Frontiers in HIV Research

Over thirty antiretroviral agents have been developed since the beginning of the fight against the human immunodeficiency virus (HIV). This breakthrough was fostered by the enormous leaps made in understanding viral replication, a cycle that begins with the interaction between the virus and the host cell, usually a CD4-bearing T-lymphocyte. This results into the fusion of the viral membrane with the cellular plasma membrane and the transfer of viral material, including RNA, into the cytoplasm of the host cell. Then, using viral DNA-dependent RNA reverse transcriptase, viral DNA is formed from RNA. Viral DNA is soon translocated to the host cell nucleus where it is integrated into the host DNA in a reaction catalyzed by integrase enzyme. The proviral DNA formed at this stage is used to produce immature viral polypeptides that are eventually cleaved and packaged into mature virions by protease enzyme. Drugs have been developed that target each of these steps; they include entry inhibitors, reverse transcriptase inhibitors, integrase inhibitors, and protease inhibitors. The reverse transcriptase inhibitor, Zidovudine, a nucleoside analogue, was the first antiretroviral agent to be approved in 1987. It was followed by many other nucleotide, nucleoside and non-nucleoside reverse transcriptase inhibitors, and eventually, by protease inhibitors, integrase inhibitors and entry inhibitors. Other viral targets are still under research.

Current therapeutic intervention in HIV infection relies upon over 30 different therapeutic options. Despite the efficacy shown by these drugs, clinicians are confronted with an unexpected frequency of adverse effects and resistance, including transmitted resistance. There is now a great need for new drugs with reduced toxicity, increased activity against drug-resistant viruses and a greater capacity to reach tissue sanctuaries of the virus. Drugs that target the interactions between the HIV envelope and the cellular receptor complex are a ‘new entry’ into the scenario of HIV therapy and have recently raised great interest because of their activity against multidrug-resistant viruses. Two such drugs include maraviroc, a CCR5 antagonist, and enfuvirtide, a fusion inhibitor, both of which work via separate mechanisms to block the entry of HIV into the cell. The clinical pharmacology, and studies of efficacy and safety of these two agents, and investigational drugs within this class, are described in this current chapter.

The first revelation of HIV belonging to retroviruses with its genetic material stored as RNA indicated its need for reverse transcription as one of the steps in its lifecycle. This opened the way to the therapeutic battle against the virus. Reverse transcriptase inhibitors are the oldest antiretroviral agents inhibiting the formation of viral DNA from RNA. Some of these agents work as analogues of the naturally occurring nucleoside and nucleotide bases required for DNA formation, hence their insertion into a growing DNA chain leads to its termination. Another group does not mimic natural DNA bases but rather bind to and disfigure the reverse transcriptase enzyme. The former are referred to as nucleoside and nucleotide reverse transcriptase Inhibitors (NRTI), while the later are non-nucleoside reverse transcriptase inhibitors (NNRTI). These agents are used in combination with other antiretroviral agents, and some of them have activity against hepatitis B which is a common HIV co-infection.

Antiretroviral agents target specific steps in the HIV replication cycle. This chapter focuses on HIV DNA integration, a step catalyzed by the integrase enzyme. Appreciating the structure of this enzyme and its mechanism of action is vital to understanding how the drugs inhibit this step. The integrase enzyme constitutes vital domains and amino acids that can be drug targets during 3' processing (3'-P) and strand transfer (ST). Active against these processes are some derivatives of Diketo Acids (DKA), Strylquinolones (SQL) and Phenyldipyrimidine (PDP). To date, three drugs active against strand transfer – Raltegravir, Elvitegravir and Dolutegravir – have been approved by the Food and Drug Authority (FDA). Several other agents are still undergoing pre-clinical and clinical trials. Integrase inhibitors are effective against HIV1 and HIV2, including multidrug resistant strains of HIV1. Therefore antiretroviral combinations containing these drugs are effective as first or second line regimens. Resistance to integrase inhibitors mainly follows amino acid substitutions in the catalytic core domain of the enzyme. Y143C/R, Q148H/K/R and N155H mutations have been attributed to Raltegravir and Elvitegravir resistance. These mutations, however, have minimal effect on the action of Dolutegravir.

