radical cure: In P. vivax and P. ovale infections only, this comprises a cure as defined above plus prevention of relapses by killing hypnozoites. Rapid diagnostic test (RDT): An antigen-based stick, cassette or card test for malaria in which a coloured line indicates that plasmodial antigens have been detected. Recrudescence: The recurrence of asexual parasitemia after treatment of the infection with the same infection that caused the original illness. This results from incomplete clearance of parasitemia due to inadequate or ineffective treatment. It is, therefore, different to a relapse in P. vivax and P. ovale infections, and it differs from a new infection or re-infection (as identified by molecular genotyping in endemic areas). Recurrence: The recurrence of asexual parasitemia following treatment. This can be caused by a recrudescence, a relapse (in P. vivax and P. ovale infections only) or a new infection. Relapse: The recurrence of asexual parasitemia in P. vivax and P. ovale malaria deriving

13 National Treatment Guidelines for Malaria in Cambodia xi from persisting liver stages. Relapse occurs when the blood stage infection has been eliminated but hypnozoites persist in the liver and mature to form hepatic schizonts. After variable intervals of weeks to months, the hepatic schizonts burst and liberate merozoites into the bloodstream. Ring stage: Young usually ring-shaped intra-erythrocytic malaria parasites, before malaria pigment is evident under microscopy. Schizonts: Mature malaria parasites in host liver cells (hepatic schizonts) or red blood cells (erythrocytic schizonts) that are undergoing nuclear division. This process is called schizogony. Selection pressure: Resistance to antimalarials emerges and spreads because of the selective survival advantage that resistant parasites have in the presence of antimalarials to which they are resistant. Selection pressure describes the intensity and magnitude of the selection process; the greater the proportion of parasites in a given parasite population exposed to concentrations of an antimalarial that allows proliferation of resistant, but not sensitive parasites, the greater the selection pressure. Severe anemia: Haemoglobin concentration of < 5 g/100 ml (haematocrit< 15%). Severe falciparum malaria: Acute falciparum malaria with signs of severity and/or evidence of vital organ dysfunction. Sporozoites: Motile malaria parasites that are infective to humans, inoculated by a feeding female anopheline mosquito. The sporozoites invade hepatocytes. Transmission intensity: The intensity of malaria transmission measured by the frequency with which people living in an area are bitten by anopheline mosquitoes carrying sporozoites. This is often expressed as the annual entomological inoculation rate (EIR), which is the number of inoculations of malaria parasites received by one person in one year. Uncomplicated malaria: Symptomatic infection with malaria parasitemia without signs of severity and/or evidence of vital organ dysfunction.

14 1 National Treatment Guidelines for Malaria in Cambodia 6. INTRODUCTION Despite considerable progress in reducing both the morbidity and mortality of the disease, efficacy of first line antimalarial drug regimens is compromised by resistance to the artemisinin combination therapies. As of 2014, no feasible replacement regimens, capable of producing reliable cure rates on a countrywide basis, are currently available. This edition of the Cambodia National Treatment Guidelines for Uncomplicated and Severe Malaria has subsequently been developed to keep pace with the changing efficacy of antimalarial drugs in Cambodia and are based on the best available evidence. 7. COMPARISON BETWEEN 2012 and 2014 CAMBODIA NATIONAL MALARIA TREATMENT GUIDELINES 7.1 Recommendations changed from the 2012 Cambodia National Treatment Guidelines Since 2012, reduced efficacy of antimalarial treatments against P. falciparum has been measured in several areas in Cambodia. Because treatment responses may vary by geography, specific first-line regimens also vary by geography. DHA-piperaquine, while still recommended for use in certain provinces/ operational districts (OD), is no longer the only recommended first line antimalarial treatment. For uncomplicated P. falciparum, new fixed dose combination (FDC) formulation of artesunate-mefloquine will be introduced in certain locations. Because treatment responses may vary from one year to the next, specific first-line treatment for P. falciparum are listed in Annex 1: Province/OD specific P. falciparum treatment regimens

