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Infectious diseases Board Review Manual
Statement of
Editorial Purpose
The Hospital Physician Infectious Diseases Board
Review Manual is a study guide for fellows
and practicing physicians preparing for board
exam­inations in infectious diseases. Each manual reviews a topic essential to current practice in the subspecialty of infectious diseases.
PUBLISHING STAFF
PRESIDENT, Group PUBLISHER
Bruce M. White
Senior EDITOR
Robert Litchkofski
executive vice president
Barbara T. White
Antiretroviral Therapy in HIV
Infection
Series Editor:
Varsha Moudgal, MD
Infectious Diseases Fellowship Program Director, St. Joseph
Mercy Hospital, Ann Arbor, MI; and Assistant Professor
of Medicine, Wayne State University School of Medicine,
Detroit, MI
Contributors:
Christopher T. Miller, MD
Infectious Diseases Fellow, Department of Infectious
Diseases, Thomas Jefferson University Hospital,
Philadelphia, PA
Jason Schafer, PharmD, BCPS, AAHIVP
Assistant Professor, Department of Pharmacy Practice,
Jefferson School of Pharmacy, Thomas Jefferson University,
Philadelphia, PA
executive director
of operations
Jean M. Gaul
NOTE FROM THE PUBLISHER:
This publication has been developed without involvement of or review by the
Amer­ican Board of Internal Medicine.
Table of Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
HIV Replication Cycle . . . . . . . . . . . . . . . . . . . . . 1
HIV Antiretroviral Drug Classifications. . . . . . . . 3
Use of Antiretroviral Therapy . . . . . . . . . . . . . . 14
Postexposure Prophylaxis. . . . . . . . . . . . . . . . . .24
Immune Reconstitution Inflammatory
Syndrome.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
Board Review Questions. . . . . . . . . . . . . . . . . . . 27
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
Antiretroviral Therapy in HIV Infection
Infectious Diseases Board Review Manual
Antiretroviral Therapy in HIV Infection
Christopher T. Miller, MD, and Jason Schafer, PharmD, BCPS, AAHIVP
INTRODUCTION
The first cases of HIV infection were described in
the early 1980s, prompting an aggressive search
for a cure for this deadly infection. In 1987, zidovudine became the first medication approved for the
treatment of HIV infection, ushering in a new age
in HIV management. As our understanding of HIV
evolved through the 1990s, new therapies gradually emerged, as did hope that a curative medication regimen may be discovered. Single-drug
nucleoside reverse transcriptase inhibitor therapy
initially conferred only 6 to 12 months of benefit
to patients before viral resistance rendered this
approach ineffective. Therapeutic strategy then
evolved into dual-drug therapy, which extended
benefit to 2 to 3 years. In the mid-1990s, a 3-drug
regimen (ie, highly active antiretroviral therapy, or
HAART) became the predominant regimen and
remains the standard of care today.
Along with these drug developments came new
frustrations, manifested as mutated and resistant
HIV strains, high pill burdens, and significant toxicities. These multidrug regimens have been refined
over the past 10 years, to the point where many
patients are able to maintain an intact immune
system with no detectable virus on single-pill,
triple-drug co-formulated, minimally toxic antiretroviral therapy (ART) regimens. While the goal of
HIV eradication has remained elusive, the modern
age of ART has commonly rendered HIV disease
a chronic condition in which infected patients have
a reasonable life expectancy when the disease is
ideally managed.
This article provides a brief overview of HIV replication along with a more detailed review of the
currently approved ART medications and classes,
including their indications and combinations. Use
of ART in the setting of a variety of host and viral
characteristics, monitoring, and the immune reconstitution inflammatory syndrome are discussed
as well. Note that most recommendations in this
article apply only to HIV-1 virus.
HIV REPLICATION CYCLE
A better understanding of the HIV replication
cycle has led to the development of antiretroviral medications targeted against viral enzymes
and even host proteins. A visualization of this
replication cycle is essential to understanding
how these medications function. Current ART
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Infectious Diseases Volume 14, Part 3 1
Antiretroviral Therapy in HIV Infection
Figure 1. HIV replication cycle. (Adapted with permission from
Tsibris AMN, Hirsch MS. Antiretroviral therapy for human immunodeficiency virus infection. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and practice of infectious diseases. 7th ed.
Philadelphia (PA): Elsevier; 2010:1834.)
Figure 2. Fusion of HIV and host cell membranes. (Adapted with permission from Tsibris AMN, Hirsch MS. Antiretroviral therapy
for human immunodeficiency virus infection. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and practice of infectious diseases. 7th ed. Philadelphia (PA): Elsevier; 2010:1843.)
medications inhibit entry of virus into host cells,
reverse-transcription of viral DNA from an RNA
template, integration of this viral DNA into the
host genome, and processing of newly transcribed viral proteins.
Fusion of HIV with the host cell membrane with
subsequent viral RNA entry into the host cell is
the first step of HIV viral replication (Figure 1).
