Evaluación ambiental de las PCH

2.3.1 Plasmodium species and types of vectors

Malaria is still a major public health problem in Yemen. The epidemiology is classified as an Afrotropical type with 99% of malaria cases being caused by P. falciparum as the predominant species and the remainder are P. vivax and P. malariae (NMCP, 2002; Al-Maktari et al., 2003; Azazy & Raja'a, 2003; Bassiouny & Al-Al-Maktari, 2005; Al-Taiar et al., 2006; Alkadi et al., 2006; Abdulsalam et al., 2010). The epidemiology of falciparum malaria in the Arabian Peninsula including Yemen can be divided according to topographical criteria into three eco-epidemiological zones of malaria; Oriental, Palaearctic and Afrotropical, leading to a wide variation in vectors and transmissions of malaria parasites and the subsequent increased risk of malaria (Zahar, 1974;

Kouznetsov, 1976; Kravchenko, 1979; Snow et al., 2013).

In Yemen, many species of anopheline mosquitoes have been reported to be responsible for malaria transmission (Figure 2.4). The most common vectors include Anopheles arabiensis which has been reported as the main vector within the country, Anopheles culicifacies which is an important vector in the coastal areas and it is the predominant vector in Socotra Island and the eastern governorate of Al Maharah, Anopheles sergenti has been reported to be a vector in the mountainous hinterland and highland areas, and recently An. algeriensis (Sinka et al., 2010; Snow et al., 2013).

Understanding the time of biting and indoor or outdoor resting behaviours, distribution of Yemeni anopheline mosquitoes, the susceptibility of vectors to insecticides and their role are important in the control and transmission of malaria and can assist in planning for vector control strategies in Yemen. Increase or decrease of malaria incidence depends on the densities of mosquitoes. Peak transmission of malaria in endemic areas

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is mostly related to rainy seasons as there are plentiful of breeding sites available for mosquitoes. Yemen shares many similarities of the ecology of mosquitoes with Saudi Arabia, Jazan Provine. In addition, high transmission of malaria in Yemen as a result of illegal immigration of people from the malaria endemic countries in the horn of Africa such as Eritrea, Somalia and Ethiopia due to conflict, political instability, civil wars and poverty (Soucy, 2011).

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Source: (NMCP, 2006)

Figure 2.4: Modified map of distribution of Anopheles mosquito in governorates, Yemen

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2.3.2 Trend of confirmed malaria cases in the last 23 years

The estimate of malaria cases in Yemen fluctuates from year to year, making estimation of malaria cases incidences difficult (WHO, 2013). For example, there were 2.7 million cases in 1999 and 3.2 million cases in 2001 after which the malaria cases declined gradually between 800,000 -900,000 cases in 2006 with 1% estimated related deaths (Figure 2.5). According to a WHO report, malaria cases in Yemen in 2009 were 265,074 cases with 779 related deaths (WHO, 2008a; NMCP, 2011). The weather and climate of Yemen varies from one region to another due to diverse topography, changes in climates especially in rainfall, temperature and humidity leading to variation in the rates of malaria transmission.

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Figure 2.5: Malaria trend in Yemen from 1990 till 2014

0 150000 300000 450000 600000 750000 900000 1050000 1200000 1350000 1500000 1650000 1800000 1950000 2100000 2250000 2400000 2550000 2700000 2850000 3000000

1990 1991 1992 1993 1994 1995 1996 1997 1999 2000 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

Malaria cases

Years

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2.3.3 Risk factors

Yemen is the remaining country in the Arabian Peninsula with high transmission rate of malaria because of unstable political issues and civil wars for many years. The country undergoes numerous environmental and social stresses such as food and water insecurity, and severe depletion in water resources, weak institutions and health system, rapid population growth and climate change (Husain & Chaudhary, 2008).

The research on risk factors for malaria in Yemen is still very scant as there were only four studies in particular governorates such as Taiz, Hodiedah, Dhamar and Raymah that have determined some factors that could be associated with the increased risk of acquiring malaria (Table 2.8). For example, Al‐Taiar et al. (2008) study found that socioeconomic factors (distance to nearest health center >2 km, driving time to reach health center > 10 min and house with earth roof), behavior factors (spray insecticides at home, delay of treatment > 3 days, burning mosquito coils) and environmental factors (nearby the water pump to house, nearby the man-made water collection/tank and more than 2 km of the distance from health center) were risk factors for malaria. In addition, Al-Taiar et al. (2009) have also demonstrated that socioeconomic factors (house with earth roof with or without opening in the roof, and traveling to another endemic area in the last 2 month), behavior factors (burning animal dung) and environmental factors (water collections nearby, presence of water stream/spring, presence of water pump, swamp existence/marshy land, presence of latrine outside the house or non and water storage at home:in jerry cans) could be risk factors that lead to increase the chance of acquiring malaria in the country.