15 National Treatment Guidelines for Malaria in Cambodia Recommendations unchanged from the 2012 Cambodia National Malaria Treatment Guidelines Parasitological confirmation by microscopy or alternatively by RDTs is recommended in all patients suspected of malaria before treatment is started. Treatment solely on the basis of clinical suspicion should only be considered when a parasitological diagnosis is not accessible. Artemisinin-based combination therapies (ACTs) are the recommended treatments for uncomplicated P. falciparum malaria. Oral artemisinin and its derivatives should not be used as monotherapy for uncomplicated malaria. Second-line antimalarial treatment consists of quinine plus tetracycline or doxycycline for 7 days. Treatment of uncomplicated P. falciparum malaria in special risk groups: o First trimester of pregnancy: oral quinine for 7 days, with ACT indicated only if quinine is not immediately available. o ACTs known to be effective in the region. o Lactating women: standard antimalarial treatment (including ACTs) except for primaquine and tetracycline. o Infants and young children: ACTs for first-line treatment in infants and young children with attention to accurate dosing and ensuring the administered dose is retained. Severe malaria: after rapid clinical assessment and confirmation of the diagnosis, full doses of parenteral antimalarial treatment should be started without delay with whichever effective antimalarial is first available o For adults, children and infants, IV artesunate is first line treatment; intramuscular artemether is an acceptable alternative if parenteral artesunate is not available o If complete treatment of severe malaria is not possible, patients should be given pre-referral treatment and referred immediately to an appropriate facility for further treatment. o Patients should be given pre-referral treatment and referred immediately

16 3 National Treatment Guidelines for Malaria in Cambodia 8. EVALUATION OF PATIENTS WITH POSSIBLE MALARIA 8.1 Taking a patient history Taking a patient history will help to determine whether a patient may have malaria, but the only way to be sure that a patient has malaria is if he/she has a positive diagnostic test. This is known as confirmed malaria. However, as malaria incidence decreases in Cambodia, it is important to diagnose and treat every possible malaria case even if many patients must be tested. In addition, P. falciparum malaria in Cambodia can be difficult to treat because of resistance to certain drugs. It is important to use the proper drugs to treat P. falciparum malaria for two reasons. First, inappropriate treatment can allow drug resistance to spread more rapidly, possibly making current treatments ineffective. Second, using the right drugs will ensure that patients are completely cured. For these reasons, patients diagnosed with a second P. falciparum malaria infection within a 28 day period should be referred to a referral hospital (or former district hospital) or health center/post and treated with second line agent. When evaluating potential malaria cases, providers should take a medical history by asking the questions listed in the table below. Table 8.1: Questions to ask when evaluating for suspected malaria Question In the past one month, have you had any risk factors for malaria such as travel to the forest, not using a bednet in areas with known malaria cases? Reason These risk factors place a patient at higher risk of having malaria Have you recently travelled from an area without malaria to one where there is? These patients are at higher risk of both getting malaria and getting sicker once they contract it Have you had malaria in the past 28 days? If you had malaria in the last 28 days what medicines did you take? Patients with recent malaria may have failed treatment and may require retreatment with a second line agent This will help determine if the patient really had malaria and avoid retreating with the same medicines