Viral glycoproteins 120 and 41 group together and
interact with host cell CD4 receptors and CCR5 or
CXCR4 co-receptors, causing fusion of the viral
and host membranes and entry of viral factors
(Figure 2). After fusion, viral RNA is released into
the host cell along with essential viral enzymes,
including the viral reverse transcriptase enzyme
2 Hospital Physician Board Review Manual
(RT). RT then uses host cell nucleosides and
nucleotides to construct a double-stranded viral
complementary DNA (cDNA).1 Viral cDNA interacts with the viral integrase protein in the host cell
cytoplasm. It is then transported into the nucleus
of the host cell, where integrase incorporates
viral cDNA into the host DNA genome.1 Once
incorporated into the host genome, viral DNA is
transcribed and translated into polyproteins by
host enzymes and ribosomes. Viral proteases
then cleave these polyproteins into functional
and mature viral proteins. Full HIV virions are
constructed. These new virions then bud from
the host cell surface, detach, and infect new host
cells, repeating the cycle (Figure 1).1
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Antiretroviral Therapy in HIV Infection
Table 1. Summary of Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs)
Agent
Analogue
Metabolism
Dosing
Zidovudine
(AZT, ZDV)
[Retrovir]
Thymidine
Hepatic glucuronidation
Renal excretion
300 mg orally every TAM1, TAM2 Headache, malaise,
12 hr or
anorexia, nausea,
vomiting, anemia,
200 mg orally every
granulocytopenia,
8 hr
lactic acidosis, hepatic
100 mg orally every
steatosis, peripheral
8 hr for dialysis paneuropathy, lipotients
dystrophy, myopathy
Stavudine
(d4T)
[Zerit]
Thymidine
Didanosine
(ddI)
[Videx]
Adenosine
Adverse Effects
Comments
Alternative NRTI in
combination with 3TC
First antiretroviral
First-line therapy in
combination with 3TC
for pregnant patients
with HIV
Antagonizes d4T and
should not be coadministered
Antagonizes AZT and
Renal excretion
60 kg: 40 mg orally TAM1, TAM2 Peripheral neuropathy,
every 12 hr
hyperlactatemia, lactic
should not be coacidosis,
hepatic
administered
<60 kg: 30 mg orally
steatosis,
lipoatrophy,
Risk of fatal lactic acievery 12 hr
pancreatitis, hyperdosis in combination
lipidemia
with ddl and should
not be co-administered
Peripheral neuropathy,
Should not co-adminCellular metabolism 60 kg: 400 mg orally L74V, 69
pancreatitis, myocardial ister with d4T (see
daily
insertion,
infarction (possible),
above)
<60 kg: 250 mg orally Q151M
mitochondrial
toxicity
Concentration increase
daily
(worst of all NRTIs)
in combination with
Decrease dose with
ganciclovir, allopurinol,
renal dysfunction
TDF
Poor absorption with
Concentration
decrease
food
with methadone
(continued on page 4)
HIV ANTIRETROVIRAL DRUG
CLASSIFICATIONS
Nucleoside and Nucleotide Reverse
Transcriptase Inhibitors
Viral RT uses a pool of available host cellular
nucleosides and nucleotides to construct viral
cDNA from a viral RNA template. Nucleoside/
nucleotide reverse transcriptase inhibitors (NRTIs)
are designed to mimic the structure of these natural nucleosides and nucleotides. When viral RT
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Resistance
erroneously incorporates an NRTI into the growing
viral cDNA chain, the chain is prematurely terminated. NRTIs block further chain elongation in the
3’ direction.1 Table 1 presents a summary of the
drugs in the NRTI class.
With few exceptions, in a modern ART regimen
2 NRTI agents are combined to form an NRTI
backbone that comprises 2 of the 3 active drugs.
A third active agent is then added to this NRTI
backbone. Emtricitabine (FTC) and lamivudine
(3TC) are similar, roughly equivalent cytosine
Infectious Diseases Volume 14, Part 3 3
Antiretroviral Therapy in HIV Infection
Table 1. Summary of Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (continued)
Agent
Analogue
Abacavir (ABC) Guanosine
[Ziagen]
Tenofovir (TDF) Adenosine
[Viread]
Metabolism
Dosing
Resistance
Adverse Effects
Comments
Hepatic glucuronida- 300 mg orally every
tion
12 hr or
600 mg orally daily
200 mg orally every
12 hr with mild
hepatic dysfunction
Contraindicated with
moderate-severe
hepatic dysfunction
Renal excretion
300 mg orally daily
(as prodrug tenofovir disoproxil
fumarate)
K65R, L74V, Hypersensitivity synCurrent preferred alterY115F,
drome (possibly fatal), native NRTI in combination with 3TC
M184V, 69 in- myocardial infarction
(possible)
sertion,
Screen patients for
HLA-B5701 allele to
Q151M
assess risk for hypersensitivity
K65R, TAM1,
69 insertion
Lamivudine
(3TC)
[Epivir]
Cytosine
Renal excretion
300 mg orally daily
or 150 mg orally
every 12 hr
M184V
Emtricitabine
(FTC)
[Emtriva]
Cytosine
Renal excretion
200 mg orally daily
M184V
Possible decline in GFR, Current preferred NRTI
decrease in bone min- in combination with
eral density, Fanconi
FTC
syndrome
Active against HBV
Decrease dose with
renal dysfunction,
(GFR <50 mL/min),
discontinue with GFR
<30 mL/min
Headache, fatigue,
Current preferred alternaneutropenia
tive NRTI in combination
with ABC
Similar to FTC
Active against HBV
Often continued in face
of M184V mutation, as
this mutation leads to
decrease in viral load
and hypersensitivity
of HIV to AZT, even in
presence of TAMs
Headache, fatigue,
Current preferred NRTI in
neutropenia
combination with TDF
Similar to 3TC
Active against HBV
M184V mutation exploited in same manner as
with 3TC
Note: Drug trade names are listed in brackets.
GFR = glomerular filtration rate; HBV = hepatitis B virus.
analogs, and are both very well tolerated. One
of these 2 medications is typically combined with
a second preferred or alternative agent of this
class to form most front-line NRTI backbones.
Tenofovir (TDF) is currently the preferred NRTI
4 Hospital Physician Board Review Manual
in combination with FTC. Abacavir (ABC) is the
main alternative NRTI and is generally combined
with 3TC.
Resistance to NRTIs generally occurs due to
RT mutations. Mutations resulting in resistance to
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Antiretroviral Therapy in HIV Infection
NRTIs and to the other classes of ART medications occur most commonly in the setting of noncompliance or incomplete adherence to a full ART
regimen. Prolonged viremia is often necessary
for the development of such mutations. With the
exception of the M184V and K65R mutations, significant resistance to a drug may take several serial
mutations, which may require several months of
viremia.
Table 1 lists specific mutations conferring resistance to each drug in the NRTI class, but there are
several major mutations of notable importance.
Thymidine analogue mutations (TAMs) were commonly seen prior to the use of triple-drug therapy,
especially in patients taking zidovudine (AZT) or
stavudine (d4T). They allow for excision of NRTIs
from the growing viral cDNA strand. TAM1 mutations occur at positions 41, 210, and 215 on RT and
can confer resistance to multiple drugs across the
NRTI class (eg, TAMs can decrease TDF activity
by a factor of 4).1–4 TAM2 mutations cluster at RT
positions 67, 70, and 219 and do not confer class
resistance to the extent that TAM1 mutations do.1
Insertion mutations can be significant as well, with
an insertion at position 69 conferring classwide resistance.5 Important substitution mutations include
the K65R mutation, which can decrease TDF activity as well as activity of other NRTIs,1 and the
M184V substitution mutation, which may reduce
FTC and 3TC activity by a factor of 1000. However,
M184V also confers a fitness disadvantage to the
HIV virus and reduces the viral load6,7 and renders
HIV highly sensitive to AZT, even in the face of
TAM mutations.8 Therefore, FTC or 3TC therapy
may be continued in patients with known M184V
mutation as an inactive drug to exploit such secondary advantages. This strategy may prove especially useful in patients with multidrug-resistant
(MDR) HIV strains.
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Certain toxicities of this drug class can be attributed to the mechanism of action of NRTIs. In
addition to terminating viral DNA transcription, they
can also inhibit host DNA transcription enzymes.
