Ch 64 Antiretroviral Agents & HIV Treatment PDF

64 Chapter PATHOGENESIS OF HIV-RELATED DISEASE Virus Structure Virus Life Cycle Antiretroviral Agents and Treatment of HIV Infection Charles W. Flexner...

64 Chapter PATHOGENESIS OF HIV-RELATED DISEASE Virus Structure Virus Life Cycle Antiretroviral Agents and Treatment of HIV Infection Charles W. Flexner Nucleoside and Nucleotide Reverse Transcriptase Inhibitors Nonnucleoside Reverse Transcriptase Inhibitors HIV Protease Inhibitors How the Virus Causes Disease Entry Inhibitors Integrase Inhibitors PRINCIPLES OF HIV CHEMOTHERAPY Long-Acting and Extended-Release Antiretroviral Formulations Future Treatment Guidelines DRUGS USED TO TREAT HIV INFECTION Safe and effective pharmacotherapy to treat and prevent human immu- Virus Life Cycle nodeficiency virus (HIV) is one of the greatest achievements of science Understanding the HIV life cycle (Figure 64–1) is crucial to understand- and public health in the past century. Infected individuals who maintain ing rational therapy of the infection. HIV tropism is controlled by the a daily oral regimen now have a normal or near-normal life expectancy. envelope protein gp160 (env). The major target for env binding is the More than 30 approved drugs and dozens of formulations have produced CD4 receptor present on lymphocytes and macrophages, although cell thousands of possible drug combinations, but most patients receive one entry also requires binding to a coreceptor, generally the chemokine of a handful of well-tolerated and rigorously tested regimens. Unique fea- receptors CCR5 or CXCR4. CCR5 is present on macrophage lineage cells. tures of antiretroviral therapy include the need for lifelong treatment to Most infected individuals harbor predominantly the CCR5-tropic virus; control virus replication and the possibility of rapid emergence of perma- HIV with this tropism is responsible for nearly all naturally acquired nent drug resistance if these agents are not used properly. Although three- infections. A shift from CCR5 to CXCR4 utilization is associated with drug and two-drug combination oral regimens have radically altered the advancing disease, and the increased affinity of HIV-1 for CXCR4 allows course of this epidemic, future options will include long-acting injectable infection of T-lymphocyte lines. A phenotypic switch from CCR5 to and implantable formulations. CXCR4 heralds accelerated loss of CD4+ helper T cells and increased risk of immunosuppression. Whether coreceptor switch is a cause or a con- Pathogenesis of HIV-Related Disease sequence of advancing disease is still controversial, but it is possible to Human immunodeficiency viruses are lentiviruses, a family of retrovi- develop clinical AIDS without this switch (Deeks et al., 2015). ruses evolved to establish chronic persistent infection with gradual onset The gp41 domain of env controls the fusion of the virus lipid bilayer of clinical symptoms. Replication is constant following infection, and with that of the host cell. Following fusion, full-length viral RNA enters although some infected cells may harbor nonreplicating virus for years, in the cytoplasm, where it undergoes replication to a short-lived RNA- the absence of treatment, there is generally no true period of latency fol- DNA duplex; the original RNA is degraded by the RNase H activity of lowing infection (Deeks et al., 2015). Humans and nonhuman primates reverse transcriptase to allow creation of a full-length double-stranded are the only natural hosts for these viruses. DNA copy of the virus. Because the HIV reverse transcriptase is error There are two major families of HIV. Most of the epidemic involves prone and lacks a proofreading function, mutation is frequent and occurs HIV-1; HIV-2 is more closely related to simian immunodeficiency virus at about three bases for every full-length (9300-base-pair) replication (SIV) and is concentrated in western Africa. HIV-1 is genetically diverse, (Coffin, 1995). Virus-derived DNA is transported into the nucleus, where with at least five distinct subfamilies or clades. HIV-1 and HIV-2 have it is integrated into a host chromosome by the viral integrase in a random similar sensitivity to most antiretroviral drugs, although the nonnucle- or quasi-random location (Greene and Peterlin, 2002). oside reverse transcriptase inhibitors (NNRTIs) are HIV-1 specific and Following integration, the virus may remain quiescent, not producing have no activity against HIV-2. RNA or protein but replicating as the cell divides. When a cell that har- bors the viral DNA is activated, viral RNA and proteins are produced. Virus Structure Structural proteins assemble around full-length genomic RNA to form a HIV is a typical retrovirus with a small RNA genome of 9300 base nucleocapsid. The envelope and structural proteins assemble at the cell pairs. Two copies of the genome are contained in a nucleocapsid core surface, concentrating in cholesterol-rich lipid rafts. The nucleocapsid surrounded by a lipid bilayer, or envelope, that is derived from the host cores are directed to these sites and bud through the cell membrane, cell plasma membrane (Figure 64–1). The viral genome encodes three creating new enveloped HIV particles containing two complete sin- major open reading frames: gag encodes a polyprotein that is processed gle-stranded