17 National Treatment Guidelines for Malaria in Cambodia 4 Have you had any symptoms such as fever, chills, and/or sweats? These are typical malaria symptoms, but patients can still have malaria without having these symptoms Have you had other signs that could point to malaria such as headache, nausea, vomiting, or diarrhoea? These symptoms are less typical, but could be a sign the patient has malaria Are you, or could you be pregnant? (If the patient is a young female) Do you have any allergies to medicines? Pregnant women are at risk of malaria complications and should be treated with medicines which are safe in pregnancy Medicine allergies can be dangerous, even life threatening. Patients who have previously had lip or throat swelling or difficulty breathing after taking medicines should avoid taking those medicines. 8.2 Malaria Diagnosis: When to perform a diagnostic test? Prompt diagnosis of malaria is an important part of malaria case management. Diagnosis includes two components: first, providers must assess malaria risk in order to determine whether a patient may have suspected malaria based on symptoms or risk factors. Secondly, patients with suspected malaria should be confirmed to have malaria with a parasitological diagnosis. Obtaining a parasitological diagnosis has the following advantages: Improved patient care Identification of parasite negative patients who might have another disease Preventing the unnecessary use of antimalarial drugs Improved malaria case detection and reporting Confirmation of treatment failures Recent data show that many patients may have malaria without the typical symptoms of fevers, chills or sweating. In fact, because some patients acquire immunity to malaria, patients may not exhibit symptoms at all even though they have a malaria infection. It is therefore necessary to test patients even if they don t have typical symptoms. To determine who should be tested for malaria, providers should evaluate malaria risk based on epidemiological risk factors in addition to symptoms. Such risk factors include having a recent malaria infection, travel to the forest, recent arrival in a malaria endemic area, and living or working around other patients with confirmed malaria.

18 5 National Treatment Guidelines for Malaria in Cambodia Box 8.1: Criteria for malaria diagnostic testing Patients should be suspected to have malaria based on risk factors and physical symptoms. Consider testing if: They have one of the following: Fever Chills Sweats OR Two of the following: Headache Nausea Vomiting Diarrhoea Travel to the forest in the past month Confirmed malaria in the past 28 days Travel to a malaria endemic area from a non-endemic area Live or work around others with a recently confirmed malaria diagnosis 8.3 Malaria diagnosis: rapid diagnostic tests vs. microscopy Two laboratory methods are routinely used to diagnose malaria in field settings: microscopic examination of thick and thin stained blood films and rapid diagnostic tests. Quality assured microscopic examination of thick and thin stained blood films remains the gold standard for diagnosing malaria in field settings. Microscopy based diagnosis can provide information on mixed infections and level of parasite burden. In addition, microscopy can be used to follow patient treatment response over the course of time. Because of the high degree of technical skill needed to perform microscopy, rapid diagnostic tests (RDT) can be used in certain settings so that treatments can be given more quickly. If RDTs are used, it is important to use a test that differentiates between P. falciparum and P. vivax malaria. The choice of microscopy vs. RDT is based on many factors. Microscopy can be useful to determine species and quantitate parasite burden. The main disadvantage of microscopy is the requirement for a high degree of technical skill

19 National Treatment Guidelines for Malaria in Cambodia 6 to assure accurate results. The use of RDTs, however, allows diagnosis to occur at the community level so that treatment can be given more quickly and at greater convenience for patients. Parasitological diagnosis should be made, within two hours of the patient presenting for care. RDT manufacturer recommendations should be followed. Unless the patient has signs of severe malaria, treatment should NOT be started prior to confirming malaria with a positive diagnostic test. If a suspected malaria patient has signs of severe malaria, it is permissible to treat for malaria while awaiting the results of a confirmatory test. In severe malaria, blood films are preferred over RDT as they have the added advantage of following up response to treatment. 8.4 Evaluating for uncomplicated vs. severe malaria Patients with malaria are classified as having either uncomplicated or severe malaria. This distinction is significant because patients with severe malaria are at greater risk for complications (including death), and are not treated with the same medicines as patients with uncomplicated malaria. When evaluating malaria patients, providers should rapidly assess patients to determine if they meet criteria for severe malaria so that a decision can be made to administer appropriate treatment. Although all malaria species can cause severe malaria, P. falciparum is most associated with severe disease. Many symptoms of malaria, especially fevers, chills and sweats, are also shared with diseases such as meningitis, encephalitis, typhoid fever, pneumonia, septicemia (blood poisoning), dengue hemorrhagic fever or pre-ecclampsia (in pregnant women). Providers should remember that many of the signs and symptoms of severe malaria may also indicate the presence of another serious disease. Patients may turn out to have one of these potentially serious diseases, either instead of malaria, or in addition to malaria. For this reason, patients with signs or symptoms of severe malaria should be sent as quickly as possible to a referral hospital where they can get proper treatment.