Mitochondrial DNA polymerase-g is particularly
susceptible to these drugs, and lactic acidosis, peripheral neuropathy, hepatic steatosis, myopathy,
and lipoatrophy can all result from inhibition of this
enzyme.1 Insulin resistance and diabetes may also
be potential adverse effects. The first-line NRTIs
have minimal overlapping interaction with mitochondrial DNA polymerase-g, and therefore are
much better tolerated than their predecessors.
Care must be taken with TDF regimens in patients with renal dysfunction or osteoporosis. ABC
regimens should be avoided in patients with the
HLA-B5701 allele (severe hypersensitivity reaction
may occur) or HIV viral loads >100,000 copies/mL.
Non-nucleoside Reverse Transcriptase
Inhibitors
Non-nucleoside reverse transcriptase inhibitors
(NNRTIs) are allosteric RT inhibitors that bind to
a dedicated site that lies apart from the enzyme’s
active functional site. The result of NNRTI binding is a change to the enzyme’s conformation,
rendering it ineffective at viral DNA transcription.
Table 2 presents a summary of the drugs in the
NNRTI class.
First-generation NNRTIs include nevirapine (NVP)
and efavirenz (EFV). EFV is considered the preferred medication of this class. It has demonstrated superior virologic suppression compared to
triple-NRTI regimens or protease inhibitor–based
regimens with nelfinavir (NFV), indinavir (IDV),
and ritonavir-boosted lopinavir (LPV/r; a 3-letter
antiretroviral abbreviation followed by “/r” indicates
that the antiretroviral is “boosted” with the protease
inhibitor ritonavir.)9–13 and noninferior suppression
Infectious Diseases Volume 14, Part 3 5
Antiretroviral Therapy in HIV Infection
Table 2. Summary of Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Agent
Metabolism
Dosing
Resistance
Adverse Effects
Delavirdine
(DLV)
[Rescriptor]
Etravirine
(ETR)
[Intelence]
Hepatic CYP3A4
400 mg orally every
8 hr
Hepatic CYP3A4,
CYP2C9,
CYP2C19
200 mg orally every
12 hr
Absorption decreased
with food 50%
Nevirapine
(NVP)
[Viramune]
Hepatic CYP3A4,
CYP2B6
200 mg orally daily for K103N, V106A/M, Rash, including
Y181C, Y188L,
Stevens-Johnson
2 weeks, then 400
mg orally daily
G190A/S
syndrome; hepatic
necrosis
Adjustment needed for
dialysis patients
Efavirenz
(EFV)
[Sustiva]
Hepatic CYP3A4,
CYP2B6
Rilpivirine
(RPV)
[Edurant]
Hepatic CYP3A4
Comments
Rarely used due to frequent dosing and paucity of data
Y181C, G190A,
multiple other
mutations
Rash, nausea
Only medication of this class that
cannot be inactivated by a single
point mutation
Current alternative NNRTI
Contraindicated in women with CD4
>250 cells/μL and men with CD4
>400 cells/μL due to risk of hepatic
toxicity
Can precipitate acute methadone
withdrawal
Current preferred NNRTI
600 mg orally daily on K103N, 100, 106, Rash, hepatotoxicity,
empty stomach
181, 188, 190,
vivid dreams, insom- Must be taken on empty stomach
225
nia, dizziness, poor
(usually before bed)
concentration, terato- Can precipitate acute methadone
genicity (Pregnancy
withdrawal
Category D)
25 mg orally every day, V90I, K101E/P/T, Depression, insomnia, Current alternative NNRTI
taken with minimum
E138K/G,
headache, rash, QT Take with minimum 400-kcal meal
400-kcal meal
V179I/L, Y181I/C, prolongation
H2Bs must be taken 12 hr before
Caution in severe renal V189I, H221I,
or 4 hr after RPV
F227C/L, M230L
impairment
Antacids should be taken 2 hr beContraindicated with
fore or 4 hr after RPV
PPIs, anticonvulsants,
Caution with combination with
rifampin/rifabutin/ rifamedications that prolong QT
pentine, dexamethainterval
sone, St. John’s wort
ddl should be given 2 hr before or
(all decrease RPV
4 hr after
levels)
Contraindicated when
initial HIV viral load
>100,000 copies/mL
(more virologic failure
than EFV)
Note: Drug trade names are listed in brackets.
H2Bs = histamine2-receptor blockers; PPI = proton-pump inhibitor.
compared to atazanavir-based (ATV) therapy.14
EFV should be taken on an empty stomach. Neuropsychiatric side effects have been described in
approximately 50% of patients, but are generally
6 Hospital Physician Board Review Manual
mild and self-limited (within 2–6 weeks). EFV is
the only FDA pregnancy category D antiretroviral
and should not be initiated during pregnancy. NVP
should not be administered to men with a CD4
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Antiretroviral Therapy in HIV Infection
count >400 cells/μL and women with a CD4 count
>250 cells/μL, as usage in these groups has been
associated with hepatic necrosis.
Second-generation NNRTIs include etravirine
(ETR) and rilpivirine (RPV). These NNRTIs have
been chemically altered from their predecessors
with the theoretical goal of rendering them more effective against drug-resistant HIV. RPV, the newest
drug from the NNRTI class, has been demonstrated
to have a higher rate of virologic failure compared
to EFV in patients with higher HIV viral loads. The
E138K mutation is commonly seen in the setting of
RPV virologic failure, and the M184V/I and K65R/N
mutations are seen with greater frequency in this
setting than with EFV.15,16 Administration of RPV
in patients with a viral load >100,000 copies/mL
should be avoided, and its use is only approved in
treatment-naïve patients. RPV must also be taken
with a high-calorie meal. Its absorption requires
an acidic environment, so care must be taken to
avoid direct co-administration with antacids and
H2-blocking medications. Proton pump inhibitors
should be avoided altogether in patients on RPV.
RPV may cause an artifactual rise in creatinine and
decrease in glomerular filtration rate (GFR). ETR
has been studied only in treatment-experienced patients and is approved only in this setting (see ART
Selection in Multidrug-Resistant HIV, page 19).
Unfortunately, since it is not directly involved in
the action of the RT enzyme, the conformation
of the dedicated NNRTI binding site is not important for RT functionality.1 Therefore, mutations
at this site may block NNRTIs from binding, but
generally do not affect RT functionality. Simple
single-point mutations to the enzyme can render
every first-generation NNRTI ineffective (hence
the development of second-generation NNRTIs).
Currently, ETR is the only NNRTI that is approved
in the setting of NNRTI mutations. The low barrier
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to resistance with the NNRTIs may limit the use
of these medications in patients with a history of
noncompliance to ART.
