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Thursday, July 18, 2019

Refugee children

From Wikipedia, the free encyclopedia
 
Bantu refugee children from Somalia at a farewell party in Florida before being relocated to other places in the United States.
 
Nearly half of all refugees are children, and almost one in three children living outside their country of birth is a refugee. These numbers encompass children whose refugee status has been formally confirmed, as well as children in refugee-like situations. 

In addition to facing the direct threat of violence resulting from conflict, forcibly displaced children also face various health risks, including: disease outbreaks and long-term psychological trauma, inadequate access to water and sanitation, nutritious food, and regular vaccination schedules.  

Refugee children, particularly those without documentation and those who travel alone, are also vulnerable to abuse and exploitation. Although many communities around the world have welcomed them, forcibly displaced children and their families often face discrimination, poverty, and social marginalization in their home, transit, and destination countries. Language barriers and legal barriers in transit and destination countries often bar refugee children and their families from accessing education, healthcare, social protection, and other services. Many countries of destination also lack intercultural supports and policies for social integration. Such threats to safety and well-being are amplified for refugee children with disabilities.

This woodcut by Julius Schnorr von Karolsfeld, 1860 depicts Jesus as a refugee child fleeing the Massacre of the Innocents.

Legal protection

The Convention on the Rights of the Child, the most widely ratified human rights treaty in history, includes four articles that are particularly relevant to children involved in or affected by forced displacement:
  • the principle of non-discrimination (Article 2)
  • best interests of the child (Article 3)
  • right to life and survival and development (Article 6)
  • the right to child participation (Article 12)
States Parties to the Convention are obliged to uphold the above articles, regardless of a child's migration status. As of November 2005, a total of 192 countries have become States Parties to the Convention. Somalia and the United States are the only two countries that have not ratified it.

The United Nations 1951 Convention on the Status of Refugees is a comprehensive and rigid legal code regarding the rights of refugees at an international level and it also defines under which conditions a person should be considered as a refugee and thus be given these rights. The Convention provides protection to forcibly displaced persons who have experienced persecution or torture in their home countries. For countries that have ratified it, the Convention often serves as the primary basis for refugee status determination, but some countries also utilize other refugee definitions, thus, have granted refugee status not based exclusively on persecution. For instance, the African Union has agreed on a definition at the 1969 Refugee Convention, that also accommodates people affected by external aggression, occupation, foreign domination, and events seriously disturbing public order. South Africa has granted refugee status to Mozambicans and Zimbabweans following the collapse of their home countries’ economies.

Other international legal tools for the protection refugee children include two of the Protocols supplementing the United Nations Convention against Transnational Organized Crime which reference child migration:
  • the Protocol to Prevent, Suppress, and Punish Trafficking in Persons, especially Women and Children;
  • the Protocol against the Smuggling of Migrants by Land, Sea, and Air.
Additionally the International Convention on the Protection of the Rights of All Migrant Workers and Members of Their Families covers the rights of the children of migrant workers in both regular and irregular situations during the entire migration process.

Stages of the refugee experience

Refugee experiences can be categorized into three stages of migration: home country experiences (pre-migration), transit experiences (transmigration), and host country experiences (post-migration). However, the large majority of refugees do not travel into new host countries, but remain in the transmigration stage, living in refugee camps or urban centres waiting to be able to return home.

Home country experiences (pre-migration)

Former child soldiers in the eastern Democratic Republic of the Congo.
 
The pre-migration stage refers to home country experiences leading up to and including the decision to flee. Pre-migration experiences include the challenges and threats children face that drive them to seek refuge in another country. Refugee children migrate, either with their families or unaccompanied, due to fear of persecution on the premise of membership of a particular social group, or due to the threat of forced marriage, forced labor, or conscription into armed forces. Others may leave to escape famine or in order to ensure the safety and security of themselves and their families from the destruction of war or internal conflict. A 2016 report by UNICEF found that, by the end of 2015, five years of open conflict in the Syrian Arab Republic had forced 4.9 million Syrians out of the country, half of which were children. The same report found that, by the end of 2015, more than ten years of armed conflict in Afghanistan had forced 2.7 million Afghans beyond the country's borders; half of the refugees from Afghanistan were children. During times of war, in addition to being exposed to violence, many children are abducted and forced to become soldiers. According to an estimate, 12,000 refugee children have been recruited into armed groups within South Sudan. War itself often becomes a part of the child's identity, making reintegration difficult once he or she is removed from the unstable environment.

Examples of children's pre-migration experiences:
  • Some Sudanese refugee children reported that they had either experienced personally or witnessed potentially traumatic events prior to departure from their home country, during attacks by the Sudanese military in Darfur. These events include instances of sexual violence, as well as of individuals being beaten, shot, bound, stabbed, strangled, drowned, and kidnapped.
  • Some Burmese refugee children in Australia were found to have undergone severe pre-migration traumas, including the lack of food, water, and shelter, forced separation from family members, murder of family or friends, kidnappings, sexual abuse, and torture.
  • In 2014 the President of Honduras testified in front of the United States Congress that more than three-quarters of unaccompanied child migrants from Honduras came from the country's most violent cities. In fact, 58 percent of 404 unaccompanied and separated children interviewed by the UN Refugee Agency, UNHCR, about their journey to the United States indicated that they had been forcibly displaced from their homes because they had either been harmed or were under threat of harm.
In general, children may also cross borders for economic reasons, such as to escape poverty and social deprivation, or some children may do so to join other family members already settled in another State. But it is the involuntary nature of refugees' departure that distinguishes them from other migrant groups who have not undergone forced displacement. Refugees, and even more so their children, are neither psychologically nor pragmatically prepared for the rapid movement and transition resulting from events outside their control. Any direct or witnessed forms of violence and sexual abuse may characterize refugee children's pre-migration experiences.

Transit experiences (transmigration)

The transmigration period is characterized by the physical relocation of refugees. This process includes the journey between home countries and host countries and often involves time spent in a refugee camp. Children may experience arrest, detention, sexual assault, and torture during their translocation to the host country. Children, particularly those who travel on their own or become separated from their families, are likely to face various forms of violence and exploitation throughout the transmigration period. The experience of traveling from one country to another is much more difficult for women and children, because they are more vulnerable to assaults and exploitation by people they encounter at the border and in refugee camps.

Trafficking

Smuggling, in which a smuggler illegally moves a migrant into another country, is a pervasive issue for children travelling both with and without their families. While fleeing their country of origin, many unaccompanied children end up travelling with traffickers who may attempt to exploit them as workers. Including adults, sex trafficking is more prevalent in Europe and Central Asia, whereas in East Asia, South Asia, and the Pacific labour trafficking is more prevalent.

Many unaccompanied children fleeing from conflict zones in Moldova, Romania, Ukraine, Nigeria, Sierra Leone, China, Afghanistan or Sri Lanka are forced into sexual exploitation. Especially vulnerable groups include girls belonging to single-parent households, unaccompanied children, children from child-headed households, orphans, girls who were street traders, and girls whose mothers were street traders. While refugee boys have been identified as the main victims of exploitation in the labor market, refugee girls aged between 13 and 18 have been the main targets of sexual exploitation. In particular, the number of young Nigerian women and girls brought into Italy for exploitation has been increasing: it was reported that 3,529 Nigerian women, among them underage girls, arrived by sea between January and June 2016. Once they reached Italy, these girls worked under conditions of slavery, for periods typically ranging from three to seven years.