20 7 National Treatment Guidelines for Malaria in Cambodia Box 8.2: Signs and symptoms of severe malaria Clinical signs/symptoms Impaired consciousness or unarousable coma Prostration, i.e. generalized weakness so that the patient is unable walk or sit up without assistance Failure to feed Multiple convulsions more than two episodes in 24 h Deep breathing, respiratory distress (acidotic breathing) Circulatory collapse or shock, systolic blood pressure < 70 mm Hg in adult and < 50 mm Hg in children Clinical jaundice plus evidence of other vital organ dysfunction Anuria or oliguria ( Urine output < 400 ml/24h) Haemoglobinuria Abnormal spontaneous bleeding Pulmonary oedema (radiological) Laboratory signs of severe malaria Hypoglycaemia (blood glucose < 2.2 mmol/l or < 40 mg/dl) Metabolic acidosis (plasma bicarbonate < 15 mmol/l) Severe normocytic anaemia (Hb< 5 g/dl, packed cell volume < 15%) Hyperparasitaemia (> 2%/ /μl in low intensity transmission areas or > 5% or /µl in areas of high stable malaria transmission intensity) Hyperlactataemia (lactate > 5 mmol/l) Renal impairment (serum creatinine> 265 µmol/l). In patients with signs/symptoms of severe malaria: It is ALWAYS PREFERRED to make a blood smear However, treatment should be started immediately if testing is not readily available At village or community level, treat with rectal artesunate before referral Because patients can have malaria with another serious disease, it is acceptable to treat patients with severe symptoms with both antimalarial drugs and antibiotics if response is not seen with antimalarial treatment alone

21 National Treatment Guidelines for Malaria in Cambodia 8 Figure 1: Flow chart for malaria diagnosis and treatment Definition of Suspected Malaria Case ONE of the following: Fevers, chills or sweats OR TWO of the following: Headache, nausea, vomiting, diarrhea, forest travel, confirmed malaria in the past six weeks, travel to malaria endemic area from nonendemic, or living/working around others with confirmed malaria Perform diagnostic test (microscopy or RDT) Evaluate for signs of severe malaria (See Box 13.1 Clinical, laboratory and radiological signs of severe malaria and Blantyre/Modified Glasgow coma scale) Positive test with severe malaria signs: If IV AS or IM AM available treat for severe malaria If not available, give rectal artesunate and refer (see Figure 2: Referral patterns & required treatment capabilities by health facility type Recommended Referral Patterns by Facility Type ) Positive test without severe malaria signs: Treat for uncomplicated malaria Observe first dose, DOT for remainder of treatment if possible Negative test with severe malaria signs: If malaria still suspected, treat as test (+) for malaria, look for other causes of illness and refer to RH/FDH Negative test Without severe malaria signs: Consider other illnesses; if patient at high risk for malaria, retest in 1-2 days If P. falciparum or mixed infection with Pf and known G6PD non-deficient, give primaquine: 0.25mg/kg or 15 mg x 1 dose If P. vivax or ovale and known G6PD non-deficient, give primaquine: 15 mg X 14d (0.25 mg/kg) or 45 mg (0.75 mg/kg) weekly X 8 weeks

