CHAPTER ONEINTRODUCTION

1.1.     Background of the Study

HIV drug resistance can decrease the effectiveness of antiretroviral (ARV) drugs used for HIV treatment and prevention. This increase the prevalence of HIV, illness, and death. To inform public health interventions, the World Health Organization (WHO) recommends monitoring and surveillance of HIV drug resistance as part of comprehensive antiretroviral therapy (ART) and pre-exposure prophylaxis (PrEP) programs (World Health Organization, 2017). The World Health Organization recommends the integrase strand inhibitor – Dolutegravir (DTG)-based antiretroviral therapy (ART) as the preferred first- and second-line treatment, and more than 25 million people currently receive it. As part of the scale-up and maintenance of populations on ART, WHO recommends routinely implementing HIV drug resistance surveillance for DTG-based ART rollout to effectively manage and prevent potential drug resistance.

An increasing prevalence of non-nucleoside reverse transcriptase inhibitor (NNRTI) associated mutations in naïve and experienced patients as transmitted and acquired resistance, respectively, has led to global policy recommendations to adopt Integrase Strand Transfer Inhibitors (INSTIs) in first line regimens (Rutherford and Horvath, 2016). Dolutegravir is a potent second-generation INSTI with a high genetic barrier to resistance (Günthard et al., 2016; Vitoria et al., 2018). Before 2020, the ART strategy in several resource-limited settings (RLS), including Cameroon, was based on a public health approach that recommended the use of NNRTIs in combination with two NRTIs as a first-line regimen, ritonavir-boosted protease inhibitors (PI/r) in combination with two NRTIs as second-line, and ritonavir-boosted darunavir (DRV/r, a second-generation PI/r) and/or INSTI as third-line ART guided by genotyping (Moorhouse et al., 2019; Fokam et al. 2022) . DTG combined with Tenofovir and Lamivudine (abbreviated TLD) is a single tablet regimen recommended for 1st, 2nd and 3rd line public health ART. Today, most patients in Cameroon are receiving the renowned TLD regimen.

The rise of HIV drug resistance jeopardizes the United Nations’ aim to eradicate the HIV/AIDS pandemic by 2030 (Hamers, Rinke De Wit, and Holmes 2018). Increased access to antiretroviral therapy (ART) in low- and middle-income nations has significantly fueled this resistance (Gregson et al., 2016; Gupta et al. 2018). A common ART regimen, combining nucleo side reverse transcriptase inhibitors (NRTIs) tenofovir and emtricitabine with the non NRTI (NNRTI) efavirenz, included three drugs with low resistance barriers. Consequently, many people with HIV (PWH) experiencing treatment failure on this regimen developed resistance to both NRTIs and NNRTIs (Gupta et al. 2018). Furthermore, pretreatment drug resistance (PDR) has steadily risen. By 2016, NNRTI PDR surpassed 10% in Southern and Eastern Africa and neared this level in Latin America and the Caribbean. The WHO recommends altering the standard first-line ART regimen when NNRTI PDR reaches 10% (World Health Organization 2017a; 2017b). In response to widespread resistance, the WHO adopted dolutegravir (an integrase strand transfer inhibitor or INSTI) in 2019 as the preferred first- and second-line ART for all populations, including pregnant women (8). By mid-2022, over 100 nations had integrated dolutegravir into their treatment guidelines (Egger et al., 2024). Dolutegravir possesses a high genetic barrier to resistance (Cottrell, Hadzic, and Kashuba 2013; Llibre et al., 2015), and to date, few PWH have developed resistance (Scherrer et al., 2016; Pena et al., 2019; Cevik, Orkin, and Sax 2020). The specific mutations causing dolutegravir resistance can vary depending on prior treatment and HIV-1 subtype.