RNA genomes. Reverse transcriptase is incorporated into to release the major structural proteins of the virus; pol overlaps gag and virus particles, so replication can begin immediately after the virus enters encodes three important enzyme activities (an RNA-dependent DNA a new cell. polymerase or reverse transcriptase with RNAase activity, protease, and the viral integrase); and env encodes the large transmembrane envelope How the Virus Causes Disease protein responsible for cell binding and entry. Several small genes encode Sexual acquisition of HIV infection is likely mediated by one or, at most, regulatory proteins that enhance virion production or combat host a handful of infectious virus particles. Soon after infection, there is a defenses. These include tat, rev, nef, and vpr. rapid burst of replication peaking at 2 to 4 weeks, with ≥109 CD4+ cells https://ebooksmedicine.net/  1246 Abbreviations Eventually, the host CD4+ T-lymphocyte count begins a steady decline, accompanied by a rise in the plasma HIV RNA concentration. Once the peripheral CD4 cell count falls below 200 cells/mm3, there ABC: abacavir is an increasing risk of opportunistic diseases and, ultimately, death. ADME: absorption, distribution, metabolism, excretion Sexual acquisition of CCR5-tropic HIV-1 is associated with a median time to clinical AIDS of 8 to 10 years if the patient is not treated. Some CHAPTER 64 ANTIRETROVIRAL AGENTS AND TREATMENT OF HIV INFECTION AIDS: acquired immunodeficiency syndrome 5′-AMP: adenosine 5′-monophosphate patients, termed long-term nonprogressors, can harbor HIV for more AUC: area under plasma concentration-time curve than two decades without significant decline in peripheral CD4 cell CBT: cabotegravir count or clinical immunosuppression; this may reflect a combination of cDNA: complementary DNA favorable host immunogenetics and immune responses. An important question relevant to treatment is whether AIDS is a CLCr: creatinine clearance consequence of CD4+ lymphocyte depletion alone. Most natural history CMP: cytidine monophosphate data suggest that this is true. Regardless, successful therapy is based CNS: central nervous system on inhibition of HIV replication; interventions designed specifically CSF: cerebrospinal fluid to boost the host immune response without exerting a direct antiviral CYP: cytochrome P450 effect have had no reliable clinical benefit (Deeks et al., 2015). dCMP: deoxycytidine monophosphate ddC: dideoxycytidine ddI: didanosine Principles of HIV Chemotherapy DF: disoproxil fumarate Current treatment assumes that all aspects of disease derive from the DRESS: drug reaction with eosinophilia and systemic symptoms direct toxic effects of HIV on host cells, mainly CD4+ T lymphocytes. d4T: stavudine The goal of therapy is to suppress virus replication as much as possible for eCLCr: estimated creatinine clearance as long as possible. The current standard of care is to use three different env: envelope protein gp160 antiretroviral drugs simultaneously for initial treatment and two to three FDA: Food and Drug Administration drugs for the remaining duration of treatment (Flexner, 2019). FTC: emtricitabine Two large randomized clinical trials found substantial clinical ben- GI: gastrointestinal efit from initiating antiretroviral therapy regardless of baseline CD4 HBV: hepatitis B virus count (INSIGHT START Study Group, 2015; TEMPRANO ANRS HCV: hepatitis C virus 12136 Study Group, 2015); thus, the current global standard of care is HIV: human immunodeficiency virus to offer treatment to all infected individuals whenever possible (World HTLV: human T-cell lymphotrophic virus Health Organization, 2021). Substantial evidence confirms the value IMP: inosine 5′-monophosphate of antiretroviral therapy in preventing transmission of the virus from InSTI: integrase strand transfer inhibitor person to person (Cohen et al., 2011) and suggests that infected indi- IRIS: immune reconstitution inflammatory syndrome viduals with an undetectable viral load are incapable of transmitting the LA: long-acting virus to others. LTR: long terminal repeat Drug resistance remains a key problem. There is a high likelihood NDP: nucleoside diphosphate that all untreated infected individuals harbor viruses with single- NNRTI: nonnucleoside reverse transcriptase inhibitor amino-acid mutations that confer some degree of resistance to every NRTI: nucleos(t)ide reverse transcriptase inhibitor known antiretroviral drug because of the high mutation rate of HIV OATP: organic anion-transporting polypeptide and the tremendous number of infectious virions (Coffin, 1995). Thus, PI: protease inhibitor a combination of active agents is required to prevent drug resistance, PK: pharmacokinetic analogous to strategies employed in the treatment of tuberculosis (see PRPP: phosphoribosyl pyrophosphate Chapter 65). Prolonged drug holidays may allow the virus to replicate QTc: corrected cardiac QT interval anew, increasing the risk of drug resistance and disease progression; such RNase H: ribonuclease H breaks in treatment are associated with increased morbidity and mortal- ity and are not generally recommended (Lawrence et al., 2003). RPV: rilpivirine The expected outcome of initial therapy in a previously untreated RT: reverse transcriptase patient is an undetectable viral load (plasma HIV RNA