Detention

Children may be detained in prisons, military facilities, immigration detention centers, welfare centers, or educational facilities. While detained, migrant children are deprived of a range of rights, such as the right to physical and mental health, privacy, education, and leisure. And many countries do not have a legal time limit for detention, leaving some children incarcerated for indeterminate time periods. Some children are even detained together with adults and subjected to a harsher, adult-based treatment and regimen.

In North Africa, children travelling without legal status are frequently subjected to extended periods of immigration detention. Children held in administrative detention in Palestine only receive a limited amount of education, and those held in interrogation centers receive no education at all. In two of the prisons visited by Defense for Children International Palestine, education was found to be limited to two hours a week. It has also been reported that child administrative detainees in Palestine do not receive sufficient food to meet their daily nutritional requirements.

Documented cases of child detention are available for more than 100 countries, ranging from the highest to the lowest income nations. Even so, a growing number of countries, including both Panama and Mexico, prohibit the detention of child migrants. And Yemen has adopted a community-driven approach, using small-group alternative care homes for child refugees and asylum-seekers, as a more age-appropriate way of detention. In the United States unaccompanied children are placed in single purpose non-secure “children’s shelters” for immigration violations, rather than in juvenile detention facilities. However, this change has not ended the practice of administrative detention entirely. Although there is commitment by the Council of Europe to work toward ending the detention of children for migration control purposes, asylum-seeking and migrant children and families often undergo detention experiences that conflict with international commitments.

Refugee camps

Some refugee camps operate at levels below acceptable standards of environmental health; overcrowding and a lack of wastewater networks and sanitation systems are common.

Hardships of a refugee camp may also contribute to symptoms following a refugee child's discharge from a camp. A small number of Cuban refugee children and adolescents, who were detained in a refugee camp, were assessed months after their release, and it was found that 57 percent of the youth exhibited moderate to severe posttraumatic stress disorder (PTSD) symptoms. Unaccompanied girls at refugee camps may also face harassment or assault from camp guards and fellow male refugees. In addition to having poor infrastructure and limited support services, there are a few refugee camps that can present danger to refugee children and families by housing members of armed forces. Also, at a few refugee camps, militia forces may try to recruit and abduct children.

Host country experiences (post-migration)

The third stage, host country experiences, is the integration of refugees into the social, political, economic, and cultural framework of the host country society. The post-migration period involves adaptation to a new culture and re-defining one's identity and place in the new society. This stress can be exacerbated when the children arrive in the host country and are expected to adapt quickly to a new setting.

It is only a minority of refugees who travel into new host countries and who are allowed to start a new life there. Most refugees are living in refugee camps or urban centres waiting to be able to return home. For those who are starting a new life in a new country there are two options:

Seeking asylum

Asylum seekers are people who have formally applied for asylum in another country and who are still waiting for a decision on their status. Once they have received a positive response from the host government, they will legally be considered as refugees. Refugees, like citizens of the host country, have the rights to education, health, and social services, whereas asylum seekers do not.

For instance, the majority of refugees and migrants who arrived in Europe in 2015 through mid-2016 were accommodated in overcrowded transit centers and informal settlements, where privacy and access to education and health services were often limited. In some accommodation centers in Germany and Sweden, where asylum seekers stayed until their claims were processed, separate living spaces for women, as well as sex-separated latrines and shower facilities, were unavailable.

Unaccompanied children face particular difficulties throughout the asylum process. They are minors who are separated from their families once they reach the host country, or minors who decide to travel from their home countries to a foreign country without a parent or guardian. More children are traveling alone, with nearly 100,000 unaccompanied children in 2015 filing claims for asylum in 78 countries. Bhabha (2004) argues that it is more challenging for unaccompanied children than adults to gain asylum, as unaccompanied children are usually unable to find appropriate legal representation and stand up for themselves during the application process. In Australia, for instance, unaccompanied children, who usually do not have any kind of legal assistance, must prove beyond any reasonable doubt that they are in need of the country's protection. Many children do not have the necessary documents for legal entry into a host country, often avoiding officials due to fear of being caught and deported to their home countries. Without documented status, unaccompanied children often face challenges in acquiring education and healthcare in many countries. These factors make them particularly vulnerable to hunger, homelessness, and sexual and labor exploitation. Displaced youth, both male and female, are vulnerable to recruitment into armed groups. Unaccompanied children may also resort to dangerous jobs to meet their own survival needs. Some may also engage in criminal activity or drug and alcohol abuse. Girls, to a larger extent than boys, are vulnerable to sexual exploitation and abuse, both of which can have far-reaching effects on their physical and mental health.

Refugee resettlement

Third country resettlement refers to the transfer of refugees from the country they have fled to another country that is more suitable to their needs and that has agreed to grant them permanent settlement. Currently the number of places available for resettlement is less than the number needed for children for whom resettlement would be most appropriate. Some nations have prioritized children at risk as a category for resettlement.

The United States established its Unaccompanied Refugee Minor Program in 1980 to support unaccompanied children for resettlement. The Office of Refugee Resettlement (ORR) by the Department of Homeland Security currently works with state and local service providers to provide unaccompanied refugee children with resettlement and foster care services. This service is guaranteed to unaccompanied refugee minors until they reach the age of majority or until they are reunited with their families.

Some European nations have established programs to support the resettlement and integration of refugee children. The European countries admitting the most refugee children in 2016 via resettlement were the United Kingdom (2,525 refugee children), Norway (1,930), Sweden (915), and Germany (595). Together, these accounted for 66% of the child resettlement admissions to all of Europe. The United Kingdom also established a new initiative in 2016 to support the resettlement of vulnerable refugee children from the Middle East and North Africa, regardless of family separation status. It was reported in February 2017 that this program has been partially suspended by the government; the program would no longer accept refugee youth with "complex needs," such as those with disabilities, until further notice. Refugee children without caretakers have a greater risk of exhibiting psychiatric symptoms of mental illnesses following traumatic stress. Unaccompanied refugee children display more behavioral problems and emotional distress than refugee children with caretakers. Parental well-being plays a crucial role in enabling resettled refugees to transition into a new society. If a child is separated from his/her caretakers during the process of resettlement, the likelihood that he/she will develop a mental illness increases.

Health

This section covers health throughout the different stages of the refugee experience.

Health status

Nutrition

Refugee children arriving in the United States often come from countries with a high prevalence of undernutrition. Nearly half of a sample of refugee children who arrived to the American state of Washington, the majority of which were from Iraq, Somalia, and Burma, were found to have at least one form of malnutrition. In the under five age range refugee children had significantly higher rates of wasting syndrome and stunted growth, as well as a lower prevalence of obesity, in comparison to low-income non-refugee children.

However, some time after they arrived in the United States and Australia, many refugee children demonstrated an increasing rate of overnutrition. An Australian study, assessing the nutritional status of 337 sub-Saharan African children aged between three and 12 years, found that the prevalence rate for overweight amongt refugee children was 18.4%. The prevalence rate of overweight and obesity among refugee children in Rhode Island, increased from 17.3% at initial measurement at first arrival to 35.4% at measurement three years after.

But the nutritional profiles of refugee children also often vary by their country of origin. A study involving Syrian refugee children in Jordanian refugee camps found them to be on average more likely overweight than acutely malnourished. The low prevalence of acute malnutrition among them was attributed, at least partly, to UNICEF's infant and child feeding interventions, as well as to the distribution of food vouchers by the World Food Programme (WFP).