22 9 National Treatment Guidelines for Malaria in Cambodia 9. REFERRAL OF MALARIA PATIENTS Many factors can alter malaria patient outcomes, but one of the most important is ensuring the shortest time possible between the onset of symptoms and delivery of appropriate treatment. The choice of medicine depends on several factors such as those illustrated in Table 9-1: Factors affecting choice of malaria treatment: Table 9.1: Factors affecting choice of malaria treatment Patient Classification Treatment Reason Severe malaria and severe malaria in pregnancy in 2nd and 3rd trimester) Severe malaria (pregnant, 1st trimester) Pregnancy (uncomplicated, 1st trimester) Suspected treatment failure IV or IM AS or IM AM IV quinine Oral quinine Quinine/ doxycycline Patients with severe malaria may not absorb medicines given by mouth into the bloodstream AS and AM are not established to be safe in the 1st trimester of pregnancy ACTs and doxycycline are not established to be safe in the 1st trimester of pregnancy Treatment failures may result from drug resistance so a second line drug regimen should be used To provide malaria patients with the most appropriate treatments in a timely manner, specific diagnosis and treatment capability must be provided at various levels in the health care system. Figure 2, below, illustrates the classification of malaria patient and the desired corresponding diagnosis and treatment capabilities at each level of the health system. Malaria patients requiring a higher level of care should be referred as shown. 9.1 Pre-referral treatment for severe malaria with rectal artesunate If complete treatment with IV AS or IM AM is not possible, patients with severe malaria should be given pre-referral treatment with rectal AS and referred immediately to an appropriate facility (usually a referral hospital or former district hospital). If referral is impossible, rectal AS treatment should be continued until the patient can tolerate oral medication; at this point, a full course of the recommended ACT for uncomplicated malaria should be given.

23 National Treatment Guidelines for Malaria in Cambodia 10 Figure2: Referral patterns & required treatment capabilities by health facility types Referral and FD Hospitals Receive from private sector, HC/HP and VMW/MMWs: Severe Uncomplicated pregnant women in 1st trimester Suspected treatment failure(tf) Health Centers/ posts Receive from private sector, VMW/MMWs: Uncomplicated pregnant women in 1st trimester <5 Y from PPs Refer to Referral and FDHs Severe malaria Suspected TF VMW/MMWs Refer to RH/FDH Severe Suspected TF Refer to HC/HP or RH/ FDH Uncomplicated pregnant women in 1st trimester Referral Hospitals and Former District Hospitals Patient classification Required treatment capacity Severe RDTs and microscopy ACTs Uncomplicated, Quinine (oral for 1st including 1st trimester trimester pregnancies and pregnancy 2nd line treatment; Children < 5 Quinine IV for severe pregnant) Doxycycline (2nd line Suspected TF treatment) IV AS or IM artemether Health Centers and Health Posts Patient classification Required treatment capacity Uncomplicated, RDTs and microscopy including 1st ACTs trimester pregnancy Quinine (oral for 1st trimester pregnancies and 2nd line treatment) Children < 5 Doxycycline/Tetracycline (2nd line treatment) Pre-referral rectal AS for severe cases VMW/MMWs Patient classification Required treatment capacity Uncomplicated, except 1 st trimester pregnancy Children < 5 RDTs +/- microscopy ACTs Pre-referral rectal AS for severe cases Registered private outlets providing health services should only provide treatment to uncomplicated malaria among 5Y and Non-pregnancy. All others should be referred to the above MoH facilities as appropriate Health facilities under ministry of national defense (MOND) and national police should use the same treatments as at MoH public sector facilities

24 11 National Treatment Guidelines for Malaria in Cambodia 10. TREATMENT OF UNCOMPLICATED MALARIA 10.1 Principles Malaria parasites infect the body through the bite of an infected mosquito by passing through the liver, and entering the blood stream. Some malaria species (vivax and ovale) form sleeping forms in the liver (hypnozoites), which can cause malaria relapses weeks or months after the initial infection. Malaria parasites in the blood stream cause malaria symptoms and can be passed to others when mosquitoes bite patients and ingest the form of malaria parasite that reproduces in mosquitoes (gametocytes). Malaria medicines reduce malaria incidence in three ways: first, by killing forms in the blood that cause symptoms, second by killing hypnozoites, and third, by killing gametocytes so that they cannot reproduce in the mosquito. As Cambodia makes progress towards reducing malaria throughout the country, malaria treatments will focus on killing malaria at each of these points in its lifecycle by using primaquine to kill hypnozoites and gametocytes and DHA-PIP/ASMQ-FDC for other malaria parasite stages in the blood. The National Malaria Programme recommendations for treatment regimens for all malaria species are based on the principles: First line treatment regimens will be those with expected maximum efficacy against P. falciparum. Treatment for other malaria species will be the same as that for P. falciparum Treatments may differ by geographical area and are determined by resistance data. See Annex A: Patients with P. vivax and ovale with non-deficient G6PD status should be treated with primaquine to prevent relapse. Treatment of uncomplicated malaria will only be initiated after a parasitological diagnosis First Line Treatment for Uncomplicated P. falciparum, vivax, ovale and malariae species As in the past, current first line treatments for uncomplicated P. falciparum malaria are guided by treatment responses as measured by therapeutic efficacy studies or other drug resistance data. The first and second line treatments and dosing for P. falciparum malaria are also used for P. vivax, P. ovale, or P. malariae species. P. falciparum treatments for malaria include either dihydroartemisinin-piperaquine (DHA + PPQ) or artesunatemefloquine (ASMQ). The artesunate-mefloquine formulation recommended by CNM

