Reverse Transcriptase Inhibitors

This chapter summarizes a number of functionally important genetic polymorphisms in drug-metabolizing enzymes and drug transporters and their genotyping methodologies, by which individuals susceptible to drug toxicity or loss of efficacy can be identified or predicted easily in the clinical setting. The human cytochrome P450 (CYP) enzyme system contributing to drug metabolism comprises the CYP families CYP1, CYP2, and CYP3. Among these CYPs, proteins encoded by the human CYP3A genes catalyze the metabolism of nearly half of all currently used drugs, and approximately 40% of all marketed drugs are substrates for CYP2C9, CYP2C19, and CYP2D6. Moreover, the CYP2B6, CYP2C9, CYP2C19, and CYP2D6 enzymes exhibit large variations in the levels of their protein expression and enzymatic activity as a result of frequently occurring, functionally important genetic polymorphisms. Typically, in addition to passive diffusion, a drug is transported into cells by uptake (or influx) transporters, such as organic anion transporters (OATs), organic anion transport peptides (OATPs), and organic cation transporters (OCTs), whereas the drug and its metabolite(s) are removed from the cells by efflux transporters, such as P-glycoprotein (P-gp), multidrug resistance proteins (MRPs), and breast cancer resistance protein (BCRP). Anti-infective drugs may be substrates for some uptake transporters, drug-metabolizing enzymes, and efflux transporters.

This chapter discusses the clinical features, diagnosis, and management of HIV distal sensory polyneuropathy (DSP); toxic neuropathies, with emphasis on the antiretroviral (ARV)-associated neuropathies; and other neuropathies found in HIV-infected individuals. Subjects were classified as having asymptomatic DSP if they only had neurologic signs or as having symptomatic DSP if they also had paresthesias or pain in a study by Schifitto and coworkers. The study showed that use of these drugs was not a significant risk factor for incident symptomatic DSP. Such an effect may be related to preservation of immune function, forestalling the potential occurrence of neurotoxicity. This study also addressed the important issue of whether the presence of asymptomatic DSP is a risk factor for incident symptomatic DSP. Thus, it is not surprising that patients with advanced HIV infection and severe immunosuppression remain at the greatest risk of neurotoxicity due to ARV agents. The incidence, severity, progression, and reversibility of peripheral neuropathy from zalcitabine (ddC), as with other toxic neuropathies, are dose dependent. Unlike other toxic neuropathies, dapsone-induced peripheral neuropathy involves primarily motor nerves. Mononeuropathy multiplex (MM) is an infrequent manifestation of HIV infection. A reduced number of oxytocin neurons in the paraventricular nucleus of the hypothalamus have also been described, although the clinical significance of this is unclear. It has been suggested that the pathophysiological mechanism may be due to HIV infection itself as well as an autoimmune mechanism. It may arise from HIV itself or from medications used to treat HIV infection and other concomitant infections.

This chapter reviews of the epidemiology, diagnosis, and treatment of the major psychiatric aspects of HIV infection, in addition to somatic symptoms such as sleep disorder, fatigue, sexual dysfunction, and HIV-associated lipodystrophy, all of which have substantial quality of life impact. Benzodiazepines should be avoided in patients with cognitive impairment and delirium. Delirium is common among hospitalized HIV/AIDS patients. Most studies documenting rates of delirium were conducted in the pre-highly active antiretroviral therapy (HAART) era and were restricted to subsets of patients seen in psychiatric consultation. Sleep disorders, primarily insomnia disorders, are prevalent in the HIV-infected population. Hepatitis C virus (HCV) infection is increasingly recognized as a significant comorbid condition that affects the clinical outcome of patients with substance abuse disorders and HIV disease. Fatigue is common among patients with HIV/AIDS and may contribute to impairment in physical function and disability. With the advent of nucleoside analog reverse transcriptase inhibitors (NRTIs) (e.g., zidovudine), nonnucleoside analog reverse transcriptase inhibitors (NNRTIs) (e.g., efavirenz), and PIs (e.g., indinavir) as part of HAART, there has been heightened interest in the issue of drug interactions in the context of HIV psychopharmacology. HIV-associated lipodystrophy is an increasingly recognized complication of prolonged treatment with HAART that may have significant impact on the psychological well-being and quality of life of those affected.

In 1987, zidovudine became the first approved agent in the United States for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. Two decades later, 24 additional agents in six drug classes had been approved. These include nucleoside analog reverse transcriptase inhibitors (NRTIs), a nucleotide analog reverse transcriptase inhibitor, nonnucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), entry inhibitors, and an integrase inhibitor. This chapter describes the major characteristics of antiretroviral agents that are currently approved, or at a promising stage of development, and is organized according to the virus replication cycle. The current therapeutic niche of chemokine receptor 5 (CCR5) inhibitors is as one component of combination regimens for patients with multidrug-resistant R5 virus. In vitro, maraviroc demonstrates no antagonism with existing antiretroviral agents and additive or synergistic activity in combination with enfuvirtide. Vicriviroc is a potent inhibitor of most R5 viruses in vitro, with an IC50 in the range of 20 nM. It demonstrates additive or synergistic activity in combination with other approved antiretroviral agents. Additive or synergistic in vitro inhibition has been reported with double or triple combinations of numerous antiretroviral agents, except for zidovudine-stavudine, which is an antagonistic combination. Stavudine enjoys relatively few drug-drug interactions compared to other antiretroviral agents. The major mechanism of clearance of raltegravir in humans is by hepatic uridine diphosphoglucuronosyl transferase (UGT)-1A1. Amprenavir is additive with a number of other antiretroviral agents (zidovudine, didanosine, abacavir, saquinavir, indinavir, and ritonavir).

This chapter focuses on the various technologies that are currently available from commercial companies for the diagnosis and monitoring of human immunodeficiency virus (HIV) infections, and it is not meant to duplicate more extensive reviews of HIV. Infection with HIV type 1 (HIV-1) results in the induction of a humoral antibody response specific to viral proteins, with the production of immunoglobulin A (IgA), IgM, and IgG. The majority of the automated immunoassay analyzers provide walk-away simplicity to perform assays from sample processing through interpretation of results. The major advantage of Western blot assays over enzyme immunoassays (EIAs) is that the specific interaction of antibody and antigen can be directly visualized. Immunofluorescence assay (IFA) is a very useful and inexpensive alternative to performing Western blot assays for confirmation of HIVspecific antibody responses. The Fluorognost HIV-1 IFA is based on the specific binding of HIV-1 antibodies in a specimen to HIV-1 antigens expressed on the surfaces of immortalized human T- cells fixed to glass slides. Specific antibody-antigen complexes are then detected using an anti-human antibody conjugated with fluorescein isothiocyanate. The development of molecular assays to quantitate the levels of HIV RNA in infected patients has provided one of the most valuable tools to assess the progression of HIV disease, monitor the impact of antiviral therapy, predict treatment failure and the emergence of drug-resistant viruses, and facilitate our understanding of the natural history and pathogenesis of this virus.