Over the past 20 years, the development of antiretroviral medications has transformed HIV from a deadly illness into a manageable chronic condition that can be controlled with long-term drug treatment. However, individuals living with HIV continue to face an elevated risk of developing various age-related health problems, including cognitive impairment, cardiovascular disease, and reduced physical capabilities (Crane et al., 2019). In line with these findings, people living with HIV (PLWH) generally report significantly lower health-related quality of life (HRQoL) compared to the general population (Cooper et al., 2017). Data indicates that beyond the challenges of managing a chronic infection, PLWH are more susceptible to being negatively impacted by changes in their surrounding environment and social circumstances (Drewes, Gusy, and Rüden 2013).

                In contrast to overall quality of life, health-related quality of life (HRQoL) is a more narrowly defined concept that represents how an individual’s health status is estimated to impact their quality of life, or how a person perceives their own well-being across the physical, mental, and social aspects of their health (Dutra et al., 2019). Measures of health-related quality of life (HRQoL) for individuals living with chronic conditions like HIV enable the evaluation of the effectiveness of certain medications, as well as the exploration of the impact of HIV and associated coexisting conditions (Bozzette et al., 1994; Cooper et al., 2017). The 36-Item Short Form Health Survey (SF-36) is a widely recognized and validated instrument used for evaluating health-related quality of life (HRQoL) (Lins-Kusterer et al., 2019). This tool has demonstrated its usefulness in estimating the burden of various conditions on HRQoL across many different populations (Ware and Gandek 1998). The application of the SF-36, along with other instruments, to assess HRQoL in HIV-infected populations has been documented in high-income settings (Clayson et al., 2006; Meng et al., 2008; Wu et al., 2013), but not specifically in the Nkwen health district. Research has demonstrated that adults living with HIV have significantly lower health-related quality of life (HRQoL) compared to adults without HIV. However, no studies have investigated this issue in the context of Nkwen Health District. The crisis in the English-speaking parts of Cameroon since 2017 has probably imparted socio-environmental changes in the lives of residents living with HIV in these parts of the country. Measures of HRQoL in individuals living with chronic conditions such as HIV allows for the evaluation of the efficacy of certain medications as well as for exploring the influence of HIV and associated comorbidities (Bozzette et al., 1994b; Cooper et al., 2017).

It is with the above background that we seek to carry out this study to evaluate the effectiveness of DTG-based regimens, investigate any drug resistance profiles in virally unsuppressed cases, and assess the overall health-related quality of life in PLWH in the study sites.

1.2.     Problem Statement

The widespread use of dolutegravir (DTG)-based antiretroviral therapy (ART), including the tenofovir-lamivudine-dolutegravir (TLD) regimen, has significantly improved the treatment outcomes for people living with HIV. However, the emergence of drug resistance and its impact on the health-related quality of life (HRQoL) of HIV-infected adults remains a critical concern that requires investigation.

In 2017, Wenk et al., conducted a previous study on the prevalence of pre-treatment Integrase Strand Transfer Inhibitor (INSTI) resistance mutations in antiretroviral-naive HIV-1-infected individuals in the North West and South West Regions of Cameroon (Wenk et al., 2021: Wenk et al., 2021). This was to investigate the prevalence of pre-treatment HIV-1 drug resistance to INSTIs. This study was done just before the INSTI drug Dolutegravir was introduced into the country for the treatment of HIV-1 infection. They detected major HIV-1 drug resistance mutations to INSTIs in 5.1% of study participants. Additionally, 140/255 (54.9%) individuals harboured polymorphic accessory INSTI-resistance mutations, mainly at high frequencies. They concluded that pre-treatment HIV-1 resistance to INSTIs was low in these study sites, which supported the use of INSTIs in Cameroon. However, they also highlighted the presence of many polymorphic accessory INSTI-resistance mutations in the patients before the introduction of any INSTI-based ART regimen in Cameroon. While the impact of some of these polymorphic accessory resistance mutations on treatment outcome is not fully known and requires further studies, a number of them are well known to significantly reduce susceptibility to INSTIs when occurring in combination with other major INSTI-resistance mutations. Based on these previous findings, we believe it is very imperative to conduct a new study to monitor patients on the now famous Dolutegravir-based HIV regimens in this similar study site, for any drug resistance to this relatively new HIV treatment, after its rollout in the country.