25 National Treatment Guidelines for Malaria in Cambodia 12 is a fixed dose combination (FDC) and will be used instead of the loose artesunate and mefloquine tablets previously used in Cambodia. Use of the FDC formulation will simplify dosing and likely reduce side effects compared to giving artesunate and mefloquine separately. 1st line treatment: o Dihydroartemisinin-piperaquine (DHA + PPQ) OR o Artesunate + mefloquine (A+M) Fixed Dose Combination (FDC) The choice of DHA +PPQ or A+M FDC depends on region where malaria was acquired 2nd line treatment: o quinine + doxycycline/tetracycline, regardless of where infection was acquired 10.3 DHA+PPQ dosing DHA-piperaquine is a fixed dose combination with tablets containing 40 mg of dihydroartemisinin and 320 mg of piperaquine. The target dose is 2-4 mg/kg/day dihydroartemisinin and 20 mg/kg/day piperaquine for 3 days. Table 10.1: DHA + PPQ daily dosing for uncomplicated malaria Weight (kg) Age (years) Number of Tablets Day 1 Day 2 Day 3 Total 5 w<10 3 months a<1 year ½ ½ ½ 1 ½ 10 w<19 1 year a < 5 years w<30 5 years a < 10 years 1 ½ 1 ½ 1 ½ 4 ½ 30 w<40 10 years a <15 years w<60 15 years kg 15 years

26 13 National Treatment Guidelines for Malaria in Cambodia 10.4 Artesunate + mefloquine FDC dosing The CNM recommended fixed dose combination is available in a tablet form containing 25 mg AS + 50 mg mefloquine (small tablets) or 100 mg artesunate mg mefloquine (large tablets). The target dose of 4 mg/kg/day artesunate and 6 mg/kg/day of mefloquine should be given once a day for 3 days: Table 10.2: Artesunate + mefloquine FDC daily dosing for uncomplicated malaria Patient weight (kg) Number of artesunate-mefloquine tablets (25 mg artesunate + 50 mg mefloquine) Total # tablets (ASMQ 25/50 mg Number of artesunate-mefloquine tablets (100 mg artesunate mg mefloquine) Total # tablets (ASMQ 100/200 mg) Day 1 Day 2 Day 3 Total/ 3days Day 2 Day 2 Day 3 Total/ 3days 5-< < < > Mefloquine adverse effects and contraindications Mefloquine is a component of artesunate-mefloquine FDC. Mefloquine adverse effects include: o Nausea, vomiting, abdominal pain, poor appetite, diarrohea o Headache, dizziness, loss of balance, sleep disorders, abnormal dreams. AS+MQ should be avoided in patients with psychiatric disorders AS+MQ should be avoided in patients who received mefloquine in the past 4 weeks

