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ANTIRETROVIRALS AND MECHANISMS OF ACTION

CHAPTER ONE

INTRODUCTION

1.1 Background of the Study

Antiretrovirals (ARVs) are crucial in the management and treatment of human immunodeficiency virus (HIV) infection. They function by inhibiting the replication of HIV, thereby slowing the progression of the disease and improving the quality of life for individuals living with HIV. The development of antiretroviral therapy (ART) has significantly transformed the prognosis of HIV infection from a fatal illness to a manageable chronic condition (UNAIDS, 2022). Understanding the mechanisms of action of these drugs is essential for optimizing treatment regimens and improving patient outcomes.

Antiretrovirals are categorized into several classes, each targeting different stages of the HIV lifecycle. The primary classes include nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), integrase strand transfer inhibitors (INSTIs), and entry inhibitors (EI) (Panel on Antiretroviral Guidelines for Adults and Adolescents, 2021). NRTIs, such as zidovudine and tenofovir, work by mimicking the natural building blocks of DNA. When incorporated into the growing viral DNA strand, they terminate the chain elongation, thus halting the reverse transcription process (Mendelson & Morris, 2019).

NNRTIs, including efavirenz and nevirapine, bind directly to the reverse transcriptase enzyme but do not mimic the nucleotides. This binding induces a conformational change in the enzyme, preventing it from converting viral RNA into DNA (Eron et al., 2019). Protease inhibitors, such as ritonavir and lopinavir, interfere with the protease enzyme, which is crucial for processing viral polyproteins into functional proteins. By inhibiting this enzyme, protease inhibitors prevent the maturation of new viral particles (Mocroft et al., 2020).

INSTIs, like dolutegravir and raltegravir, target the integrase enzyme, which is responsible for integrating viral DNA into the host cell genome. By inhibiting this enzyme, INSTIs prevent the integration of viral DNA, thereby blocking viral replication (Gallant et al., 2020). Entry inhibitors, such as maraviroc and enfuvirtide, block the virus from entering the host cells. Maraviroc inhibits the CCR5 co-receptor, while enfuvirtide inhibits the fusion of the viral and cellular membranes (Kern et al., 2021).

The evolution of ARV therapy has been characterized by the development of combination therapies, which enhance efficacy and reduce the likelihood of drug resistance. The concept of Highly Active Antiretroviral Therapy (HAART) emerged in the 1990s, combining drugs from different classes to achieve a more potent suppression of HIV replication (Clavel et al., 2018). Recent advancements in ARV therapy include the development of long-acting formulations and single-tablet regimens, which improve adherence and simplify treatment regimens (Gulick et al., 2021).

The mechanisms of action of ARVs are complex and involve intricate interactions between the drugs and viral enzymes. Each class of ARVs targets specific steps in the HIV lifecycle, and understanding these mechanisms is crucial for designing effective treatment regimens and addressing challenges such as drug resistance and treatment adherence (Smith et al., 2022). This study aims to provide a comprehensive overview of the mechanisms of action of different ARV classes and their impact on HIV treatment outcomes.

1.2 Statement of the Problem

Despite the significant advancements in antiretroviral therapy (ART), several challenges persist in the management of HIV infection. Issues such as drug resistance, adherence to treatment, and the long-term side effects of ARVs continue to affect the effectiveness of ART. Drug resistance, in particular, poses a serious threat to the efficacy of existing treatments, leading to virological failure and the need for more complex and costly second-line therapies (Gulick et al., 2021). Additionally, the complexity of ART regimens can impact patient adherence, further exacerbating the problem of drug resistance and treatment failure (Eron et al., 2019). Understanding the mechanisms of action of different ARV classes is essential for addressing these challenges and improving the overall effectiveness of HIV treatment.

1.3 Objectives of the Study

The main objective of this study is to determine the mechanisms of action of various antiretrovirals and their impact on HIV treatment outcomes. Specific objectives include:

i. To evaluate the impact of different ARV classes on viral suppression and treatment efficacy. ii. To determine the role of drug resistance in compromising the effectiveness of ARVs. iii. To find out how adherence to ART affects the overall success of HIV treatment.

1.4 Research Questions

i. What is the impact of different ARV classes on viral suppression and treatment efficacy? ii. What is the role of drug resistance in compromising the effectiveness of ARVs? iii. How does adherence to ART affect the overall success of HIV treatment?

1.5 Research Hypotheses

Hypothesis I

H0: There is no significant impact of different ARV classes on viral suppression and treatment efficacy.

H1: There is a significant impact of different ARV classes on viral suppression and treatment efficacy.

Hypothesis II

H0: There is no significant role of drug resistance in compromising the effectiveness of ARVs.

H2: There is a significant role of drug resistance in compromising the effectiveness of ARVs.

Hypothesis III

H0: There is no significant effect of adherence to ART on the overall success of HIV treatment.

H3: There is a significant effect of adherence to ART on the overall success of HIV treatment.

1.6 Significance of the Study

This study is significant as it provides insights into the mechanisms of action of various antiretroviral drugs and their impact on treatment outcomes. By understanding how different ARV classes function and the effects of drug resistance and adherence, healthcare providers can better tailor treatment regimens to individual patient needs, potentially improving treatment efficacy and patient quality of life. Additionally, the findings may inform future research and contribute to the development of more effective HIV treatments.

1.7 Scope of the Study

The study will focus on the mechanisms of action of various classes of antiretrovirals, their impact on viral suppression and treatment efficacy, the role of drug resistance, and the effect of adherence to ART. The scope will be limited to recent advancements in ARV therapy and will exclude older therapies that are no longer widely used.

1.8 Limitations of the Study

The study may be limited by the availability of recent and comprehensive data on ARV mechanisms and resistance patterns. Additionally, variations in adherence rates and the effectiveness of treatment regimens across different populations may affect the generalizability of the findings. The study will also rely on secondary data sources, which may limit the depth of analysis.

1.9 Definition of Terms

Antiretrovirals (ARVs): Medications used to treat HIV infection by inhibiting the replication of the virus.

Nucleoside Reverse Transcriptase Inhibitors (NRTIs): A class of ARVs that mimic natural nucleotides to prevent the synthesis of viral DNA.

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs): A class of ARVs that bind directly to the reverse transcriptase enzyme, inhibiting its function.

Protease Inhibitors (PIs): ARVs that inhibit the protease enzyme, preventing the maturation of new viral particles.

Integrase Strand Transfer Inhibitors (INSTIs): ARVs that block the integrase enzyme, preventing the integration of viral DNA into the host genome.

Entry Inhibitors (EIs): ARVs that prevent HIV from entering host cells by blocking viral fusion or co-receptors.

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