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A more recent study in 2011 found a significance risk factors for malaria include children ≤ 12 year, large family size, gender, living in rural area, low income, not working, not sleeping under bed nets, burning mosquito coils, spray insecticides at home, wear short clothes and water collections nearby the houses (Al-Mekhlafi et al., 2011a) (Table 2.8).

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Table 2.8: Socio-economic, behavioral and environmental risk factors associated with acquiring malaria in four governorates in Yemen

Factors Governorates References

Socio-economic factors:- Family size (more than 5) Gender

Distance to nearest health center >2 km

Driving time to reach health center

> 10 min

Poorly constructed houses Material of the roof (earth)

Presence of opening in the roof Presence of latrine:

Outside the house Not at all

Traveling to another endemic area In the last 2 month

Not sleeping under bed nets Burning mosquito coils

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2.3.4 Malaria distribution and intensity of transmission

In Yemen, malaria is seasonal and unstable, the malaria endemicity ranges from mesoendemic in the south to hyperendemic in the north, especially the coastal plains, including Tehama areas, foothill regions and coastal districts in the Hadhramout governorate which is characterised by extensive wadis and seasonal rainfall (Yahia, 2005; Mohanna et al., 2007). From the past to present, the prevalence of malaria in Yemen fluctuates and is a major health problem with prevalence ranging from 12.8% to 18.6% (Alkadi et al., 2006; Mohanna et al., 2007; Abdulsalam et al., 2010; Othman et al., 2015).

Yemen has four major epidemiological stratification of malaria, and the classification was based on the attitude, rainfall, and topography (Table 2.8) (NMCP, 2011; Adeel et al., 2015). The areas of the first stratum has an attitude of 0-600 meters with an average of 4-6 months of rain. The transmission season mainly occur in winter from November to April and is characterised by occurrence of malaria infection in wadis along the coastal areas whereas the desert areas are malaria free zones (e.g Hadhramout). The second stratum consists of an attitude of 601-1000 meters above the sea level, and malaria transmission occurs in the winter season from November to April.

In addition, there is partial transmission in summer from May to September and is characterised by occurrence of malaria infection in the Wadis (valleys), and in the foothills (e.g. Tihama region). The third stratum has an attitude above 1001-2000 meters, malaria transmission occurs in the summer season, especially in the foothills and wadis of the central highlands. The four stratum is the areas above 2000 meters and the desert areas which are usually free from malaria. Hadhramout governorate is divided into three zones which are, coastal plain, mountains and foothill areas (Yahia, 2005).

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The area is classified by the NMCP as belonging to stratum one and peak malaria transmission occurs in winter between October and April.

2.3.5 Prevention and control

The National Control Malaria Program (NCMP) in Yemen, is proactive in combating malaria through the implementation of several interventions that include distribution of insecticide-treated mosquito nets (ITNs), indoor residual spraying (IRS), proper diagnosis, proper treatment, and reactive and proactive case surveillance.

2.3.6 Malaria diagnosis

In Yemen, the diagnosis of malaria depends on clinical examination and confirmation by microscopic detection of malaria parasites in blood smear. The microscopic examination is usually conducted in the main hospitals and health centers where trained technicians are present. However, this technique may not be available in the rural areas due to the lack of required facilities and qualified health workers. Furthermore, WHO reported that the standard of microscopy examination in Yemen is poor due to the lack of effective national standards; poor quality of blood films, poor quality stains and staining techniques, generally unsatisfactory laboratory equipment; and the absence of an effective quality assurance program (WHO, 2009). Therefore, malaria rapid diagnostic test (RDT) was introduced as alternative tool for malaria diagnosis in areas where good quality microscopy is not available or cannot be carried out (McMorrow et al., 2010; WHO, 2015b).

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2.3.7 Malaria treatment in Yemen

2.3.7.1 The old strategy (from 1999)

The national antimalarial drug policy in Yemen was formulated in 1999, consisting of chloroquine (CQ) as first-line, sulphadoxine-pyrimethamine (SP) as a second line and the third line is mefloquine and primaquine as a gametocytocidal treatment monotherapy for treating uncomplicated falciparum malaria. However, quinine intravenous infusion was used for treating complicated and severe falciparum malaria.

In addition, chloroquine and primaquine treatment drug were used for treating non-falciparum malaria as anti-relapse treatment for Plasmodium vivax and as gametocytocidal treatment for Plasmodium malariae (NMCP, 2006).

