Managing Antimalarial Drug Resistance In Ghana

Published Date: 02 Nov 2017

Abuaku, Benjamin; Quaye, Lydia; Koram, Kwadwo Ansah

Abstract

In 1998, following reports of inadequate responses to drug treatment of uncomplicated malaria, six sentinel sites were established across the country to monitor the efficacy of antimalarial drugs. Besides providing empirical data to confirm or refute the anecdotal reports, the main aim was to provide real-time data to facilitate evidence-based decision making by the National Malaria Control Programme. In 2005, four more sites were added to broaden the coverage of the surveillance activities. Surveillance activities in the 10 sentinel sites have been coordinated by the Noguchi Memorial Institute for Medical Research with support from the Ghana Health Service and the Ministry of Health. In-vivo studies conducted between 1999 and 2010 evaluated clinical and parasitological responses to directly observed treatment for uncomplicated malaria using protocols by the World Health Organization. Prior to the change of antimalarial drug policy in Ghana in 2005, surveillance data showed a declining pcr-uncorrected efficacy of chloroquine (CHQ) from 91.1% in 1989 to 38.2% in 2003. Pcr-corrected day-28 cure rates for CHQ, sulphadoxine-pyrimethamine (SP), artesunate-amodiaquine (AS-AQ) combination, and artemether-lumefantrine (AL) combination in 2003 were 25% (95% CI: 12.4, 43.1), 60% (95% CI: 39.3, 77.9), 100% (95% CI: 91.3, 100), and 97.5% (95% CI: 86.7, 99.8), respectively. Evidence of declining efficacy of CHQ influenced the decision for its replacement with AS-AQ as first-line antimalarial drug as well as its replacement with SP as drug of choice for intermittent preventive treatment among pregnant women (IPTp).Surveillance data on AS-AQ, AL, and dihydroartemisinin-piperaquine (DHAP) combination, after change of drug policy, showed that artemisinin-based combination therapies (ACTs) remain efficacious in Ghana. Monitoring of ACTs should continue to help detect early changes in parasite sensitivity to artemisinins.

Keywords: Antimalarial drug; ACTs; Uncomplicated malaria; Surveillance

Introduction

Malaria remains a major public health problem in the world affecting 99 countries. It is estimated that 216 million episodes of malaria occurred in 2010. Of these, 81% or 174 million cases were in the WHO African region. In the same year an estimated 655,000 malaria deaths were reported, of which 91% were in Africa. It is also estimated that about 86% of malaria deaths in 2010 occurred among children under 5 years.1In2010, malaria was estimated to account for 38.2% of all out patient attendance; 34.9% of all admissions; and 33.7% of under-five mortality in Ghana.2 The current control strategy has its main focus on case management based on prompt diagnosis and adequate treatment. Adequate treatment of uncomplicated malaria has the advantages of limiting the duration of disease, preventing progression to severe disease, and minimizing the risk of developing and spreading drug resistant parasites.

Antimalarial drug resistance is defined 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 limits of tolerance of the subject, provided drug exposure at site of action is adequate.3 Antimalarial drug resistance is a result of parasite mutations that occur spontaneously and affect the structure and activity, at the molecular level, of the drug target in the parasite. Mutant parasites are subsequently selected if drug levels are adequate enough to inhibit the multiplication of only susceptible parasites and not mutants.4,5

Factors influencing the development and spread of antimalarial drug resistance are related to drug, parasite, and human host interactions. Drugs with a long terminal elimination half-life enhance the development of resistance, particularly in areas of high transmission. Additionally, increased drug pressure increases the probability of exposure of parasites to sub-optimal drug levels leading to the selection of resistant mutants. Parasite factors associated with the spread of resistance include the relative risk of drug-resistant parasites transmitting viable gametocytes as well as the intensity of transmission.6-8

Chloroquine and SP had been first-line and second-line antimalarial drugs, respectively, for the treatment of uncomplicated malaria in Ghana until 2005 when evidence of progressively high treatment failure rates necessitated the change of policy to focus on the use of artemisinin-based combinations (ACTs) because they had rapid effect on fever and parasite clearance as well as a reduction in gametocyte carriage rates thereby slowing down the spread of drug resistance.9

This article provides trends of in-vivo antimalarial drug efficacy from 1999 to 2010 with the view of demonstrating the importance of surveillance in the management of antimalarial drug resistance in Ghana. The article uses data obtained from surveillance activities in 10 sentinel sites across the country coordinated by the Noguchi Memorial Institute for Medical Research. The surveillance in 1999 and 2000 covered only CHQ efficacy; 2003 surveillance covered CHQ, SP, AS-AQ, and AL; 2008 surveillance covered AS-AQ and DHAP; whilst 2010 surveillance covered AS-AQ combination and AL combination.