Among newly arrived refugees in Washington state, significantly higher rates of obesity were observed among Iraqi children, whereas higher rates of stunting were found among Burmese and Somali children. The latter also had higher rates of wasting. Such variation in the nutrition profiles of refugee children may be explained by the variance in refugees' location and time in transition.

Communicable diseases

Communicable diseases are a pervasive issue faced by refugee children in camps and other temporary settlements. Governments and organizations are working to address a number of them, such as measles, rubella, diarrhea, and cholera. Refugee children often arrive in the United States from countries with a high prevalence of infectious disease.

Measles has been a major cause of child deaths in refugee camps and among internally displaced people; measles also exacerbates malnutrition and vitamin A deficiency. Some countries, such as Kenya, have developed preventative, detective, and curative programs to specifically target measles within the refugee children population. Kenya has reached over 20 million children with a measles and rubella immunization campaign carried out at the national level in May 2016. In 2017 the Kenya Ministry of Health even reported a routine vaccination coverage of 95 percent in the Dadaab refugee camp. As of April 2017, in response to the first confirmed cases of measles in the camp, UNICEF and UNHCR have collaborated with the Kenya Ministry of Health to swiftly implement an integrated measles vaccination program in Dadaab. The campaign, which has been targeting children aged six to 14 years, also includes screening, treatment referrals for cases of malnutrition, vitamin A supplementation, and deworming.

Diarrhea, acute watery diarrhea, and cholera can also put children's lives at risk. Countries, such as Bangladesh, have identified the introduction and development of proper sanitation habits and facilities as potential solutions to these medical conditions. A 2008 study comparing refugee camps in Bangladesh reported that camps with sanitation facilities had cholera rates of 16%, whereas camps without such facilities had cholera rates that were almost three times higher. In a single week in 2017, 5,011 cases of diarrhea in refugee camps in Cox's Bazar in Bangladesh were reported. In response, UNICEF started a year-long cholera vaccination campaign in October 2017, targeting all children in the camps. At health centers in the refugee camps, UNICEF has been screening for potential cholera cases and providing oral rehydration salts. Community-based health workers are also going around the camps to share information on the risks of acute watery diarrhea, the cholera vaccination campaign, and the importance and necessity of good hygiene practices.

Noncommunicable diseases

During all points of the refugee experience, refugee children are often at risk of developing several noncommunicable diseases and conditions, such as lead poisoning, obesity, type 2 diabetes, and pediatric cancer. 

Many refugee children come to their host countries with elevated blood lead levels; others encounter lead hazards once they have resettled. A study published in January 2013 found that the blood lead levels of refugee children who had just arrived to the state of New Hampshire were more than twice as likely to be above 10 µg/dL as the blood lead levels of children born in the United States. Evidence from the Centers for Disease Control and Prevention (CDC) in the United States also found that nearly 30% of 242 refugee children in New Hampshire developed elevated blood lead levels within three to six months of their arrival to the United States, even though their levels were not found to be elevated at initial screening. A more recent study reported that refugee children in Massachusetts were 12 times more likely to have blood lead levels over 20 µg/dL a year after an initial screening than non-refugee children of the same age and living in the same communities.

A study analyzing the medical records of former refugees residing in Rochester, New York between 1980 and 2012 demonstrated that former child refugees may be at increased risk of obesity, type 2 diabetes, and hypertension following resettlement.

Many Afghan children lack access to urban diagnosis centers in Pakistan; those who do have access have been found to have various types of cancer. It is also estimated that, within Turkey's Syrian refugee population, 60 to 100 children are diagnosed with cancer each year. Overall, the incidence rate of pediatric cancers among Turkey's Syrian refugee population was similar to that of Turkish children. The study additionally noted, however, that most refugee children affected by cancer were diagnosed when the tumor was already at an advanced stage. This could indicate that refugee children and their families often face obstacles such as poor prognoses, language barriers, financial problems, and social problems in adapting to a new setting.

Mental health and illness

Traditionally, the mental health of children experiencing conflict is understood in terms of either post-traumatic stress disorder (PTSD) or toxic stress. Prolonged and constant exposure to stress and uncertainty, characteristic of a war environment may result in toxic stress that children express with a change in behavior that may include anxiety, self-harm, aggressiveness or suicide. A 2017 study conducted in Syria by Save the Children determined that 84% of all adults and most children considered ongoing bombing and shelling to be the main psychological stressor, while 89% said that children were more fearful as the war progressed, and 80% said that children had become more aggressive. These stressors are leading causes of the symptoms described above, which lead to diagnosis of PTSD and toxic stress, among other mental conditions. These issues may then be further exacerbated by a forced migration to a foreign country, and the beginning of the process of refugee status determination.

Refugee children are extremely vulnerable during migration and resettlement, and may experience long-term pathological effects, due to "disrupted development time." Psychoanalysts of refugee health have proposed that refugee children experience mourning for their culture and countries, despite the fact that the war-torn state of their homes is unsafe. This sudden loss of familiarity places children at a greater risk for mental dysfunction. In addition, studies have shown that refugee children show a higher vulnerability to stress when separated from their families. Studies from treatment facilities and small community samples have confirmed that refugee youth are at higher risk for psychopathologic disorders, including post-traumatic stress disorder, depression, conduct disorder, and problems resulting from substance abuse. However, it is important to note that other large-scale community surveys have found that the rate of psychiatric disorder among immigrant youth is not higher than that of native-born children. Nonetheless, experiments have shown that these adverse outcomes can be prevented through adequate protective factors, such as social support and intimacy. Additionally, effective adaptation strategies, such as absorption in work and creation of pseudofamilies, have led to successful coping in refugees. Many refugee populations, particularly Southeast Asian, undergo a secondary migration to larger communities of kinfolk from their countries of origin, which serve as social support networks for refugees. Research has shown that family reunification, formation of new social groups, community groups, and social services and professional support have contributed to successful resettlement of refugees.

Refugees can be stigmatized if they encounter mental health deficiencies prior to and during their resettlement into a new society. Differences between parental and host country values can create a rift between the refugee child and his/her new society. Less exposure to stigmatization lowers the risk of refugee children developing PTSD.

Access to healthcare

Cognitive and structural barriers make it difficult to determine the medical service utilization rates and patterns of refugee children. A better understanding of these barriers will help improve mental healthcare access for refugee children and their families.

Cognitive and emotional barriers

Many refugees develop a mistrust of authority figures due to repressive governments in their country of origin. Fear of authority and a lack of awareness regarding mental health issues prevent refugee children and their families from seeking medical help. Certain cultures use informal support systems and self-care strategies to cope with their mental illnesses, rather than rely upon biomedicine. Language and cultural differences also complicate a refugee's understanding of mental illness and available healthcare.

Other factors that delay refugees from seeking medical help are:
  • Fear of discrimination and stigmatization
  • Denial of mental illness as defined in the Western context
  • Fear of the unknown consequences following diagnosis such as deportation, separation from family, and losing children
  • Mistrust of Western biomedicine

Language barriers

A broad spectrum of translation services are available to all refugees, but only a small number of those services are government-sponsored. Community health organizations provide a majority of translation services, but there are a shortage of funds and available programs. Since children and adolescents have a greater capacity to adopt their host country's language and cultural practices, they are often used as linguistic intermediaries between service providers and their parents. This may result in increased tension in family dynamics where culturally sensitive roles are reversed. Traditional family dynamics in refugee families disturbed by cultural adaptation tend to destabilize important cultural norms, which can create a rift between parent and child. These difficulties cause an increase of depression, anxiety and other mental health concerns in culturally-adapted adolescent refugees.