NNRTIs are hepatically metabolized by cytochrome P450 (CYP) enzymes, making drug-drug
interactions a concern. Particular care must be
taken when combining these medications with
anticonvulsant, antimycobacterial, and certain antifungal therapies. Protease inhibitors (PI) may have
strong interactions with NNRTIs as well, and their
combination should generally be avoided, except
in special cases.
Protease Inhibitors
PIs inhibit HIV aspartyl protease, an enzyme
used by the virus to cleave and construct gag and
pol proteins. Gag proteins form structural aspects
of the virus, while pol proteins comprise the vital
viral enzymes RT, protease, and integrase.
PIs are primarily metabolized by hepatic CYP enzymes, especially CYP3A4. They may also induce
or inhibit these enzymes. Drug-drug interactions
are therefore significant, especially in the setting
of co-administration with immunosuppressants,
antiarrhythmics, antibiotics, statins, opiates, oral
contraceptives, benzodiazepines, or other ART
medications. For example, acute withdrawal may
occur when PIs are administered to patients taking
chronic opiates like methadone. Efficacy of contraceptives may be reduced significantly. Table 3
presents a summary of the drugs in the PI class.
The metabolism of PIs by CYP3A4 is exploited
with the relatively recent concept of “boosting.” The
PI ritonavir (RTV) is an especially powerful inhibitor of CYP3A4. Owing to pill burden, toxicity, and a
host of potential drug-drug interactions via its effect
on other CYP enzymes, RTV is no longer considered a preferred stand-alone PI. However, when
RTV is given at subtherapeutic doses in combiInfectious Diseases Volume 14, Part 3 7
Antiretroviral Therapy in HIV Infection
Table 3. Summary of Protease Inhibitors (PIs)
Agent
Metabolism
Dosing
Resistance
Adverse Effects
Comments
Ritonavir (RTV) Hepatic CYP3A4,
CYP2D6
[Norvir]
For boosting,
M46L, V82A, I84V; minor mu- Diarrhea, nausea/vom100–200 mg orally
tations at 10, 20, 24, 32, 36,
iting, altered taste,
every 12 hr
54, 71, 73, 76, 77, 90
paresthesias, dyslipidemia
Stand-alone, 300 mg
orally every 12 hr,
increase to 600 mg
orally every 12 hr
over 5 days
Indinavir (IDV) Hepatic CYP3A4
[Crixivan]
800 mg orally every M46L, V82A, I84V; minor mu- Nephrolithiasis, uncon12 hr boosted with
tations at 10, 20, 24, 32, 36,
jugated hyperbilirubiRTV 100 mg orally
54, 71, 73, 76, 77, 90
nemia (no jaundice),
every 12 hr
abdominal pain, nausea, dry skin
Saquinavir
(SQV)
[Invirase]
May prolong PR/QT
intervals
One randomized trial
showed non-inferiority
to atazanavir and better side effect profile*
Poor efficacy compared
to other PIs
RTV does not boost
levels
Should not be used in
treatmentexperienced patients
700 mg orally every I50V, I84V; minor mutations at Diarrhea, rash, hyperlip- Prodrug of amprenavir
idemia, may increase Sulfonamide compo12 hr boosted with
10, 32, 46, 47, 54, 73, 76,
RTV 100 mg orally
82, 90
risk for cardiovascular
nent may cause reacevery 12 hr
disease
tion in sulfa-allergic
patients
400 mg orally every V82A, V32I, I47A; minor muta- Diarrhea, nausea/vomit- Current alternative PI
12 hr boosted with
tions at 10, 20, 24, 33, 46, 50, ing, hyperlipidemia,
Often compared with
RTV 100 mg orally
53, 54, 63, 71, 73, 76, 84, 90 may increase risk for
newer PIs for nonevery 12 hr
cardiovascular disease inferiority
Concurrent V32I, I47A, and
position 46 mutation confers
Generally 6 or more
high resistance
mutations required for
significant drug resistance
(continued on page 9)
Nelfinavir
(NFV)
[Viracept]
Hepatic CYP3A4
1000 mg orally every L90M, G48V; minor mutations Nausea/vomiting, diar12 hr boosted with
at 10, 24, 54, 62, 71, 73, 77, rhea, abdominal pain,
RTV 100 mg orally
82, 84
hyperlipidemia
every 12 hr
Take within 2 hr of
high-calorie/fat meal
Hepatic CYP2C19, 1250 mg orally every D30N, L90M; minor mutations Diarrhea, hyperlipidemia
CYP3A4, CYP2D6 12 hr
at 10, 36, 46, 71, 77, 82, 84,
88
Take with meals
Fosamprenavir Hepatic CYP3A4,
(FPV)
biliary excretion
[Lexiva/Telzir]
Lopinavir
(LPV)
[Kaletra
(lopinavir/r
combination
pill)]
Powerful CYP3A4 inhibition exploited at
low doses to boost
levels of other PIs
Rarely used as
stand-alone agent
due to toxicity
Also inhibits CYP2D6
Induces CYP3A,
CYP1A2, CYP2C9,
CYP2C19, CYP2B6
Must increase water
intake to avoid
nephrolithiasis
Infrequently used
due to toxicity
Hepatic CYP3A4
8 Hospital Physician Board Review Manual
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Antiretroviral Therapy in HIV Infection
Table 3. Summary of Protease Inhibitors (continued)
Agent
Metabolism
Dosing
Resistance
Adverse Effects
Comments
Tipranavir
(TPV)
[Aptivus]
Hepatic CYP3A4
500 mg orally every
12 hr boosted with
RTV 200 mg orally
every 12 hr
Take with high-fat
meal
Atazanavir
(ATV)
[Reyataz]
Hepatic CYP3A4
300 mg orally daily
boosted with 100
mg RTV orally
daily
400 mg orally daily
unboosted if not
given with TDF/
FTC
Take with food
Absorption requires
low pH, avoid
H2Bs and PPIs
Darunavir
(DRV)
[Prezista]
Hepatic CYP3A4
800 mg orally daily
boosted with 100
mg RTV orally
daily in treatmentnaïve patients
600 mg orally every
12 hr boosted with
RTV 100 mg orally
every 12 hr in
treatmentexperienced
patients
Hepatotoxicity, intracra- Used in treatmentnial hemorrhage, nauexperienced
sea, diarrhea; GI side
patients with resiseffects largely due to
tance to other PIs;
higher dose of ritonavir efficacy demonused
strated in RESIST-1
and -2 trials for this
population
Contraindicated in
patients at risk for
serious bleeding
Sulfonamide component may cause
reaction in sulfaallergic patients
Current preferred PI
I50L, I84V; minor mutations at Nausea, hyperbilirubinemia with jaundice/
10, 16, 20, 24, 32, 33, 34,
Should not be used
scleral icterus, nephro- in treatment-expe36, 46, 48, 53, 54, 60, 62,
lithiasis, hyperlipidemia rienced patients on
64, 71, 73, 85, 90, 93
renal dialysis
Does not affect methadone levels
Should not be used in
combo with ddl/FTC
due to inferiority
Can prolong PR interval
PI with least effect on
lipids
Only PI shown to be
non-inferior to EFV†
I50V, V11I, I54L, G73S, L89V, Diarrhea, nausea, head- Current preferred PI
V32I, L33F, I47V, I54M, I76V, ache, nasopharyngitis, Sulfonamide compoI84V
acute hepatitis, hypernent may cause reaclipidemia
tion in sulfa-allergic
patients
Should be taken with
food
Note: Drug trade names are listed in brackets.