Approach

The antimalarial drug resistance surveillance in-vivo studies were evaluations of clinical and parasitological responses to directly observed treatment for uncomplicated malaria using WHO protocols.10-12 Children with uncomplicated malaria who met the study inclusion criteria were enrolled, treated on site, and monitored for a minimum of 14 days and a maximum of 28 days. The inclusion criteria were children aged between 6 months and 59 months; mono-infection with P. falciparum detected by microscopy; asexual parasitaemia of 2,000 – 200,000/µl (for surveillance periods prior to 2009); asexual parasitaemia of 1,000 – 250,000/µl (for surveillance periods after 2009); presence of axillary temperature ≥ 37.5oC (for surveillance periods prior to 2009); presence of axillary temperature ≥ 37.5oC or history of fever during the past 24 hours (for surveillance periods after 2009); ability to swallow oral medications; parent/guardian giving consent; and parent/guardian willing to comply with the study protocol for the duration of the study and to comply with the study visit schedule. The exclusion criteria were presence of general danger signs or signs of severe falciparum malaria; mixed or mono-infection with another Plasmodium species detected by microscopy; presence of severe malnutrition; presence of febrile conditions due to diseases other than malaria (e.g. measles, acute lower respiratory tract infection, severe diarrhoea with dehydration) or other known underlying chronic or severe diseases (e.g. cardiac, renal and hepatic diseases, HIV/AIDS); regular medication, which may interfere with antimalarial pharmacokinetics (e.g. antihistamines); and history of hypersensitivity reactions or contraindication to any of the medicines being tested.

The follow-up consisted of a fixed schedule of check-up visits on days 1, 2, 3, 7, 14, 21, and 28 after treatment (day of treatment was counted as day 0). During each visit, children were physically examined and information on symptoms, axillary temperature, and respiratory rates noted in a case record form (CRF). Parasitaemia was assessed on days 2, 3, 7, 14, 21, 28, and any day within the 28-day follow-up period that a child is brought to the study clinic with fever. Filter paper blots were obtained on day-0 and at recurrence of parasitaemia for PCR genotyping, and merozoite surface proteins 1 and 2 (MSP1, MSP2), and glutamate-rich protein (GLURP) used to distinguish between re-infection and recrudescence.

Clinical responses were classified based on WHO criteria as follows:

Early treatment failure (ETF) in cases of development of danger signs or severe malaria in the presence of parasitaemia by day-3; parasitaemia on day-2 > day-0 irrespective of axillary temperature; parasitaemia on day-3 with axillary temperature ≥ 37.5oC; parasitaemia on day 3 ≥ 25% of day-0; fever and parasitaemia on day-3.

Late clinical failure (LCF) in cases of development of danger signs or severe malaria after day-3 in the presence of parasitaemia; presence of parasitaemia and axillary temperature ≥ 37.5oC anytime from day-4.

Late parasitological failure (LPF) in cases of parasitaemia with axillary temperature < 37.5oC on day 14 or 28 without previously meeting any of the criteria for ETF and LCF.

Adequate clinical and parasitological response (ACPR) in cases of absence of parasitaemia on day 14 or 28 irrespective of axillary temperature without previously meeting any of the criteria of ETF or LCF.

The studies were conducted in ten sentinel sites across the country (one site in each of the ten administrative regions of the country). Three of the sites (Yendi, Wa, and Navrongo) are in the northern belt, which is savannah; four sites (Sunyani, Bekwai, Begoro, and Hohoe) are in the middle belt, which is forest; and three are in the southern belt, which is coastal (Cape-Coast and Prampram) and forest (Tarkwa). Generally, malaria in the savannah zone is perennial with marked seasonal variation. The peak transmission season coincides with the major rains between June and October. Malaria transmission in the forest zone is intense and perennial whilst transmission in the coastal zone is perennial but not intense.13-16

All studies received ethical approval from the WHO Secretariat Committee on Research Involving Human Subjects (SCRIHS) and the Institutional Review Board of the Noguchi Memorial Institute for Medical Research, University of Ghana.

Findings and Discussions

Continuous monitoring of anti-malarial drug resistance across the country is critical in ensuring that data is always available for timely evidence-based decision making by the NMCP. Surveillance activities over the past 15 years have yielded significant findings influencing anti-malarial drug policy in the country.

