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The pharmacotherapy of HIV infection is a rapidly moving field. Three-drug combinations are the current minimum standard of care for this infection, so available agents and formulations constitute several thousand possible regimens. Knowing the essential features of the pathophysiology of this disease and how chemotherapeutic agents affect the virus and the host is critical in developing a rational approach to therapy. Unique features of this drug class include the need for lifelong administration to control virus replication and the possibility of rapid emergence of permanent drug resistance if these agents are not used properly.
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Abbreviations
ABC: abacavir
ADME: absorption, distribution, metabolism, excretion
AIDS: acquired immunodeficiency syndrome
5′-AMP: adenosine 5′-monophosphate
AUC: area under plasma concentration-time curve
cDNA: complementary DNA
CLCr: creatinine clearance
CMP: cytidine monophosphate
CNS: central nervous system
CSF: cerebrospinal fluid
CYP: cytochrome P450
dCMP: deoxycytidine monophosphate
ddC: dideoxycytidine
ddI: didanosine
DF: disoproxil fumarate
DRESS: drug reaction with eosinophilia and systemic symptoms
d4T: stavudine
eCLCr: estimated creatinine clearance
env: envelope protein gp160
FDA: Food and Drug Administration
FTC: emtricitabine
GI: gastrointestinal
HBV: hepatitis B virus
HIV: human immunodeficiency virus
HTLV: human T-cell lymphotrophic virus
IMP: inosine 5′-monophosphate
InSTI: integrase strand transfer inhibitor
IRIS: immune reconstitution inflammatory syndrome
LTR: long terminal repeat
NDP: nucleoside diphosphate
NNRTI: nonnucleoside reverse transcriptase inhibitor
NRTI: nucleos(t)ide reverse transcriptase inhibitor
OATP: organic anion-transporting polypeptide
PI: protease inhibitor
PK: pharmacokinetic
PRPP: phosphoribosyl pyrophosphate
QTc: corrected cardiac QT interval
RNase H: ribonuclease H
RT: reverse transcriptase
SIV: simian immunodeficiency virus
t1/2: half-life of elimination
TAF: tenofovir alafenamide
TAM: thymidine analogue mutation
3TC: lamivudine
TDF: tenofovir disoproxil fumarate
vRNA: viral RNA
ZDV: zidovudine
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PATHOGENESIS OF HIV-RELATED DISEASE
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Human immunodeficiency viruses are lentiviruses, a family of retroviruses evolved to establish chronic persistent infection with gradual onset of clinical symptoms. Replication is constant following infection, and although some infected cells may harbor nonreplicating virus for years, in the absence of treatment there generally is no true period of viral latency following infection (Deeks et al., 2015). Humans and nonhuman primates are the only natural hosts for these viruses.
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There are two major families of HIV. Most of the epidemic involves HIV-1; HIV-2 is more closely related to SIV and is concentrated in western Africa. HIV-1 is genetically diverse, with at least five distinct subfamilies or clades. HIV-1 and HIV-2 have similar sensitivity to most antiretroviral drugs, although the NNRTIs are HIV-1 specific and have no activity against HIV-2.
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HIV is a typical retrovirus with a small RNA genome of 9300 base pairs. Two copies of the genome are contained in a nucleocapsid core surrounded by a lipid bilayer, or envelope that is derived from the host cell plasma membrane (Figure 64–1). The viral genome encodes three major open ...