The protease inhibitors are a potent, durable class of antiretroviral agents recommended as preferred initial therapy for the treatment of HIV-1 infection in combination with a nucleoside/nucleotide reverse transcriptase inhibitor. These agents play a critical role as salvage therapy in treatment-experienced patients with extensive antiretroviral drug exposure given their high genetic barrier to drug resistance. Each antiretroviral within this class is unique in virologic potency, drug-drug interaction potential, pharmacokinetic characteristics and adverse effect profile. This chapter will summarize and review protease inhibitors currently available on the market and provide guidance for the application of their use in clinical practice.

Recent developments in the pharmacogenomics of antiretroviral therapy have provided new prospects for the prediction of treatment efficacy and adverse effects. Current antiretroviral treatment has limitations such as high rates of adverse drug reactions and the development of resistance in a significant proportion of patients. HIV- 1 protease inhibitors and non-nucleoside reverse transcriptase inhibitors are particularly suitable for genomic investigations since drug exposure/concentration and treatment response can be quantified and adverse effects can be assessed with validated measures. Additionally, there is an extensive knowledge of the pharmacokinetics of these agents, and candidate genes implicated in metabolism, transport and adverse effects have been identified. Although no unifying conclusions have been reached regarding the association of genetic variants with pharmacokinetics and adverse drug reactions, this chapter attempts to review the most recently published research and summarize the state of research in this area. Future directions for research in individualizing these agents are discussed.

The roll-out of life saving antiretroviral medication has improved the quality of life and increased the life expectancy of HIV-infected individuals. HIV-infected individuals suffer more ailments compared to the general population, necessitating frequent co-medications. There is considerable geographic overlap between areas with high prevalence of HIV and other infectious diseases such as malaria, tuberculosis, and neglected tropical diseases raising the possibility of complex polypharmacy and drugdrug interactions. The cytochrome P450 (CYP450) enzymes play a major role in metabolism of many of the ARVs and drugs used for the treatment of other prevalent diseases; thus co-treatment creates potential for CYP450 mediated drug interactions. Some ARVs pose a particularly high-risk for potential drug-drug interactions, which may be pharmacokinetic or pharmacodynamic in nature and can result in raising or lowering plasma or tissue concentrations of co-prescribed drugs. Elevated drug concentrations may be associated with drug toxicity and lower drug concentrations may be associated with therapeutic failure. This chapter provides an in-depth understanding of clinically relevant drug-drug interactions during treatment of HIV and common illnesses and reviews the currently available data on interactions between ARVs and drugs used in the management of some other common illnesses.

Access and well-modulated use of antiretroviral agents (ARVs) in North America dates as early as 1990 with the initial guidelines recommended zidovudine monotherapy, just 4 years after FDA approved the drug. Continued review of emerging data, led to the recommendation of highly active antiretroviral treatment (HAART) in 1998. Clear documentation of access and use of antiretroviral therapy (ART) in resource limited settings was first observed in 2002 after the World Health Organization (WHO) issued guidelines for resource limited settings, and included key ARVs into the WHO essential drug list. Delayed access to ART heavily impacted the initial control of the HIV epidemic in resource limited settings, but even with improved access to ART, differences in the management of HIV still exist; including timing for ART initiation and HIV/ART monitoring strategies. Access to key HIV/ART monitoring tools including viral load testing is limited in low resource settings, leading to gaps in HIV/ART management that may no longer be experienced in resource rich settings. Geographical variations in HIV sub-types and key co-infections further subject the control and management of HIV to demographic influence. Until now, resource availability and demographic differences are key determinants in treatment initiation and regimen selection, while variable access to ART and key monitoring tools possibly affect the HIV epidemic, making its control less effective in some settings.