27 National Treatment Guidelines for Malaria in Cambodia Second-line treatment for uncomplicated P. falciparum malaria Quinine-doxycycline/tetracycline dosing The second line treatment for all species of uncomplicated malaria is quinine + doxycycline/tetracycline. This regimen must be taken for 7 days to achieve desired cure rates so it is important to explain to patients the importance of adhering to a complete 7 day regimen. Quinine: o Adult and paediatric dose is 10 mg/kg X 3 times daily X 7 days o Quinine has a bitter taste--for small children, tablets can be crushed and mixed with a solution of water and sugar Doxycycline: o Adults: 100 mg twice daily X 7 days o Children: 2mg/kg twice daily X 7 days (only for children > 8 years). For adults and children over 8 years: tetracycline may be substituted for doxycycline. Tetracycline is dosed at 8.3 mg/kg X 3X daily (25 mg/kg/day). Table 10.3: Quinine-doxycycline dosage Number of tablets Age Weight (kg) Dose/ 8h Quinine (300mg) Total/day Total/ 7days Doxycycline (100mg) Total/ day (single dose) Total/ 7days < 6 month < 7 ¼ ¾ 5 ¼ m - 2 years 7-15 ½ 1 ½ 10 ½ <8 years <15 years ½ 4 ½ 31 ½ 1 15 years >

28 15 National Treatment Guidelines for Malaria in Cambodia Table 10.4: Quinine-tetracycline dosing Age Weight (kg) Dose/8h Quinine (300mg) Total/ day Number of tablets Total/ 7days Dose/8h Tetracycline (250mg) Total/ day < 6 month < 7 ¼ ¾ 5 ¼ m - 2 years 7-15 ½ 1 ½ 10 ½ <8 years <15 years ½ 4 ½ 31 ½ 1¼ 4¼ 31¼ 15 years > Total/ 7days Doxycycline/tetracycline contraindications Doxycycline and tetracycline are contraindicated in pregnancy and children < 8 years old. Children < 8 years requiring second line treatment should be treated with 7 days of quinine without doxycycline or tetracycline Use of Malarone in Cambodia for use in special situations Malarone will be registered in Cambodia for use in special situations and only by special permission by the national malaria control program (CNM). Because of concerns for resistance, Malarone is only recommended in combination with another antimalarial drug such as artesunate Additional considerations for treating uncomplicated malaria To assure accurate dosing, it is preferable to use weight to assure correct dosing. If no scale is available, treat according to patient s age. Providers should explain to patients: o The importance of adhering to the medications given, and that patients should complete their entire course even if they feel better. o Possible side effects, such as headache, dizziness, nausea, vomiting, diarrhoea, or loss of appetite. Many of these symptoms can be caused by malaria as well. If a patient has taken quinine, providers should wait at least 12 hours before treating with ASMQ. Providers should observe patient for one hour after taking medicine to assure

29 National Treatment Guidelines for Malaria in Cambodia 16 patient doesn t vomit medicine. Fever is common in malaria. Using antipyretics (fever reducing medicine such as paracetamol) will not only reduce patient discomfort, but also reduce the likelihood that patients will vomit their medicine. In addition to antipyretics, patients can be cooled by using fanning and sponging with cloths soaked in cool water Drug resistance, treatment failures, and strategies to reduce transmission of resistant parasites In Cambodia, most patients can be successfully cured. Patients with recurrent symptoms after a recent malaria diagnosis and treatment may have a new infection, a different disease, or a treatment failure. Treatment failures occur when malaria parasites are not completely cleared from the body and return later to cause a second infection. Treatment failures can occur for a variety of reasons including inadequate levels of antimalarial drug in the blood stream where they exert their effect.1 Treatment failures can result from incomplete adherence (i.e. the patient did not take all the required doses) Poor quality medicine, or poor absorption of drug into the blood stream Resistance of parasites to antimalarial treatment (In Cambodia, there is widespread resistance to many drugs, including ACTs) Drug resistance is more likely to develop when patients are not completely cured, thus it is important to detect treatment failures and treat them appropriately. This will help ensure that currently available treatment remains effective. The continued use of a medicine to which parasites are partially resistant will encourage the selection of resistant parasites and their transmission. After treatment, gametocyte densities are higher in patients with resistant parasites than sensitive parasites and recrudescent infections are associated with higher rates of gametocyte carriage than primary infections. The cumulative effect of incompletely cured infections is the generation of more gametocytes capable of malaria transmission. Gametocytes with resistant genes are also more infectious to mosquitoes, producing higher parasite densities in the mosquito. Therefore, providers have a special role to ensure that drug resistance is prevented as shown in Box 10.1

