Safe and effective pharmacotherapy to treat and prevent human immunodeficiency virus (HIV) is one of the greatest achievements of science and public health in the past century. Infected individuals who maintain a daily oral regimen now have a normal or near-normal life expectancy. More than 30 approved drugs and dozens of formulations have produced thousands of possible drug combinations, but most patients receive one of a handful of well-tolerated and rigorously tested regimens. Unique features of antiretroviral therapy include the need for lifelong treatment to control virus replication and the possibility of rapid emergence of permanent drug resistance if these agents are not used properly. Although three-drug and two-drug combination oral regimens have radically altered the course of this epidemic, future options will include long-acting injectable and implantable formulations.
Abbreviations
ABC: abacavir
ADME: absorption, distribution, metabolism, excretion
AIDS: acquired immunodeficiency syndrome
5′-AMP: adenosine 5′-monophosphate
AUC: area under plasma concentration-time curve
CBT: cabotegravir
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
HCV: hepatitis C 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
LA: long-acting
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
RPV: rilpivirine
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
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 is generally no true period of latency following infection (Deeks et al., 2015). Humans and nonhuman primates are the only natural hosts for these viruses.
There are two major families of HIV. Most of the epidemic involves HIV-1; HIV-2 is more closely related to simian immunodeficiency virus (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 nonnucleoside reverse transcriptase inhibitors (NNRTIs) are HIV-1 specific and have no activity against HIV-2.