Relying on other family members or community members has equally problematic results where relatives and community members unintentionally exclude or include details relevant to comprehensive care. Healthcare practitioners are also hesitant to rely on members of the community because it is breaches confidentiality. A third party present also reduces the willingness of refugees to trust their healthcare practitioners and disclose information. Patients may receive a different translator for each of their follow-up appointments with their mental healthcare providers, which means that refugees need to recount their story via multiple interpreters, further compromising confidentiality.

Culturally competent care

Culturally competent care exists when healthcare providers have received specialized training that helps them to identify the actual and potential cultural factors informing their interactions with refugee patients. Culturally competent care tends to prioritize the social and cultural determinants contributing to health, but the traditional Western biomedical model of care often fails to acknowledge these determinants.

To provide culturally competent care to refugees, mental healthcare providers should demonstrate some understanding of the patient's background, and a sensitive commitment to relevant cultural manners (for example: privacy, gender dynamics, religious customs, and lack of language skills). The willingness of refugees to access mental healthcare services rests on the degree of cultural sensitivity within the structure of their service provider.

The protective influence exercised by adult refugees on their child and adolescent dependents makes it unlikely that young adult-accompanied refugees will access mental healthcare services. Only 10-30 percent of youth in the general population, with a need for mental healthcare services, are currently accessing care. Adolescent ethnic minorities are less likely to access mental healthcare services than youth in the dominant cultural group. 

Parents, caretakers and teachers are more likely to report an adolescent's need for help, and seek help resources, than the adolescent. Unaccompanied refugee minors are less likely to access mental healthcare services than their accompanied counterparts. Internalizing complaints (such as depression and anxiety) are prevalent forms of psychological distress among refugee children and adolescents.

Other obstacles

Additional structural deterrents for refugees:
  • Complicated insurance policies based on refugee status (e.g. Government Assistant Refugees vs. Non-), resulting in hidden costs for refugee patients According to the United States Office of Refugee Resettlement, an insurance called refugee Medical Assistance is available in the short term (up to 8 months), while other such as Medicaid and CHIP are available for several years.
  • Lack of transportation
  • A lack of public awareness and access to information about available resources
  • An unfamiliarity with the host country's healthcare system, amplified by a shortage of government or community intervention in settlement services
Structural deterrents for healthcare professionals:
  • Heightened instances of mental health complications in refugee populations
  • A lack of documented medical history, which makes comprehensive care difficult
  • Time constraints: medical appointments are restricted to a small window of opportunity, making it difficult to connect and provide mental healthcare for refugees
  • Complicated insurance plans, resulting in a delay in compensation for the healthcare provider

Health education

The World Association of Girl Guides and Girl Scouts (WAGGGS) and Family Health International (FHI) have designed and piloted a peer-centered education program for adolescent refugee girls in Uganda, Zambia, and Egypt. The goal of the program was to reach young women who were interested in being informed about reproductive health issues. The program was split into three age-specific groups: girls aged seven to 10 learned about bodily changes and anatomy; girls aged 11 to 14 learned about sexually transmitted diseases; girls aged 15 and older focused on tips to ensure a healthy pregnancy and to properly care for a baby. According to qualitative surveys, increased self-esteem and greater use of health services among the program's participants were the largest benefits of the program.

Education

This section covers education throughout the different stages of the refugee experience. The report, "Left Behind: Refugee Education in Crisis," compares UNHCR sources and statistics on refugee education with data on school enrollment around the world provided by UNESCO, the United Nations Educational, Scientific, and Cultural Organization. The report notes that, globally, 91 percent of children attend primary school. For all refugees, that figure is at 61 percent. Specifically in low-income countries, less than 50 percent of refugees are able to attend primary school. As refugee children get older, school enrollment rates drop: only 23 percent of refugee adolescents are enrolled in secondary school, versus the global figure of 84 percent. In low-income countries, nine percent of refugees are able to go to secondary school. Across the world, enrollment in tertiary education stands at 36 percent. For refugees, the percentage remains at one percent.

Adapting to a new school environment is a major undertaking for refugee children who arrive in a new country or refugee camp. Education is crucial for the sufficient psychosocial adjustment and cognitive growth of refugee children. Due to these circumstances, it is important that educators consider the needs, obstacles, and successful educational pathways for children refugees.

Graham, Minhas, and Paxton (2016) note in their study that parents' misunderstandings about educational styles, teachers' low expectations and stereotyping tendencies, bullying and racial discrimination, pre-migration and post-migration trauma, and forced detention can all be risk factors for learning problems in refugee children. They also note that high academic and life ambition, parents' involvement in education, a supportive home and school environment, teachers' understanding of linguistic and cultural heritage, and healthy peer relationships can all contribute to a refugee child's success in school. While the initial purpose of refugee education was to prepare students to return to their home countries, now the focus of American refugee education is on integration.

Access to education

Structure of the education system

Schools in North America lack the necessary resources for supporting refugee children, particularly in negotiating their academic experience and in addressing the diverse learning needs of refugee children. Complex schooling policies that vary by classroom, building and district, and procedures that require written communication or parent involvement intimidate the parents of refugee children. Educators in North America typically guess the grade in which refugee children should be placed because there is not a standard test or formal interview process required of refugee children.

Sahrawi refugee children learning Arabic and Spanish, math, reading and writing, and science subjects.
 
The ability to enroll in school and continue one's studies in developing countries is limited and uneven across regions and settings of displacement, particularly for young girls and at the secondary levels. The availability of sufficient classrooms and teachers is low and many discriminatory policies and practices prohibit refugee children from attending school. Educational policies promoting age-caps can also be harmful to refugee children.

Many refugee children face legal restrictions to schooling, even in countries of first asylum. This is the case especially for countries that have not signed the 1951 Refugee Convention or its 1967 Protocol. The 1951 Convention and 1967 Protocol both emphasize the right to education for refugees, articulating the definition of refugeehood in international contexts. Nevertheless, refugee students have one of the lowest rates of access to education. The UNHCR reported in 2014 that about 50 percent of refugee children had access to education compared to children globally at 93 percent. In countries where they lack official refugee status, refugee children are unable to enroll in national schools. In Kuala Lumpur, Malaysia, unregistered refugee children described being hesitant to go to school, due to risk of encountering legal authorities at school or while on the way to and from school.

Structure of classes

Student-teacher ratios are very high in most refugee schools, and in some countries, these ratios are nearly twice the UNCHR guideline of 40:1. Although global policies and standards for refugee settings endorse child-centered teaching methods that promote student participation, teacher-centered instruction often predominates in refugee classrooms. Teachers lecture for the majority of the time, offering few opportunities for students to ask questions or engage in creative thinking. In eight refugee-serving schools in Kenya, for example, lecturing was the primary mode of instruction.

In order to address the lack of attention to refugee education in national school systems, the UNHCR developed formal relationships with twenty national ministries of education in 2016 to oversee the political commitment to refugee education at the nation-state level. The UNCHR introduced an adaptive global strategy for refugee education with the aim of "integration of refugee learners within national system where possible and appropriate and as guided by ongoing consultation with refugees".

Residence

Refugee children who live in large urban centers in North America have a higher rate of success at school, particularly because their families have greater access to additional social services that can help address their specific needs. Families who are unable to move to urban centers are at a disadvantage. Children with unpredictable migration trajectories suffer most from a lack of schooling because of a lack of uniform schooling in each of their destinations before settling.