30 17 National Treatment Guidelines for Malaria in Cambodia Box 10.1: How providers can prevent drug resistance from worsening Providers should: Be aware that the continued use of a failing regimen will selectively increase the selection of resistant parasites and hasten their spread Treat malaria patients as early as possible with an effective antimalarial (ACT) Use only high quality unexpired drugs from approved sources Explain to patients that malaria parasites may still remain in the body even after they feel better, so it is important to take all recommended doses. DOT is encouraged! If possible, use patient weight instead of age to determine correct dosing Encourage patients to take medicines with food Encourage patients to return for care if their malaria symptoms do not improve or worsen Use second line medication (quinine based regimens) for treatment failures. Refer if necessary How to manage potential treatment failure In Cambodia, P. Falciparum malaria cases reoccurring within 28 days of a previous malaria P. falciparum treatment are likely due to treatment failure. This can occur even after a patient is apparently cured and free of symptoms. If a patient is confirmed to have a second P. Falciparum diagnosis within 28 days, providers should consider the possibility of treatment failure. In this case providers should: Carefully question that patient to determine if the correct antimalarial medicine was given and whether the patient took all recommended doses. If an incorrect medication was given, retreat with the correct regimen according to the region where malaria was acquired. If the patient s adherence is doubtful, or if the patient recalls vomiting any dose within one hour, treat again with the correct first line regimen. If the patient adhered to the correct treatment regimen, treatment with second line therapy (quinine-doxycycline/tetracycline). If P. falciparum malaria is confirmed later than 28 days from a prior P. falciparum treatment, treat as a new P. falciparum diagnosis with the recommended first-line agent.

31 National Treatment Guidelines for Malaria in Cambodia Follow up of uncomplicated P. Falciparum malaria All P. falciparum malaria should be monitored for clinical response to malaria treatment. Because of heightened concern over drug resistant P. falciparum, CNM will identify certain health centres or referral (former district) hospitals where microscopy is available to participate in intensified parasitological follow up of P. falciparum cases. Those areas will follow up patients for adequate parasitological responses as summarized in Box 10.2 below. Box 10.2: Summarized recommendations on parasitological follow up of P. falciparum infections CNM will coordinate and monitor, as part of surveillance, a 28 days parasitological follow up in selected provinces. These activities consist of: Prepare blood film on the third day after treatment (D3) to confirm the negativity of the slide or the change of the parasitemia density compared to the first day (D0) If the parasitemia decreased on the third day after treatment (D3), make another slide on day 7 (D7) to confirm parasite clearance If the parasitemia increases on D3 after treatment, refer the patient to the nearest referral hospital, where he/she will be treated with second line treatment Where feasible, obtain follow up slides at D28 to confirm whether or not the treatment has been successful. Recurrent parasitemia should be treated as specified in section How to manage potential treatment failure RDTs are not suitable to assess parasitological response after treatment. They often remain positive up to and even after D14, even when malaria parasites are not present by microscopy. CNM will direct the collection of P. falciparum malaria samples at regular intervals in certain provinces in order to identify drug resistance markers. This information will help guiding future malaria drug policy Primaquine indications Primaquine plays a unique role in malaria treatment because of its ability to kill hypnozoites and prevent P. vivax and ovale relapses. In addition, primaquine at lower doses than used to kill hypnozoites may also prevent malaria transmission by killing gametocytes. Primaquine is recommended by the World Health Organization (WHO) for falciparum malaria to reduce transmission, and to eradicate dormant malaria forms (hypnozoites) of relapsing malaria species (P. vivax and P. ovale).