H2Bs = histamine2-receptor blocker; PPI = proton-pump inhibitor.
*Vrouenraets SM, Wit FW, Fernandez Garcia E, et al; BASIC Study Group. Randomized comparison of metabolic and renal effects of saquinavir/r
or atazanavir/r plus tenofovir/emtricitabine in treatment-naive HIV-1-infected patients. HIV Med 2011;12:620–31.
†Daar ES, Tierney C, Fischl MA, et al; AIDS Clinical Trials Group Study A5202 Team. Atazanavir plus ritonavir or efavirenz as part of a 3-drug
regimen for initial treatment of HIV-1. Ann Intern Med 2011;154:445–55.
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Infectious Diseases Volume 14, Part 3 9
Antiretroviral Therapy in HIV Infection
nation with another “primary” active PI, CYP3A4
metabolism becomes saturated, allowing plasma
concentrations of the primary PI to become higher
(“boosted”) and more stable (increased half-life)
with less frequent dosing. The newer primary PIs
ATV and darunavir (DRV) have less toxicity than
their predecessors (eg, nausea, diarrhea, hyperlipidemia). The overall effect of this strategy is
that fewer pills are required to be taken on a less
frequent basis with less toxicity to the patient. This
boosting effect also minimizes viral mutations to
the active PI. Before boosting was employed, the
shorter half-life of primary PIs would cause plasma
concentrations to drop quickly. If a dose of medication was accidentally missed, the plasma concentration might drop even further to the point that the
HIV virus was able to begin replicating in the presence of subtherapeutic drug, thereby allowing the
virus to mutate in a selectively resistant manner.
With the extended half-life and stable plasma concentrations now seen with boosted PIs, mutations
are much less common. However, while boosting
does allow for higher-fidelity concentrations of
less toxic drugs, adverse effects and drug-drug
interactions that still do exist with the primary PIs
may become accentuated as well. RTV toxicity is
also limited at this subtherapeutic dose, yet some
effects such as nausea and vomiting may become
clinically relevant.
Currently, DRV and ATV are the preferred
medications of this class, both boosted by RTV.
ATV was found to be noninferior with respect to
virologic response compared to EFV.14 Boosting
with RTV was clearly shown to be effective when
RTV-boosted ATV (ATV/r) was compared to unboosted ATV17 and to LPV/r.18 Once-daily DRV/r
was demonstrated to be noninferior to LPV/r in
treatment-naïve patients (once-daily DRV/r is only
approved in treatment-naïve patients; otherwise it
10 Hospital Physician Board Review Manual
should be used twice daily).19 DRV is an effective
choice in treatment-experienced patients and in
MDR HIV (see Selection of PI and ART Selection in Multidrug-Resistant HIV, pages 18 and 19,
respectively).
Dyslipidemia is a toxicity seen with drugs from
this class (ATV having the least effect in this regard1). Propensity toward insulin resistance and
diabetes may potentially occur as well. Gastrointestinal symptoms are well documented, including
abdominal pain, nausea, vomiting, and diarrhea.
With regard to the primary preferred PIs, ATV has
the notable effect of reversibly causing increased
indirect bilirubin levels due to inhibition of UDPglucuronosyltransferase.20 Jaundice or scleral icterus may even become evident in patients taking
ATV, and a change to an alternative agent should
be considered if cosmetic concerns exist. While
isolated hyperbilirubinemia itself does not constitute hepatic failure in this setting, the presence of
elevated transaminases should raise concern for
alternative pathology.
As mentioned previously, newer boosted PIs
have a high barrier to viral resistance. Several
mutations to viral protease are usually required for
resistance, and generally one or more mutations
must be major.1 DRV is especially robust in the setting of multiple PI mutations.
Entry Inhibitors
Entry inhibitors are drugs targeted at inhibition
of HIV fusion and entry into host cells. The primary drugs of this class are enfuvirtide (ENF) and
maraviroc (MVC). Neither of these medications is
included in current recommendations for preferred
ART regimens. ENF is an amino acid polypeptide
fusion inhibitor and is used primarily as a salvage
drug for patients who have prior experience with
ART and multiple resistance mutations to primary
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Antiretroviral Therapy in HIV Infection
ART medications. Two randomized trials with median patient CD4 count <100 cells/μL demonstrated significantly improved viral suppression when
ENF was added to an optimized ART regimen.21,22
ENF is dosed as a 90-mg subcutaneous injection
administered twice daily. Advantages of this drug
include no need to adjust dose for renal or hepatic
function and no known drug interactions. There is
also no evidence of teratogenicity in animal models (although experience in pregnant humans is
lacking). A major disadvantage, however, is the
need for twice daily injections to avoid gastrointestinal denaturation of the medication. Not only is this
a potential barrier to home use among patients, but
there is also additional risk of local injection reactions, which occur in 98% of patients.1 Injections
must be administered away from recent previous
injection sites or areas of reactive skin, and care
must also be taken to avoid blood vessels, large
nerves, injured skin, and tattoos. Nausea, vomiting, diarrhea, fatigue, and insomnia are additional
adverse effects that have been described. Viral
resistance can occur with amino acid substitutions
on viral glycoprotein 41, usually at position 36, 38,
40, and 43.23
MVC is a CCR5 allosteric antagonist. It is the
only approved ART medication that targets a host,
not a viral, receptor. It is designed to prevent interaction of viral gp120 with host CCR5, thereby inhibiting viral attachment. It has been demonstrated
to effectively lower viral load and raise CD4 counts
in 2 randomized, double-blind, placebo-controlled
trials.24,25 Patients must be screened with a tropism
test prior to initiation to ensure their specific HIV
strain does not use CXCR4 for entry, either in lieu
of or in conjunction with reliance on CCR5, as MVC
has not been shown to be of benefit in this patient
population. MVC was shown to be most effective
in these 2 studies when combined with at least
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2 other effective antiretrovirals. If used in combination with ENF, patients responded best when
there was no ENF resistance and when ENF was
being administered to the patient for the first time.