Language barriers and ethnicity

Acculturation stress occurs in North America when families expect refugee youth to remain loyal to ethnic values while mastering the host culture in school and social activities. In response to this demand, children may over-identify with their host culture, their culture of origin, or become marginalized from both. Insufficient communication due to language and cultural barriers may evoke a sense of alienation or "being the other" in a new society. The clash between cultural values of the family and popular culture in mainstream Western society leads to the alienation of refugee children from their home culture.

Many Western schools do not address diversity among ethnic groups from the same nation or provide resources for specific needs of different cultures (such as including halal food in the school menu). Without successfully negotiating cultural differences in the classroom, refugee children experience social exclusion in their new host culture. The presence of racial and ethnic discrimination can have an adverse effect on the well-being of certain groups of children and lead to a reduction in their overall school performance. For instance, cultural differences place Vietnamese refugee youth at a higher risk of pursuing disruptive behaviour. Contemporary Vietnamese American adolescents are prone to greater uncertainties, self-doubts and emotional difficulties than other American adolescents. Vietnamese children are less likely to say they have much to be proud of, that they like themselves as they are, that they have many good qualities, and that they feel socially accepted.

Classes for refugees, more often than not, are taught in the host-country language. Refugees in the same classroom may also speak several different languages, requiring multiple interpretations; this can slow the pace of overall instruction. Refugees from the Democratic Republic of Congo living in Uganda, for example, had to transition from French to English. Some of these children were placed in lower-level classes due to their lack of English proficiency. Many older children therefore had to repeat lower-level classes, even if they had already mastered the content. Using the language of one ethnic group as the instructional language may threaten the identity of a minority group.

The content of the curriculum can also act as a form of discrimination against refugee children involved in the education systems of first asylum countries. Curricula often seem foreign and difficult to understand to refugees who are attending national schools alongside host-country nationals. For instance, in Kakuma refugee camp in Kenya, children described having a hard time understanding concepts that lacked relevance to their lived experiences, especially concepts related to Kenyan history and geography. Similarly, in Uganda, refugee children from the Democratic Republic of Congo studying together with Ugandan children in government schools did not have opportunities in the curriculum to learn the history of their home country. The teaching of one-sided narratives, such as during history lessons, can also threaten the identity of students belonging to minority groups.

Vietnamese refugee mother and children at a kindergarten in upper Afula, 1979.

Other obstacles

Although high-quality education helps refugee children feel safe in the present and enable them to be productive in the future, some do not find success in school. Other obstacles may include:
  • Disrupted schooling - refugee children may experience disruptive schooling in their country of origin, or they may receive no form of education at all. It is extremely difficult for a student with no previous education to enter a school full of educated children.
  • Trauma - can impede the ability to learn and cause fear of people in positions of authority (such as teachers and principals)
  • School drop outs - due to self-perceptions of academic ability, antisocial behaviour, rejection from peers and/or a lack of educational preparation prior to entering the host-country school. School drop outs may also be caused by unsafe school conditions, poverty, etc.
  • Parents - when parental involvement and support are lacking, a child's academic success decreases substantially. Refugee parents are often unable to help their children with homework due to language barriers. Parents often do not understand the concept of parent-teacher meetings and/or never expect to be a part of their child's education due to pre-existing cultural beliefs.
  • Assimilation - a refugee child's attempt to quickly assimilate into the culture of their school can cause alienation from their parents and country of origin and create barriers and tension between the parent and child.
  • Social and individual rejection - hostile discrimination can cause additional trauma when refugee children and treated cruelly by their peers
  • Identity confusion
  • Behavioral issues - caused by the adjustment issues and survival behaviours learned in refugee camps

Role of teachers

North American schools are agents of acculturation, helping refugee children integrate into Western society. Successful educators help children process trauma they may have experienced in their country of origin while supporting their academic adjustment. Refugee children benefit from established and encouraged communication between student and teacher, and also between different students in the classroom. Familiarity with sign language and basic ESL strategies improves communication between teachers and refugee children. Also, non-refugee peers need access to literature that helps educate them on their refugee classmates experiences. Course materials should be appropriate for the specific learning needs of refugee children and provide for a wide range of skills in order to give refugee children strong academic support.

Educators should spend time with refugee families discussing previous experiences of the child in order to place the refugee child in the correct grade level and to provide any necessary accommodations School policies, expectations, and parent's rights should be translated into the parent's native language since many parents do not speak English proficiently. Educators need to understand the multiple demands placed on parents (such as work and family care) and be prepared to offer flexibility in meeting times with these families.

Academic adjustment of refugee children

Syrian refugee children attend a lesson in a UNICEF temporary classroom in northern Lebanon, July 2014
 
Teachers can make the transition to a new school easier for refugee children by providing interpreters. Schools meet the psychosocial needs of children affected by war or displacement through programs that provide children with avenues for emotional expression, personal support, and opportunities to enhance their understanding of their past experience. Refugee children benefit from a case-by-case approach to learning, because every child has had a different experience during their resettlement. Communities where the refugee populations are bigger should work with the schools to initiate after school, summer school, or weekend clubs that give the children more opportunities to adjust to their new educational setting.

Bicultural integration is the most effective mode of acculturation for refugee adolescents in North America. The staff of the school must understand students in a community context and respect cultural differences. Parental support, refugee peer support, and welcoming refugee youth centers are successful in keeping refugee children in school for longer periods of time. Education about the refugee experience in North America also helps teachers relate better with refugee children and understand the traumas and issues a refugee child may have experienced.

Refugee children thrive in classroom environments where all students are valued. A sense of belonging, as well as ability to flourish and become part of the new host society, are factors predicting the well-being of refugee children in academics. Increased school involvement and social interaction with other students help refugee children combat depression and/or other underlying mental health concerns that emerge during the post-migration period.

Peace education

Implemented by UNICEF from 2012 to 2016 and funded by the Government of the Netherlands, Peacebuilding, Education, and Advocacy (PBEA) was a program that tested innovative education solutions to achieve peacebuilding results. The PBEA program in Kenya's Dadaab refugee camp aimed to strengthen resilience and social cohesion in the camp, as well as between refugees and the host community. The initiative was composed of two parts: the Peace Education Programme (PEP), an in-school program taught in Dadaab's primary schools, and the Sports for Development and Peace (SDP) program for refugee adolescents and youth. There was anecdotal evidence of increased levels of social cohesion from participation in PEP and potential resilience from participation in SDP.

Peace education for refugee children may also have limitations and its share of opponents. Although peace education from past programs involving non-refugee populations reported to have had positive effects, studies have found that the attitudes of parents and teachers can also have a strong influence on students' internalization of peace values. Teachers from Cyprus also resisted a peace education program initiated by the government. Another study found that, while teachers supported the prospect of reconciliation, ideological and practical concerns made them uncertain about the effective implementation of a peace education program.

Pedagogical Approaches

Refugees fall into a unique situation where the nation-state may not adequately address their educational needs, and the international relief system is tasked with the role of a "pseudo-state" in developing a curriculum and pedagogical approach. Critical pedagogical approaches to refugee education address the phenomenon of alienation that migrant students face in schools outside of their home countries, where the positioning of English language teachers and their students create power dynamics emphasizing the inadequacies of foreign-language speakers, intensified by the use of compensatory programs to cater to 'at-risk' students. In order to adequately address state-less migrant populations, curricula has to be relevant to the experiences of transnational youth. Pedagogical researchers and policy makers can benefit from lessons learned through participatory action research in refugee camps, where student cited decreased self-esteem associated with a lack of education.

