CHAPTER ONE

INTRODUCTION

1.1. Background of the Study

More than one million children are infected with Human Immunodeficiency virus (HIV) worldwide. Development in therapies have made it possible for more than 65% of these infected children to leave past 5 years of age despite the rise in the rates of infection (Brown and Lourie, 2020). Globally, approximately 32.7 million deaths caused by AIDS-related illnesses have been recorded and 75.7 million people have become infected with HIV since the first confirmed cases were reported in 1981 (United Nations, 2020). HIV infection is a leading cause of mortality in resource-limited countries. AIDS-associated deaths and HIV transmission have been greatly reduced by antiretroviral therapy (ART) in HIV-infected patients (World Health Organization, 2021).    

Antiretroviral therapy is a life-preserving treatment for patients with HIV/AIDS which is designed to suppress viral load, restore immune function, improve quality of life, and reduce morbidity and mortality. Failure of an ART is diagnosed by monitoring the patient’s viral load as the standard method (Wisaksana et al., 2024). This failure which may be caused by restricted access to routine viral load surveillance can cause drug resistance, toxicity, high viral load, high risk of second-line failure, and risk of morbidity and mortality (Desalegn et al., 2021). Evaluation of antiretroviral therapy is not regularly done in all healthcare facilities because of the unavailability of viral load tests and cost-related issues. HIV drug resistance is caused by changes or mutations in the viral genome which affect the ability of antiretroviral drugs to block replication of the virus. All current ARV drugs, including newer classes, are at risk of becoming partly or fully inactive because of the emergence of drug-resistant viral variants. When HIV replicates in the presence of ARV drugs, drug-resistant HIV can be selected. HIV drug resistance can compromise the efficacy of ARV drugs for HIV prevention and treatment, contributing to a rise in HIV incidence, morbidity and mortality (World Health Organization, 2022).

 The elimination of HIV is greatly dependent on the use of combinations of antiretroviral (ARV) drugs to inhibit HIV replication in people infected with the disease, thereby serving the purpose of improving the health of infected individuals and preventing the spread of the disease to other people. Despite this, HIV can still develop ARV drug-associated resistance mutations (DRMs), which can reduce antiretroviral therapy (ART) efficacy (Yeganeh et al., 2018). Following the receipt of ARV drugs, DRMs can be developed and can also spread during primary infection in people who have not been exposed before. HIV DRMs can also be transmitted from mother to infant during pregnancy when the mother is not on any active ART which can suppress the viral replication (Yeganeh et al., 2018).

The selection of viruses carrying drug resistance mutations (DRMs) to antiretrovirals (ARVs) in infected neonates can result from the use of ART in HIV-infected mothers and prophylaxis in HIV-exposed newborns to prevent mother-to-child transmission of HIV (Yeganeh et al., 2018). The prevalence of DRMs and the risk of virological failure are higher in children and adolescents than in adults as a result of this selection along with other factors like adherence failures, suboptimal blood drug levels or inadequate regimens (Boerma et al., 2016). In low and middle income countries, where ARV options are limited and accurate HIV surveillance is absent, there is a high risk of acquiring drug resistant viruses, which is a cause for concern. Most HIV infected children and adolescents live in these countries (United Nations, 2020). Increased rates of morbidity and mortality along with DRM accumulation result from patients spending months or years on failing ARV regimens due to the lack of resistance monitoring. Therefore, it is important to determine the rate at which resistant viruses circulate in a country in order to establish the most adequate first-line ART in naïve patients and optimize second-line ART in the patients who are on treatment and have good adherence, but yet face virological failure caused by the absence of viraemia control (United Nations, 2020). Since about one-third of the children infected with HIV around the world experience virological failure within the first two years of ART, it is important for HIV drug resistance (HIVDR) to be monitored when the disease is diagnosed and after there is treatment failure with good adherence (World Health Organization, 2016). A large population of children who were infected with HIV perinatally over the last ten years are now growing and maturing into adolescents. Also, most adolescents are highly susceptible to HIV infections, especially those living in regions with HIV epidemics (UNICEF, 2021).

There has been a significant decrease in the number of HIV related deaths recorded thanks to the introduction of antiretroviral therapy in resource-limited settings (RLS), especially those with the highest burden of HIV like sub- Saharan Africa (SSA) which is the most affected with approximately 70% out of 37.9 million people infected worldwide. Furthermore, in SSA, approximately 80% of 1.8 million adolescents in the age gap 10-19 years live with perinatal or behaviorally acquired HIV Infection (Slogrove, 2018).  Despite this overall decrease in death rate, AIDS remains the leading cause of death among adolescents in SSA. This is particularly true for adolescents who acquire HIV as babies and survive to teen age (Ki-moon, 2015). Since 2010, AIDS related deaths have reduced by half in the general population, as compared to only 5% among adolescents. It is crucial for adequate measures to be taken to keep HIV infected children alive as they gradually grow into adolescence, to ensure a successful transition from pediatrics to adult care (Fatti et al., 2018). In addition to identifying the most suitable ART regimens for adolescents, it is important to understand challenges faced by these adolescents. These challenges may be due to individual, program and viral factors, which contribute to ART failure, emergence of HIV drug resistance, limited ART options and finally the continuous death of this vulnerable and tender population (World Health Organization, 2015).