The 48-week MERIT study in which MVC plus
AZT/3TC was compared with EFV plus AZT/3TC
(a standard primary initial HAART regimen at the
time of that study) failed to demonstrate that the
MVC regimen conferred as much viral suppression as the EFV regimen.26 However, re-analysis
of this data in the MERIT-ES study with a newer
Trofile test demonstrated improved efficacy, and
MVC may now be considered in treatment-naïve
patients in special cases.26
MVC is generally dosed at 300 mg twice daily.
There is little data to date to suggest dose adjustment in patients with renal or hepatic dysfunction.
MVC is metabolized by CYP3A, and therefore
dose adjustment is necessary with CYP3A inducers or inhibitors. Concurrent medications that inhibit CYP3A that may be encountered in the HIV
population include PIs and clarithromycin, while
common inducers encountered in this population
include EFV, NVP, and anticonvulsants. Dosing
should be decreased to 150 mg twice daily in the
presence of an inhibitor, and increased to 600 mg
twice daily with an inducer. Side effects of MVC
include dizziness, cough, rash, upper respiratory
tract infection, and fever.1
There are 2 major pathways of viral resistance
to MVC. The first occurs with an amino acid substitution on viral gp120.1 The second, and much
more common, pattern is seen when selection
of CXCR4-binding virus occurs (patients initially
screened for CXCR4-using virus may have low levels present that are undetectable by the lab assay),
as was demonstrated in the MOTIVATE trials.24
Aside from drug resistance, selection of CXCR4
virus in patients prescribed MVC may have adInfectious Diseases Volume 14, Part 3 11
Antiretroviral Therapy in HIV Infection
ditional consequences. Patients with CXCR4predominate virus may develop a faster drop in
CD4 cell count and more aggressive progression
to AIDS.5,27–29 Discontinuation of MVC in patients
who develop CXCR4 tropism may lead to a resurgence of CCR5-predominate infection in such patients (however, MVC should not be reconsidered
as a viable therapeutic option in the future).
Integrase Strand Transfer Inhibitors
Integrase strand transfer inhibitors (INSTIs) are
a class of antiretroviral medications designed to
block HIV integrase–mediated incorporation of HIV
cDNA into the host DNA genome. Raltegravir (RAL)
was the first drug of this class, and elvitegravir
(EVG) has just received FDA approval (see New
and Investigational Medications). RAL has been
demonstrated to be noninferior and better tolerated
compared to EFV-containing primary ART regimens30 for treatment-naïve patients. RAL was also
shown to decrease the viral load faster within 24
weeks compared to these EFV-based regimens.30
The clinical significance of this class-wide INSTI
effect is unknown. RAL also has demonstrated efficacy in treatment-experienced patients. It showed
greater suppression of HIV viral load at 48 weeks
compared to placebo when added to an optimal
ART backbone in 2 randomized, double-blinded
phase III studies.31 Of note, in one of these studies
patients with resistant virus concurrently started on
DRV and ENF for the first time had even greater
response, although the study was not powered to
assess this effect.32 In another investigation of RAL
use in treatment-experienced patients, substituting
RAL for ENF maintained virologic suppression.33
RAL is administered orally at 400 mg twice
daily. Dose adjustment is not necessary in renal or
hepatic insufficiency, unless hepatic insufficiency
is severe. It is metabolized by glucuronidation.
12 Hospital Physician Board Review Manual
Primary resistance mutations to the viral integrase
protein exist as substitutions at Y143, Q148, and
N155 on the integrase enzyme.34
Fixed-dose Combination Pills
The emergence of several commercial fixeddose combination (FDC) pills has made the administration of several ART regimens a more practical
venture. These combination pills lead to increased
adherence by limiting the number of pills patients
must consume. Some of these formulations have
the advantage of offering a complete ART regimen
in 1 pill taken once daily. Toxicities and drug-drug
interactions must still be considered for each individual component of these FDCs (Table 4).
New and Investigational Medications
EVG is an INSTI that received FDA approval in
August 2012. It is currently approved only for HIV
therapy in treatment-naïve patients as part of a
4-drug combination pill trade-named Stribild (EVG/
COB/TDF/FTC). This regimen contains 150 mg of
the investigational drug cobicistat (COB) for boosting (discussed below), as well as 150 mg EVG +
200 mg FTC + 300 mg TDF. This combination is 1
pill administered once daily. Phase II and III clinical
trials comparing the EVG/COB/TDF/FTC pill to Atripla (EFV/TDF/FTC) (see Table 4) have demonstrated non-inferiority with regard to viral suppression.35
An ongoing study comparing EVG/COB/TDF/FTC
to ATV/r plus TDF/FTC is demonstrating the same
result.36 EVG is also under investigation as therapy
for treatment-experienced patients in combination
with PIs. RTV is being used as the boosting medication in these studies.
EVG is primarily metabolized by CYP3A4. The
dose should be decreased to 85 mg once daily
when used in combination with ATV/r or LPV/r.
When EVG is used in combination with MVC, the
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Antiretroviral Therapy in HIV Infection
Table 4. Fixed-Dose Combination Pills
Combination (Trade Name)
Components
Dosing
Atripla*
Combivir
Complera*
Epzicom
Trizivir
Truvada
Stribild*
600 mg EFV + 200 mg FTC + 300 mg TDF
300 mg AZT + 150 mg 3TC
25 mg RPV + 200 mg FTC + 300 mg TDF
300 mg 3TC + 600 mg ABC
300 mg AZT + 150 mg 3TC + 300 mg ABC
200 mg FTC + 300 mg TDF
150 mg EVG + 150 mg COB + 200 mg FTC +
300 mg TDF
1 tablet once daily before bed on empty stomach
1 tablet twice daily
1 tablet once daily with a meal
1 tablet once daily
1 tablet twice daily
1 tablet once daily
1 tablet once daily
*Complete antiretroviral regimen.
dose of MVC should be reduced to 150 mg twice
daily. Gastrointestinal side effects (nausea) were
significantly notable with the EVG/COB/TDF/FTC
combination, although these side effects might be
most attributable to the COB portion of the new
pill. Primary viral integrase substitution mutations
demonstrated to confer resistance to EVG include
E92Q, H51Y, S147G, and E157Q.37
COB is a pharmacoenhancer medication that
strongly inhibits CYP3A4 and is used as a dedicated boosting agent. It was approved by the FDA as
part of the EVG/COB/TDF/FTC regimen in August
2012. It was designed with the intent to replace
RTV for boosting. COB has the theoretical benefit
of interacting with fewer CYP enzymes compared
to RTV. The hope that COB may have fewer side
effects when used as a booster has not yet bore
fruit, however, as a study comparing EVG/COB/
TDF/FTC to ATV/r plus TDF/FTC did not show any
difference in this regard.38 Thus far, COB has only
been approved as a booster for EVG (as part of
EVG/COB/TDF/FTC) in treatment-naïve patients.