Disabilities

Children with disabilities frequently suffer physical and sexual abuse, exploitation, and neglect. They are often not only excluded from education, but also not provided the necessary supports for realizing and reaching their full potential. 

In refugee camps and temporary shelters, the needs of children with disabilities are often overlooked. In particular, a study surveying Bhutanese refugee camps in Nepal, Burmese refugee camps in Thailand, Somali refugee camps in Yemen, the Dadaab refugee camp for Somali refugees in Kenya, and camps for internally displaced persons in Sudan and Sri Lanka, found that many mainstream services failed to adequately cater to the specific needs of children with disabilities. The study reported that mothers in Nepal and Yemen have been unable to receive formulated food for children with cerebral palsy and cleft palates. The same study also found that, although children with disabilities were attending school in all surveyed countries, and refugee camps in Nepal and Thailand have successful programs that integrate children with disabilities into schools, all other surveyed countries have failed to encourage children with disabilities to attend school. Similarly, Syrian parents consulted during a four-week field assessment conducted in northern and eastern Lebanon in March 2013 reported that, since arriving in Lebanon, their children with disabilities had not been attending school or engaging in other educational activities. In Jordan, too, Syrian refugee children with disabilities identified lack of specialist educational care and physical inaccessibility as the main barriers to their education.

Likewise, limited attention is being given to refugee children with disabilities in the United Kingdom. It was reported in February 2017 that its government has decided to partially suspend the Vulnerable Children's Resettlement Scheme, originally set to resettle 3,000 children with their families from countries in the Middle East and North Africa. As a result of this suspension, no youth with complex needs, including those with disabilities and learning difficulties, would be accepted into the program until further notice.

Countries may often overlook refugee children with disabilities with regards to humanitarian aid, because data on refugee children with disabilities are limited. Roberts and Harris (1990) note that there is insufficient statistical and empirical information on disabled refugees in the United Kingdom. While it was reported in 2013 that 26 percent of all Syrian refugees in Jordan had impaired physical, intellectual, or sensory abilities, such data specifically for children do not exist.

Discovery and development of non-nucleoside reverse-transcriptase inhibitors

From Wikipedia, the free encyclopedia
Non-nucleoside reverse-transcriptase inhibitors (NNRTIs) are antiretroviral drugs used in the treatment of human immunodeficiency virus (HIV). NNRTIs inhibit reverse transcriptase (RT), an enzyme that controls the replication of the genetic material of HIV. RT is one of the most popular targets in the field of antiretroviral drug development.

Discovery and development of NNRTIs began in the late 1980s and in the end of 2009 four NNRTI had been approved by regulatory authorities and several others were undergoing clinical development. Drug resistance develops quickly if NNRTIs are administered as monotherapy and therefore NNRTIs are always given as part of combination therapy, the highly active antiretroviral therapy (HAART).

History

Acquired immunodeficiency syndrome (AIDS) is a leading cause of death in the world. It was identified as a disease in 1981. Two years later the etiology agent for AIDS, the HIV was described. HIV is a retrovirus and has two major serotypes, HIV-1 and HIV-2. The pandemic mostly involves HIV-1 while HIV-2 has lower morbidity rate and is mainly restricted to western Africa.

In the year 2009 over 40 million people were infected worldwide with HIV and the number keeps on growing. The vast majority of infected individuals live in the developing countries.

HIV drugs do not cure HIV infection, but the treatment aims at improving the quality of patients´ lives and decreased mortality

25 antiretroviral drugs were available in 2009 for the treatment of HIV infection. The drugs belong to six different classes that act at different targets. The most popular target in the field of antiretroviral drug development is the HIV-1 reverse transcriptase (RT) enzyme. There are two classes of drugs that target the HIV-1 RT enzyme, nucleoside/nucleotide reverse-transcriptase inhibitors (NRTIs/NtRTIs) and non-nucleoside reverse-transcriptase inhibitors (NNRTIs). Drugs in these classes are important components of the HIV combination therapy called highly active antiretroviral therapy, better known as HAART.

In 1987, the first drug for the treatment of HIV infection was approved by the U.S. Food and Drug Administration (FDA). This was the NRTI called zidovudine. In the late 1980s, during further development of NRTIs, the field of NNRTIs discovery began. The development of NNRTIs improved quickly into the 1990s and they soon became the third class of antiretroviral drugs, following the protease inhibitors.

The NNRTIs are HIV-1 specific and have no activity against HIV-2 and other retroviruses. The first NNRTI, nevirapine was discovered by researchers at Boehringer Ingelheim and approved by the FDA in 1996. In the next two years two other NNRTIs were approved by the FDA, delavirdine in 1997 and efavirenz in 1998. These three drugs are so-called first generation NNRTIs. The need for NNRTIs with better resistance profile led to the development of the next generation of NNRTIs. Researchers at Janssens Foundation and Tibotec discovered the first drug in this class, etravirine, which was approved by the FDA in 2008. The second drug in this class, rilpivirine, was also discovered by Tibotec and was approved by the FDA in 2011. In addition to these four NNRTIs several other are in clinical development.

The HIV-1 reverse transcriptase enzyme

Figure 1 This ribbon representation of the RT active domain (i.e. the p66 monomer) illustrates its hand-like structure, showing fingers (blue), palm (pink) and thumb (green). The active site (red atoms), where DNA is elongated, is in the palm region. Also shown is an NNRTI drug (yellow) in the pocket where it binds.

Function

Reverse transcriptase (RT) is an enzyme that controls the replication of the genetic material of HIV and other retroviruses. The enzyme has two enzymatic functions. Firstly it acts as a polymerase where it transcribes the single-stranded RNA genome into single-stranded DNA and subsequently builds a complementary strand of DNA. This provides a DNA double helix which can be integrated in the host cell's chromosome. Secondly it has ribonuclease H (Rnase H) activity as it degrades the RNA strand of RNA-DNA intermediate that forms during viral DNA synthesis.

Structure

The HIV-1 RT is an asymmetric 1000-amino acid heterodimer composed of p66 (560 amino acids) and p51 subunits (440 amino acids). The p66 subunit has two domains, a polymerase and ribonuclease H. The polymerase domain contains four subdomains, which have been termed “fingers”, “palm”, “thumb” and “connection” and it is often compared to a right hand (figure 1). The role of the p66 subunit is to carry out the activity of RT whereas it contains the active sites of the enzyme. The p51 is believed to play mainly a structural role.

Binding and pharmacophore

Despite the chemical diversity of NNRTIs they all bind at the same site in the RT. The binding occurs allosterically in a hydrophobic pocket located approximately 10 Å from the catalytic site in the palm domain of the p66 subunit site of the enzyme. The NNRTI binding pocket (NNIBP) contains five aromatic (Tyr-181, Tyr-188, Phe-227 and Trp-229), six hydrophobic (Pro-59, Leu-100, Val-106, Val-179, Leu-234 and Pro-236) and five hydrophilic (Lys-101, Lys-103, Ser-105, Asp-132 and Glu-224) amino acids that belong to the p66 subunit and additional two amino acids (Ile-135 and Glu-138) belonging to the p51 subunit. Each NNRTI interacts with different amino acid residues in the NNIBP.

Figure 2 Chemical structure of nevirapine and the two wings.
 