2.3.7.2 The new strategy (from 2005)

In November 2005, following the emergence of chloroquine resistance and the WHO recommendation, the antimalarial treatment policy shifted to artemisinin-based combination therapy (ACT) with artesunate (AS) plus sulphadoxine-pyrimethamine (SP) as the first-line, and artemether-lumefantrine (AL) as the second line therapy for treating uncomplicated falciparum malaria (Adeel et al., 2015). However, this new policy was only implemented four years later in 2009 after proper training and distribution of the national guideline for antimalarial drugs were carried out (Bin Ghouth, 2013). Artemether or quinine infusion therapy was used for treating complicated and severe falciparum malaria. In addition, the treatment of non-falciparum malaria is still chloroquine and primaquine as an anti-relapse treatment for P. vivax (NMCP, 2010a, 2010b; WHO, 2012; Bin Ghouth, 2013).

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2.3.7.3 Monitoring anti-malarial drug resistance

A) In vivo studies

Monitoring antimalarial drug efficacy in Yemen started in 2002 to 2005 following the WHO protocol for in vivo assessment in four sentinel sites that found 39% to 57% of chloroquine resistance. In 2004, three in vivo studies on the efficacy of SP showed success rate ranging from 95% to 100%. Four years later, after launching the new policy, in vivo efficacy trials were conducted in three monitoring sites and they reported of 97.6–100 % adequate clinical and parasitological response (ACPR) for AS plus SP (NMCP, 2010b). The efficacy of AS plus SP as first-line treatment for uncomplicated falciparum malaria was also rated at 97% ACPR in a recent clinical drug efficacy trial carried out in 2013 (Adeel et al., 2015). It is noteworthy that the currently used routine clinical efficacy trial is the gold standard for the assessment of the efficiency of the combined antimalarial drugs, although it does not differentiate between the effectiveness of AS and its partner drug.

B) Molecular markers based studies

For many years, CQ had been the first line treatment in Yemen. The first case of the indigenous chloroquine resistance (CQR) in Yemen was reported in 1989 in Taiz (Mamser, 1989; Alkadi et al., 2006), and then in Hodeidah (Al-Shamahy et al., 2006).

In addition, recent studies have shown high prevalence of CQR marker Pfcrt 76T in Hodeidah, Dhammar, Rymah and Taiz (Al-Mekhlafi et al., 2011b; Abdul-Ghani et al., 2013; Al-Hamidhi et al., 2013). Although antimalarial drug policy in Yemen has changed from CQ to ACT, previous studies conducted in Hadhramout governorate

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reported that CQ is still commonly prescribed (18 out of 42 prescriptions) and some clinicians were not aware and had poor knowledge about the new national drug policy (Bashrahil et al., 2010; Bin Ghouth, 2013). Continued use of CQ sustains the selection of CQ resistant mutations leading to persistence of mutant parasite. The complete withdrawal of CQ use may enhance the emergence of CQ sensitive parasite over time and make CQ possible to be re-introduced for malaria treatment (Kublin et al., 2003;

Laufer et al., 2006). However, the persistence of CQ resistance will be prolonged if the shift to ACT and the simultaneous withdrawal of CQ are not rigorously implemented.

Molecular markers are practical for monitoring SP resistance. Quintuple mutant of combined dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) genes (Pfdhfr I51, R59, N108 plus Pfdhps G437, E540) was significantly associated with in vivo resistance to SP (Picot et al., 2009). Several studies have also been conducted for the screening of P. falciparum population for molecular markers associated SP resistance in Yemen. The mutant allele R59 of Pfdhfr was detected in 5 % of P.

falciparum isolates (5/99) in Lahj governorate, southern Yemen (Mubjer et al., 2011).

Double mutant genotype of Pfdhfr (I51/N108) was reported in 54 % of P. falciparum isolates in Taiz, Dhamar, and Hodeidah governorates in western Yemen (Al-Hamidhi et al., 2013). Pfdhfr mutant allele (N108) was also reported in 53.2 % of P. falciparum isolates collected from Hodeidah governorate (Abdul-Ghani et al., 2014). The continued use of SP in the new policy, availability of this drug in the private sector, and poor knowledge of the national policy among physicians (Bashrahil et al., 2010) may increase the monotherapy of SP against P. falciparum, which is likely to compromise drug efficacy. It is noteworthy that the data on molecular markers associated with CQ and SP resistance are not available from the Hadhramout governorate, Yemen where this study is being carried out.

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CHAPTER 3: METHODOLGY