It is also currently being studied as a booster for
ATV in a head-to-head trial with an ATV/r-boosted
regimen. COB may replace RTV where boosting is
indicated in the near future.
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The most common toxicity associated with COB
is gastrointestinal side effects. Cobicistat also
competes with creatinine excretion in the kidney,
causing an increase in serum creatinine levels that
does not represent a true reduction in GFR. This
asymptomatic elevation in serum creatinine seen
in approximately 7% of patients studied on EVG/
COB/TDF/FTC was sustained at 48 weeks of therapy. A rise in serum creatinine above 0.4 mg/dL
should prompt consideration of alternative therapy.
Stribild should also not be initiated in patients with
baseline serum creatinine clearance of less than
70 mL/min.39
Dolutegravir (DTG) is an investigational INSTI. It
does not require boosting. Phase III clinical trials are
currently underway involving patients with established resistance to other INSTIs. Eligible patients
must be older than age 18, should avoid pregnancy,
have documented HIV-1 with a viral load of at least
400 copies/mL 3 months prior to DTG initiation,
have documented RAL or EVG resistance, and be
unable to use a full viable ART regimen due to resistance. Exclusion criteria included GFR <30 mL/min,
pregnancy/breastfeeding, allergy to another integrase inhibitor, alanine aminotransferase (ALT) >5
times the upper limit of normal (ULN), ALT >3 times
Infectious Diseases Volume 14, Part 3 13
Antiretroviral Therapy in HIV Infection
ULN with total bilirubin >1.5 ULN, and severe hepatic impairment.40 DTG is administered once daily,
but in the presence of resistance to other INSTIs it is
administered twice daily.16 The presence of Q148 or
G140 mutations may indicate limited viral response
to DTG therapy.41
USE OF Antiretroviral THERAPY
Guidelines for ART Initiation
Expert consensus continues to evolve with regard to criteria for initiation of ART. When ART first
became available, consensus was initially to push
for early therapy for every patient. It soon became
clear, however, that the toxicities of these early
regimens were not benign, the high pill burden
made compliance difficult, and resistance quickly
developed if adherence was not strict. As the pendulum swung back toward delayed therapy, however, obvious detriments arose such as increased
progression to AIDS or death, increased risk of
opportunistic infection (OI) and of HIV-associated
organ dysfunction (such as HIV-associated nephropathy), and decline in absolute ability to regain
maximal CD4 counts and full viral suppression.
However, the newer ART regimens are better
tolerated and pill burdens have lessened as a
result of boosting, more potent formulations, and
fixed-dose combinations. The potential for greater
patient compliance and improved mortality has
experts once again recommending earlier initiation
of these newer ART regimens.
While HIV cure has never been achieved with
any current regimen, there are 4 other major
goals of ART treatment: (1) to reduce HIV-associated morbidity and to extend and improve patient
life; (2) to restore and maintain a patient’s immune system; (3) to suppress the HIV viral load
to undetectable levels; and (4) to prevent HIV
14 Hospital Physician Board Review Manual
transmission. Because evidence indicating that
these goals are increasingly achievable with current treatment regimens, HIV treatment guidelines
now recommend initiating ART for any HIV-infected patient, regardless of their CD4 cell count. The
strength of the recommendation increases with
lower CD4 counts. Other compelling indications
for ART initiation and strength of recommendation
are listed in Table 5.16
These most recent recommendations to start
ART in all HIV patients are backed by several studies. The HIV-CAUSAL study demonstrated a 38%
increase in AIDS or death in patients initiated on
ART at a CD4 count ≤350 cells/μL compared to
a group in which ART was initiated at CD4 count
≤500 cells/μL.42 The CASCADE and COHERE trials confirmed these results in patients with CD4
≤500 cells/μL.43,44 Expert consensus, rather than
randomized trials, have extended the recommendation to start ART at CD4 counts >500 cells/μL.
Benefit seen from administering ART to HIVpositive patients who were sexually active with
HIV-negative partners is yet another compelling
reason to extend the universal ART treatment
recommendation (not mentioned in Table 5). The
HPTN 052 trial demonstrated a 96% reduction in
HIV transmission to a noninfected partner when the
HIV-positive partner was on ART therapy.45 This effect was demonstrated in HIV-positive partners with
CD4 counts of 350 to 500 cells/μL, and these results have been extrapolated to higher CD4 counts.
Any of the approved ART regimens can be used to
achieve the specific benefit of minimizing transmission. Ideally, maximum viral suppression should be
achieved before onset of sexual activity (or attempts
at conception begin in HIV-discordant couples
desiring natural pregnancy). Patients should be
advised that even use of ART cannot prevent HIV
transmission with absolute certainty. It also cannot
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Antiretroviral Therapy in HIV Infection
Table 5. Indications for Antiretroviral Therapy Initiation
Condition
Level of Evidence
CD4 ≤500 cells/μL
AIa
Pregnancy
AIa
Opportunistic infection (within 2 weeks)*
AIa
†
Active tuberculosis infection with CD4 count <50 cells/μL (within 2 weeks of anti-tuberculosis therapy)
AIa
†
Active tuberculosis infection with CD4 count ≥50 cells/μL (within 8–12 weeks of anti-tuberculosis therapy)
AIa
Chronic hepatitis B virus co-infection
AIIa
HIV-associated nephropathy
AIIa
Age >60 years
BIIa
CD4 count >500 cells/μL
BIII
Acute primary HIV infection
BIII
Tuberculosis meningitis (within 2–8 weeks of anti-tuberculosis therapy)
BIII
Chronic hepatitis C virus co-infection
CIII
Strength of Recommendations
A Strong support
B Moderate support
C Limited support
Quality of Recommendations
Ia
Evidence from 1 or more randomized controlled clinical trials published in the peer-reviewed literature
Ib
Evidence from 1 or more randomized controlled clinical trials presented in abstract form at peer-reviewed scientific meetings
IIa
Evidence from nonrandomized clinical trials or cohort or case-control studies published in the peer-reviewed literature
IIb
Evidence from nonrandomized clinical trials or cohort or case-control studies presented in abstract form at peer-reviewed scientific meetings
III
Recommendation based on the panel’s analysis of the accumulated available evidence
*Antiretroviral therapy should be used with caution in patients with cryptococcal meningitis; this is discussed in the section on immune reconstitution inflammatory syndrome.