Dolutegravir-based treatments

The World Health Organization (WHO) recommends Dolutegravir (DTG) as a component of first-line, second-line, and third-line antiretroviral therapy (ART) regimens due to its high efficacy and resistance barrier. DTG is often combined with Lamivudine and Tenofovir. Despite initial concerns about its potential teratogenic effects, the WHO has approved DTG as a preferred treatment option for all age groups, including women of childbearing age and pregnant women (Nwachukwu et al., 2023). However, studies have suggested a possible link between DTG and an increased risk of neural tube defects in infants born to mothers taking DTG at conception. As a result, some countries have opted for alternative regimens or recommended the use of effective contraception to prevent pregnancy in women taking DTG (Nwachukwu et al., 2023).

Recent clinical trials conducted in Africa have provided new data on the safety and efficacy of Dolutegravir (DTG). These studies have revealed a more favorable safety profile, with a significantly lower risk of neural tube defects compared to initial findings. The WHO’s HIV treatment guidelines have taken into account these new findings, as well as mathematical simulations of the benefits and risks associated with DTG and other antiretroviral drugs. The guidelines also considered factors such as patient preference, implementation of HIV programs, and treatment costs. The updated 2019 guidelines reflect the advantages of DTG, including its high efficacy, ease of adherence, and lower side effect profile, making it a valuable option in the face of rising resistance to other antiretroviral drugs (Nwachukwu et al., 2023).

Dolutegravir has been shown to effectively manage liver-related issues, including elevated liver enzymes, hepatitis, and liver failure. As a precaution, patients should undergo liver enzyme testing before starting Dolutegravir therapy. The introduction of newer antiretroviral classes has significantly improved the efficacy and safety of HIV treatment. Dolutegravir has demonstrated comparable or superior efficacy to existing treatment regimens in both treatment-naïve and treatment-experienced patients. Its excellent tolerability, combined with its high efficacy, makes Dolutegravir a desirable treatment option for patients (Nwachukwu et al., 2023).

Tenofovir-Lamivudine-Dolutegravir (TLD) treatment in children and adolescents

The combination of tenofovir, lamivudine, and dolutegravir (TLD) has emerged as a highly effective antiretroviral therapy (ART) for treating HIV-infected children and adolescents (Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children, 2022). This regimen’s pharmacokinetic profile, ease of administration, and high genetic barrier to resistance make it an attractive option for this population (World Health Organization, 2021).

Efficacy

TLD’s effectiveness in achieving and maintaining viral suppression, improving CD4+ T-cell counts, and reducing HIV-related complications has been well-documented (Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children, 2022). Furthermore, TLD has demonstrated a favorable safety profile, with minimal adverse effects reported in clinical practice (World Health Organization, 2021).

Delutegravir-Based Regimens for HIV Treatment

Delutegravir-based regimens are now the preferred first-line and second-line treatment for HIV. They have been shown to be more effective, better tolerated, and less likely to lead to treatment discontinuation due to adverse events compared to other regimens, such as those containing efavirenz (Paul and Ugwu, 2020).

Benefits of Delutegravir-Based Regimens

– Rapid viral suppression

– Higher genetic barrier to resistance

– Effective against HIV strains resistant to other treatments

– Well-tolerated in various populations, including pregnant women and those with tuberculosis co-infection (Paul and Ugwu, 2020).

Availability and Affordability

Delutegravir-based regimens, such as TLD (tenofovir, lamivudine, and Dolutegravir), are now available at an affordable cost for low- and middle-income countries, with prices expected to decrease further as generic production increases (Paul and Ugwu, 2020).

Drug resistance emergence to TLD

While the emergence of drug resistance is a concern with any ART regimen, TLD’s high genetic barrier to resistance minimizes this risk (Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children, 2022). Regular monitoring of viral load and CD4+ T-cell counts, as well as adherence to treatment, are crucial in preventing the emergence of drug resistance (World Health Organization, 2021).

Risk factors for developing DRMs in children and adolescents  

The emergence of drug-resistant conditions in children and adolescents with HIV is a significant concern. Several factors increase the risk of developing drug resistance in this population.