The therapeutic efficacy of CHQ in Ghana was reported to be 91.1% in 1989.17 A decade after this report, surveillance data from 6 sentinel sites showed a marked decline of CHQ efficacy to 61.9%, and a further decline to 38.2% in 2003 (figure 1). The declining efficacy of CHQ observed in Ghana compared well with global findings necessitating change of treatment policy.8, 18-20

Analysis of pcr-uncorrected and pcr-corrected treatment outcomes in 2003 from 2 sentinel sites (Hohoe and Navrongo) showed day-14 cure rate of 100% for the 2 ACTs (AS-AQ and AL) (figures 1 and 2). Pcr-corrected day-14 cure rates for CHQ and SP were 50% (95% CI: 32.8, 67.3) and 84% (95% CI: 63.6, 94.6), respectively (p=0.014) (figure 2). Pcr-uncorrected day-28 cure rates for the 2 ACTs were above 70% (74.5%; 95% CI: 60.1, 85.2 for AS-AQ and 83%; 95% CI: 68.7, 91.9 for AL) whilst cure rates for the mono-therapies were less than 50% (34.6%; 95% CI: 17.9, 55.6 for SP and 17.7%; 95% CI: 7.4, 35.2 for CHQ) (figure 2).21 Chloroquine showed the lowest pcr-corrected day-28 cure rate whilst AS-AQ showed the highest cure rate (25%; 95% CI: 12.4, 43.1 vs. 100%; 95% CI: 91.3, 100; p<0.001) (figure 3). The superiority of SP over CHQ compared well with other findings in the country22,23, and provided evidence for the replacement of CHQ with SP in the intermittent preventive treatment of pregnant women (IPTp), a strategy aimed at preventing maternal anaemia and placental parasitaemia necessary for good birth outcomes.24 Currently, SP is the drug of choice for IPTp in Ghana.25 The observed superiority of ACTs over monotherapies compared well with other findings in Africa 26-29, and supported the revision of the anti-malarial drug policy in Ghana. Chloroquine was therefore replaced with AS-AQ as first-line drug for treating uncomplicated malaria in Ghana in 2005.25

Analysis of the overall pcr-uncorrected day-28 cure rates for AS-AQ in 9 sentinel sites during the 2005/2006, 2007/2008, and 2010/2011 surveillance years did not show any statistically significant difference between the years of surveillance. The overall cure rate for the surveillance years ranged between 92.4% (95% CI: 85.6, 96.2) and 95.6% (95% CI: 93.3, 97.2) (P=0.223) (figure 4).These findings show that AS-AQ remains efficacious in the treatment of uncomplicated malaria in Ghana, and compare well with findings in other African countries.30, 31

A comparative analysis of pcr-uncorrected cure rates of DHAP and AS-AQ in 4 sentinel sites, where both anti-malarial drugs were studied, showed no statistically significant difference between the 2 anti-malarial drugs during the 2007/2008 surveillance year(93.3%; 95% CI: 88.3, 96.3 vs. 96.4%; 95% CI: 91.9, 98.5; p=0.295). There were no statistically significant differences between cure rates within each of the 4 sentinel sites (figure 5).

Concluding remarks

Monitoring of the efficacy of anti-malarial drugs in Ghana since 1999, eleven years after the first report of chloroquine resistance 32, has shown the superiority of SP over CHQ and the superiority of ACTs over mono-therapies with SP and CHQ. The 2005 decision of the NMCP to replace CHQ with SP for IPTp was appropriate as well as the replacement of CHQ with AS-AQ as a first-line drug for uncomplicated malaria. Surveillance data after the introduction of AS-AQ has shown that AS-AQ remains efficacious in the country, and should remain a first-line anti-malarial drug. Surveillance data has also shown that other ACTs (AL and DHAP) are equally efficacious. The addition of AL and DHAP to AS-AQ in 2008 as alternate first-line drugs is also in the right direction.25 Although the addition of AL and DHAP is supposed to cater for patients who are unable to tolerate AS-AQ, the use of multiple first-line therapy goes a long way to delay the emergence and slow spread of drug resistance.33, 34

Routine monitoring of the therapeutic efficacy of the 3 first-line ACTs need to continue across the country to help detect early changes in parasite sensitivity to artemisinins. Although WHO recommends that ACT efficacy be monitored every 2 years in all sentinel sites35, inadequate funding does not allow for that in the country. The routine monitoring of treatment responses should be seen as a necessary activity for malaria control and not only as a research programme. This therefore needs to be supported by the GHS/MOH disease control unit and other health partners. Furthermore, ACTs need to remain affordable with the support of all stakeholders, particularly the government and donors, to maintain the gains achieved so far in the provision of efficacious treatment for malaria in Ghana.