The Nkwen health district in the region have seen a substantial scale-up of DTG-based ART, including the Tenofovir-Lamivudine-Dolutegravir (TLD) regimen, as part of the national HIV treatment program. Understanding the drug-resistance profiles and the associated HRQoL outcomes of HIV-infected adults receiving this treatment regimen in these health districts is essential for informing clinical management, guiding public health interventions, and ensuring the long-term effectiveness of the HIV treatment program.

1.3.     Justification of the study

Taking into consideration that studies have been done on HIV resistance worldwide, very little has been done in Cameroon’s North West Region.  This reflects the insufficient amount of data on HIV drug resistance in Bamenda. Given the potential health threats posed by HIV especially in drug-resistant cases, there are greater benefits to carrying out this research since valuable sero-epidemiological data will be generated representing the Nkwen health district. Early identification of HIV drug resistance in patients on Tenofovir-Lamivudine-Dolutegravir enables health practitioners to quickly take alternatives in the treatment process thus preventing health risks. It is crucial to monitor the development of drug resistance, as it can impact the effectiveness of treatment outcomes in patient. This study can provide valuable insights into the drug-resistance profiles of patients on this specific TLD treatment. This information can better inform treatment guidelines and help healthcare providers make informed decisions about the most appropriate treatment options. Understanding the impact of HIV treatment regimens on the health-related quality of life of HIV-infected adults is crucial for evaluating the overall effectiveness of the treatment. This data can provide insights into the physical, mental, and social well-being of patients, which can inform patient-centered care and improve the management of HIV. Conducting the study in the Nkwen Health District of Cameroon can help address regional health disparities in this domain and provide insights into the unique challenges and needs of this population. The findings can inform the development of targeted interventions and improve access to quality HIV care in these areas. Overall, this study has the potential to provide valuable insights that can improve the management of HIV, optimize treatment outcomes, and enhance the health-related quality of life of HIV-infected adults in the Nkwen Health District of Cameroon.

1.4 Research questions

1.4.1     General research question

How effective is the Dolutegravir-based regimen – TLD in the Nkwen Health District of Cameroon and is there any association between drug resistance to Dolutegravir-based ART and the health-related quality of life of HIV-infected adults receiving this treatment?

1.4.2.    Specific research questions

   – What is the prevalence of HIV-1 drug resistance mutations to the Integrase Strand Transfer Inhibitor (INSTI) Dolutegravir among HIV-infected adults on Dolutegravir-based ART?

   – What are the different HIV-1 subtypes and drug resistance mutations found in virally unsuppressed patients on Dolutegravir-based regimens, and what is the potential impact of these mutations on treatment outcomes?

  – What is the Health-Related Quality of Life (HRQoL) of HIV-infected adults on Dolutegravir-based ART?

 1.5 Research objectives

1.5.1. General objective

To evaluate the effectiveness of Dolutegravir-based HIV regimens by assessing HIV-patients’ drug resistance profiles, and correlating it to the overall health-related quality of life of HIV- patients in the Nkwen Health District. 

1.5.2.   Specific objectives

1. To determine the prevalence of HIV-1 drug resistance mutations to the Integrase Strand Transfer Inhibitor (INSTI) – Dolutegravir among HIV-infected adults on Dolutegravir-based ART.
2. To determine the different types of HIV-1 subtypes and drug resistance mutations harboured by virally unsuppressed patients on Dolutegravir-based regimens, and the possible impact of these mutations on treatment outcomes.
3. To assess the Health Related Quality of Life (HRQoL) of HIV-infected adults on Dolutegravir-based ART.