Patient-Related Factors

1. Poor Adherence: Inconsistent or incomplete adherence to antiretroviral therapy (ART) regimens is a significant risk factor for developing drug resistance (World Health Organization, 2022).
2. Age and Developmental Stage: Children and adolescents may face unique challenges in adhering to treatment due to their developmental stage (Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children, 2022).
3. Genetic Factors: Genetic variations can affect drug metabolism or efficacy, increasing the risk of drug resistance (Hirsch et al., 2018).

Treatment-Related Factors

1. Suboptimal ART Regimens: Using ART regimens that are not optimized for the individual child or adolescent increases the risk of drug resistance (World Health Organization, 2022).
2. Monotherapy or Dual Therapy: Using monotherapy or dual therapy instead of combination therapy increases the risk of drug resistance (Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children, 2022).
3. Previous Exposure to ART: Children and adolescents who have been previously exposed to ART may be at increased risk of developing drug resistance (Hirsch et al., 2018).

Healthcare-Related Factors

1. Inadequate Monitoring: Inadequate monitoring of viral load, CD4+ T-cell counts, and drug resistance mutations increases the risk of drug resistance (World Health Organization, 2022).
2. Delayed Treatment Switching: Delayed switching to alternative ART regimens when treatment failure is detected increases the risk of drug resistance (Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children, 2022).
3. Lack of Access to Viral Load Testing: Limited access to viral load testing and drug resistance testing increases the risk of drug resistance (World Health Organization, 2022).
4. Lack of Training and Expertise: Healthcare providers who lack training and expertise in pediatric HIV care may not provide optimal treatment, increasing the risk of drug resistance (World Health Organization, 2022).
5. Inadequate Communication: Poor communication between healthcare providers, children, and adolescents can lead to misunderstandings about treatment regimens, increasing the risk of drug resistance (Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children, 2022).

Social and Economic Factors

1. Socioeconomic Status: Children and adolescents from low-income families may face challenges in accessing healthcare services, increasing the risk of drug resistance (World Health Organization, 2022).
2. Stigma and Discrimination: Children and adolescents who experience stigma and discrimination may be less likely to adhere to treatment, increasing the risk of drug resistance (Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children, 2022).
3. Food Insecurity: Children and adolescents who experience food insecurity may have difficulty adhering to treatment, increasing the risk of drug resistance (World Health Organization, 2022).

As HIVDR is a major concern in the era of global ART scale-up, the use of ARV drugs with a low-genetic barrier to resistance for treating HIV vertically infected adolescents in SSA suggests higher risk of virologic failure. This phenomenon becomes even more appealing in the frame of limited access to reference ART monitoring diagnostic facilities (World Health Organization, 2012). Thus, surveillance of HIVDR among adolescents would be useful in addressing preventable HIVDR and implementing corrective actions in resource-limited settings such as Cameroon (Fokam et al., 2020). It is in line with this that our study seeks to survey and address the risk factors of drug resistance in HIV-infected children and adolescents receiving Dolutegravir-based treatments in the Ndop and Tubah Health Districts.

1.2. Problem Statement

HIV infection is a leading cause of mortality in underdeveloped countries like Cameroon. The development of ARVs has played a huge role in reducing the death rate caused by this disease and also in combating the spread to susceptible individuals by reducing the viral load in infected patients. The development of drug-associated resistance mutations (DRMs) has led to HIV drug resistance which has caused these drugs to lose their efficacy. The development of DRMs and the risk of virological failure can be caused by factors like adherence failures, suboptimal blood drug levels or inadequate regimens. There have been many reported cases of infected mothers who were not on any effective ART transmitting the disease to their babies. HIV treatment in infected children and adolescents has become very challenging due to the emergence of HIV drug resistance. In the absence of effective ARVs, the viral load count rises putting HIV infected patients at greater risk of developing many opportunistic infections which can lead to AIDS and ultimately end in death. In Cameroon’s Ndop and Tubah health districts, HIV-infected children and adolescents on Dolutegravir-containing regimens like TLD face an emerging threat of drug resistance. Unpublished data from these hospitals have revealed a higher rate of virological failure among children and adolescents on first- and second-line ART. The HIV integrase inhibitor drug – Dolutegravir, was introduced in Cameroon sometime in 2019 as a combination therapy alongside Tenofovir and Lamivudine (TLD). There has been several reports on varying rates of drug resistance to Dolutegravir globally. As a result of limited resources, the drug resistance profiles and risk factors among those on TLD treatment are not well monitored in our study areas. With very limited research focusing on pediatric HIV care in this part of Cameroon, the prevalence and risk factors of resistance in children and adolescents remain poorly understood. Existing research places greater focus on adults and not much is being done on this demographic. This knowledge gap hinders effective treatment strategies, compromising the health and well-being of this vulnerable population, thereby affecting treatment effectiveness and public health. This study aims to investigate HIV drug resistance profiles and risk factors among children and adolescents on TLD treatment, addressing a critical and important need for targeted interventions.