An important factor in the binding of the first generation NNRTIs, such as nevirapine, is the butterfly-like shape. Despite their chemical diversity they assume very similar butterfly-like shape. Two aromatic rings of NNRTIs conform within the enzyme to resemble the wings of a butterfly (figure 2). The butterfly structure has a hydrophilic centre as a ‘body’ and two hydrophobic moieties representing the wings. Wing I is usually a heteroaromatic ring and wing II is a phenyl or allyl substituent. Wing I has a functional group at one side of the ring which is capable of accepting and/or donating hydrogen bonds with the main chain of the amino acids Lys-101 and Lys-103. Wing II interacts through π-π interactions with a hydrophobic pocket, formed in most part by the side chains of aromatic amino acids. On the butterfly body a hydrophobic part fills a small pocket which is mainly formed by the side chains of Lys-103, Val-106 and Val-179. However many other NNRTIs have been found to bind to RT in different modes. Second generation NNRTIs such as diarylpyrimidins (DAPYs), have a horseshoe-like shape with two lateral hydrophobic wings and a pyrimidine ring which is the central polar part.

The NNIBP is elastic and the conformation depends on the size, specific chemical composition and binding mode of the NNRTI. The total structure of RT has segmental flexibility that depends on the nature of the bound NNRTI. It's important for the inhibitor to have flexibility to be able to bind in the modified pockets of a mutant target. Inhibitor flexibility may not affect the inhibitor-target interactions.

Mechanism of action

Figure 3 Non-nucleside reverse-transcriptase inhibitors (NNRTIs) inhibit the reverse-transcriptase enzyme (RT) and therefore the replication of new viruses
 
The NNRTIs act by binding non-competitively to the RT enzyme (figure 3). The binding causes conformational change in the three-dimensional structure of the enzyme and creates the NNIBP. Binding of NNRTI to HIV-1 RT makes the p66 thumb domain hyper extended because it induces rotamer conformation changes in amino acid residues Tyr-181 and Tyr-188. This affects the catalytic activity of the enzyme and blocks the HIV-1 replication by inhibiting the polymerase active site of the RT's p66 subunit. The global conformational change additionally destabilizes the enzyme on its nucleic acid template and reduces its ability to bind nucleotides. The transcription of the viral RNA is inhibited and therefore the replication rate of the virus reduces. Although the exact molecular mechanism is still hypothetical this has been demonstrated by multiple studies to be the primary mechanism of action.

In addition to this proposed primary mechanism of action it has been shown that the NNRTIs have other mechanisms of action and interfere with various steps in the reverse transcriptase reaction. It has been suggested that the inhibition of reverse transcription by the NNRTIs may be due to effects on the RT Rnase H activity and/or template/primer binding. Some NNRTIs interfere with HIV-1 Gag-Pol polyprotein processing by inhibiting the late stage of HIV-1 replication.

It is important to gain profound understanding of the various mechanism of action of the NNRTIs in order to develop next-generation NNRTIs and for understanding the mechanism of drug resistance.

Drug discovery and design

The development of effective anti-HIV drugs is difficult due to wide variations in nucleotide and amino acid sequences. The perfect anti-HIV drug chemical should be effective against drug resistance mutation. Understanding the target RT enzyme and its structure, mechanism of drug action and the consequence of drug resistance mutations provide useful information which can be helpful to design more effective NNRTIs. The RT enzyme can undergo change due to mutations that can disturb NNRTI binding.

Discovery

The first two classes of compounds that were identified as NNRTIs were the 1-(2-2-hydroxyethoxymethyl)-6-(phenylthio)thymine (HEPT) and tetrahydroimidazo[4,5,1-jkj][1,4]benzodiazepin-2(1H)-one and -thione (TIBO) compounds. The discovery of the TIBO compounds led to the definition of the NNRTI class in the late 1980s when they were unexpectedly found to inhibit RT. This finding initiated researches on mechanism of action for these compounds. The HEPT compounds were described before the TIBO compounds and were originally believed to be NRTIs. Later it was discovered that they shared common mechanism of action with the TIBO compounds. Both the HEPT and TIBO compounds were first to be identified as highly specific and potent HIV-1 RT inhibitors, not active against other RTs. These compounds do not interrupt the cellular or mitochondrial DNA synthesis. The specificity of the NNRTIs for HIV-1 is considered the hallmark of the NNRTI drug class.

Development

First generation NNRTIs

After the discovery of HEPT and TIBO, compounds screening methods were used to develop BI-RG-587, the first NNRTI commonly known as nevirapine. Like HEPT and TIBO, nevirapine blocked viral RT activity by non-competitive inhibition (with respect to dNTP binding). This reinforced the idea that the new class of anti-HIV inhibitors was inhibiting the activity of RT but not at the active site. Several molecular families of NNRTIs have emerged following screening and evolution of many molecules.

Three NNRTI compounds of the first generation have been approved by the FDA for treating HIV-1 infection. Nevirapine was approved in 1996, delavirdine in 1997 and efavirenz in 1998 (table 1). Two of these drugs, nevirapine and efavirenz, are cornerstones of first line HAART while delavirdine is hardly used nowadays. The structure of these three drugs show the wide array of rings, substituents, and bonds that allow activity against HIV-1 RT. This diversity demonstrates why so many non-nucleosides have been synthesised but doesn't explain why only three drugs have reached the market. The main problem has been the potency of these compounds to develop resistance.
Development from α-APA to ITU
Figure 4 The development from α-APA to ITU
 
Crystal structure analysis showed that the first generation NNRTIs (for example TIBO, nevirapine and α-APA) bind HIV-1 RT in a “butterfly-like” conformation. These first generation NNRTIs were vulnerable against the common drug-resistance mutations like Tyr-181C and Tyr-188L/H. This triggered the need for finding new and more effective NNRTIs. ITU (imidoylthiourea), a promising series of NNRTIs emerged from α-APA analogs (figure 4). The ITU compounds were obtained by extending the linker that binds the aryl side groups of the α-APA. A potent ITU compound, R100943, was obtained by an arrangement of the chemical composition of the side groups based on structure-activity relationships (SAR). A crystal structure of the HIV-1/R100943 complex demonstrated that ITU compounds are more flexible than α-APA compound. The ITU compounds showed distinct mode of binding where they bound with "horseshoe" or "U" mode. The 2,6-dichlorophenyl part of R100943 which corresponds chemically to the wing II 2,6-dibromophenyl part of the α-APA occupied the wing I part in the NNIBP whereas the 4-cyanoanilino part of R100943 occupies the wing II position in the NNIBP.

R100943 inhibited HIV-1 and was considerably effective against a number of key NNRTI-resistant mutants like G190A mutation, which caused high-level resistance to loviride (α-APA) and nevirapine. G190A mutation was thought to cause resistance by occupying a part of the binding pocket that would otherwise be filled by the linker part of the butterfly shaped NNRTIs. R100943, in the horseshoe mode of binding, is located at a distance of approximately 6.0 Å from G190. When compared with nevirapine and loviride which bind in the butterfly shape the ITU derivatives revealed improved activity against Tyr-181C and Tyr-188L mutants. A structural study suggested that a potent TIBO compound could partly supplement for the effects of the Tyr-181C mutation by moving itself in the non-nucleoside inhibitor binding pocket (NNIBP) of the mutant RT. In this context, R100943 has torsional freedom that enables the conformational alternations of the NNRTI. This torsional freedom could be used by the ITU derivate to bind to a mutated NNIBP and thus compensating for the effects of a resistance mutation. Nevertheless, the potency of R100943 against HIV-1 resistant mutants was not adequate for it to be considered as an effective drug candidate. Additionally, the chemical stability of the imidoylthiourea part of the ITU derivative was not favorable for an oral drug.
Development from ITU to DATA
Figure 5 Chemical substitutions of the DAPY series were made to obtain the highly potent etravirine
 
Changes in the imidoylthiourea complexes led to the synthesis of a new class of compounds, diaryltriazine (DATA). In these compounds, the thiourea part of the ITU compounds was replaced by a triazine ring. The DATA compounds were more potent than the ITU compounds against common NNRTI resistant mutant strains. R106168, a prototype DATA compound, was rather easy to synthesize. Multiple substitutions were made at different positions on all of the three rings and on the linkers connecting the rings. In the pocket, most of the DATA derivatives conformed a horseshoe conformation. The two wings in R106168 (2,6-dichlorobenzyl and 4-cyanoanilino) occupied positions in the pocket similar to that of the two wings of the derivatives of ITU. The central part of the DATA compounds, in which the triazine ring replaced the thiourea group of ITU derivatives, is positioned between the side chains of L100 and V179. This removed a number of torstional degrees of freedom in the central part while keeping the flexibility between the triazine ring and the wings.

Chemical substitution or modification in the three-aromatic-ring backbone of the DATA compounds had substantial effect on the activity. R120393, a DATA analog, was designed with a chloroindole part in wing I to expand interactions with the side chain of conserved W229 of the polymerase primer grip loop. R120393 had similar effect as R106168 against most of the NNRTI-resistant mutants. The cloroindole part interacted with the hydrophobic core of the pocket and influenced the binding mode of the R120393 so it went deeper into the pocket compared to the wing I position of other DATA analogs. Crystal structures showed that the DATA compounds could bind the NNIBP in different conformations. The capability to bind in multible modes made the NNRTIs stronger against drug-resistance mutations. Variability between the inhibitors could be seen when the chemical composition, size of wing I and the two linker groups connecting the rings were altered. The potency of the NNRTIs changed when the triazine nitrogen atoms were substituted with carbons.

Next generation NNRTIs

Researchers used multi-disciplinary approach to design NNRTIs with better resistance profile and an increased genetic barrier to the development of resistance. A new class of compounds, diarylpyrimide (DAPY), were discovered with the replacement of the central triazine ring from the DATA compounds, with a pyrimidine. This new class was more effective against drug resistant HIV-1 strains than the corresponding DATA analogs. The replacement enabled substitutions to the CH-group at the 5-position of the central aromatic ring. One of the first DAPY compounds, dapivirine (with R1= 2,4,6-trimethylanilino, R2 = R3 = H and Y = NH) was found to be effective against drug-resistant HIV-1 strains. Systematic chemical substitutions were made at the R1, R2, R3 and Y positions to find new DAPY derivatives. This led to the discovery of etravirine which has a bromine substitution at the 5-position (R3) of the pyrimidine ring (with R1 = 2,6-dimethyl-4-cyanoanilino, R2 = NH2 and Y = O) (figure 5). Etravirine was discovered by researchers at the Jansen Research Foundation and Tibotec and approved in 2008 by the FDA. It is used in treatment-expirenced adult patients with HIV infection that is multidrug resistant in combination with other antiretroviral drugs.

Resistance

When treating infection, whether bacterial or viral, there is always a risk of the infectious agent to develop drug resistance. The treatment of HIV infection is especially susceptible to drug resistance which is a serious clinical concern in the chemotherapeutic treatment of the infection. Drug resistant HIV-strains emerge if the virus is able to replicate in the presence of the antiretroviral drugs.

NNRTI-resistant HIV-strains have the occurring mutations mainly in and around the NNIBP affecting the NNRTI binding directly by altering the size, shape and polarity on different areas of the pocket or by affecting, indirectly, the access to the pocket. Those mutations are primarily noted in domains which span amino acids 98-108, 178-190 or 225-238 of the p66 subunit. The most frequent mutations observed in viruses isolated from patients who have been on a failing NNRTI containing chemotherapy are Lys-103N and Tyr-181C. NNRTI resistance has been linked to over 40 amino acid substitutions in vitro and in vivo.

Antiretroviral drugs are never used in monotherapy due to rapid resistance development. The highly active antiretroviral therapy (HAART) was introduced in 1996. The treatment regimen combines three drugs from at least two different classes of antiretroviral drugs.

The advance of etravirine over other NNRTIs is that multiple mutations are required for the development of drug resistance. The drug has also shown activity against viruses with common NNRTI resistance associated mutations and cross-resistance mutations.

Current status

Five drugs in the class of NNRTIs have been approved by regulatory authorities. These are the first generation NNRTIs nevirapine, delavirdine and efavirenz and the next generation NNRTIs etravirine, and rilpivirine. Several other NNRTIs underwent clinical development but were discontinued due to unfavourable pharmacokinetic, efficacy and/or safety factors. Currently there are four other NNRTIs undergoing clinical development, IDX899, RDEA-428 and lersivirine (table 2).

Rilpivirine

Rilpivirine is a DAPY compound like etravirine and was discovered when further optimization within this family of NNRTIs was conducted. The resistance profile and the genetic barrier to the development of resistance is comparable to etravirine in vitro. The advantage of rilpivirine over etravirine is a better bioavailability and it is easier to formulate than etravirine. Etravirine has required extensive chemical formulation work due to poor solubility and bioavailability. Rilpivirine was undergoing phase III clinical trials in the end of 2009. Rilpivirine was approved by the FDA for HIV therapy in May 2011 under the brand name Edurant. Edurant is approved for treatment-naive patients with a viral load of 100,000 copies/mL or less at therapy initiation. Its recommended dosage is 25 mg orally once daily with a meal, in combination with other antiretrovirals. It is contraindicated for use with proton pump inhibitors due to the increased gastric pH causing decreased rilpivirine plasma concentrations, potentially resulting in loss of virologic response and possible resistance. A fixed-dose drug combining rilpivirine with emtricitabine and tenofovir disoproxil (TDF), was approved by the U.S. Food and Drug Administration in August 2011 under the brand name Complera. A newer fixed-dose drug also combining rilpivirine with emtricitabine and tenofovir alafenamide (TAF) was approved in March 2016 under the brand name Odefsey.

RDEA806

In 2007 a new family of triazole NNRTIs was presented by researchers from the pharmaceutical company Ardea Biosciences. The selected candidate from the screening executed was RDEA806 belonging to the family of triazoles. It has similar resistance profile against selected NNRTI resistant HIV-1 strains to other next generation NNRTIs. The candidate entered phase IIb clinical trials in the end of 2009, but no further trial have been initiated. Ardea was sold to AstraZeneca in 2012.

Fosdevirine (IDX899)

Fosdevirine (also known as IDX899 and GSK-2248761) is another next generation NNRTI developed by Idenix Pharmaceuticals and ViiV Healthcare. It belongs to the family of 3-phosphoindoles. In vitro studies have shown comparable resistance profile to that of the other next generation NNRTIs. In November 2009 the candidate entered phase II clinical trials, but the trial and all further development was halted when 5 of 35 subjects receiving fosdevirine experienced delayed-onset seizures.

Lersivirine (UK-453061)

Lersivirine belongs to the pyrazole family and is another next generation NNRTI in clinical trials developed by the pharmaceutical company ViiV Healthcare. The resistance profile is similar to that of other next generation NNRTIs. In the end of 2009 lersivirine was in phase IIb. In February 2013, ViiV Healthcare announced a stop of the development program investigating lersivirine.

Classical radicalism

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