†Does not include tuberculosis meningitis.
prevent the transmission of other sexually transmitted infections. Therefore, condom use should
still be encouraged. Pre-exposure prophylaxis
therapy may be considered for HIV-negative patients who engage in sexual contact with patients
who have confirmed HIV or who have high risk
for HIV infection (see Preexposure Prophylaxis,
page 25).
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Selection of Regimen
Selection of an antiretroviral regimen is based
upon multiple considerations. Since noncompliance
can lead to ART resistance, barriers to compliance
must be addressed prior to ART initiation. Specifically, untreated mental illness such as depression,
untreated chemical dependency, homelessness,
and a chaotic life circumstance are all potential
Infectious Diseases Volume 14, Part 3 15
Antiretroviral Therapy in HIV Infection
Table 6. Antiretroviral Regimens for Treatment-Naive Patients
Preferred
NNRTI-based
PI-based
INSTI-based
Alternative
EFV + TDF/FTC
ATV/r + TDF/FTC
DRV/r + TDF/FTC
RAL + TDF/FTC
NNRTI-based
EFV + ABC/3TC*
RPV† + TDF/FTC
RPV† + ABC/3TC*
NVP + TDF/FTC
NVP + ABC/3TC *
PI-based
DRV/r + ABC/3TC*
LPV/r + TDF/FTC
ATV/r + ABC/3TC*
LPV/r + ABC/3TC*
INSTI-based
RAL + ABC/3TC*
EVG/COB + TDF/FTC
Third-line for use in special circumstances
Entry inhibitor–based
MVC + TDF/FTC
MVC + ABC/3TC *
NRTI-sparing‡
DRV/r + RAL
LPV/r + RAL
INSTI = integrase strand transfer inhibitor; NNRTI = non-nucleoside reverse transcriptase inhibitor; NRTI = nucleoside reverse transcriptase inhibitor; PI = protease inhibitor.
*ABC-based NRTI combination should be avoided in patients with HIV viral load >100,000 copies/mL and/or presence of HLA-B5701 allele.
†RPV-based regimens should be avoided in patients with HIV viral load >100,000 copies/mL.
‡Limited data exists examining the use of such regimens.
barriers to compliance. A patient’s additional medical conditions must be taken into account as well,
as should interactions with any medications the patient is taking for these conditions. Pregnancy status
or desire to become pregnant should be assessed
with female patients. Medication cost and access to
coverage or assistance may become a factor. Prior
exposure to ART and a patient’s HIV genotype are
additional factors.
All of the preferred regimens for treatment-naïve
patients contain 2 NRTI medications (an “NRTI
backbone”) combined with an additional anchoring
agent. The preferred additional agent can either be
an NNRTI, a boosted PI, or an INSTI. See Table 6
for listings of preferred, alternative, and third-line
NRTI-backbones.
NRTI Backbone
Three NRTI combination formulations are currently available (Table 4): TDF/FTC, ABC/3TC, and
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AZT/3TC. Currently the TDF/FTC backbone is preferred, and ABC/3TC is considered the primary alternative. A 48-week head-to-head comparison study
of TDF/FTC and AZT/3TC (each combination combined with EFV) demonstrated that TDF/FTC therapy
resulted in noninferior viral load suppression (primary
endpoint) as well as better CD4 improvement and
less drug resistance and side effects.46 At 96 weeks,
patients in the TDF/FTC arm had less lipodystrophy
and better serum triglyceride levels. TDF/FTC has
the additional advantage of being administered as
1 pill once daily, as opposed to AZT/3TC, which is
administered as 1 pill twice daily.
A 48-week study comparing ABC/3TC to AZT/3TC
(each combined with EFV) also demonstrated that
ABC/3TC is noninferior to AZT/3TC with respect to
viral suppression.47 Again, ABC/3TC offers the advantage of being administered as 1 pill once daily.
Two important studies have compared TDF/FTC
and ABC/3TC. The HEAT trial compared each
Infectious Diseases Volume 14, Part 3 17
Antiretroviral Therapy in HIV Infection
backbone in combination with LPV/r and demonstrated equal efficacy with respect to viral load
suppression.48 The ACTG 5202 compared each of
these NRTI backbones head-to-head in combination with both EFV and ATV/r (each separately).
The ABC/3TC arm demonstrated higher cholesterol levels, more adverse effects (most likely from
ABC hypersensitivity in the setting of HLA-B5701
positivity), and, most importantly, significantly higher virologic failure in patients with high initial viral
loads (>100,000 copies/mL) compared to the TDF/
FTC arm.49 The rate of virologic failure was so significant that this group of patients was unblinded
and offered TDF/FTC as alternative therapy. This
increased rate of virologic failure was not observed
in a second randomized trial.48
As mentioned, ABC-based backbones have
been associated with concerning adverse reactions. A severe, life-threatening hypersensitivity
reaction is possible in patients positive for the HLAB5701 allele. Also, a large cohort review trial did
show increased risk of myocardial infarction in patients using ABC over the prior 6 months, although
follow-up studies have not clearly supported this
finding.50 Caution is therefore generally recommended in patients at risk for vascular disease,
and ABC/3TC is only considered a viable NRTI
combination in the setting of an HIV viral load of
<100,000 copies/mL and a negative HLA-B5701
allele test.
Selection of NNRTI
NNRTI-based regimens are frequently employed
in treatment-naïve patients. EFV is generally considered the first-line medication in this class, with
RPV and NVP being alternatives.16 As mentioned
above, EFV is a Pregnancy Category D agent and
should not be initiated in pregnant patients. EFV
has generally demonstrated better efficacy and less
18 Hospital Physician Board Review Manual
toxicity compared to NVP. EFV is available in a
single-pill, once-daily fixed-dose combination as
EFV/TDF/FTC (Atripla). RPV is also a popular
choice since it has been made available in the
single-pill combination RPV/FTC/TDF (Complera;
see Table 4 for complete formulation). However, it
is considered less effective than EFV in patients
with high viral loads and is contraindicated in patients requiring proton-pump inhibitors for stomach
acid suppression. ETR is not approved for treatment-naïve patients.
Selection of PI
PI-based regimens all generally make use of
RTV boosting, as discussed above. ATV and
DRV are considered first-line agents of this class
because of their toxicity profiles, although LPV,
fosamprenavir (FPV), and saquinavir (SQV) have
all demonstrated noninferiority with respect to efficacy. DRV is the most robust agent in the face of
multiple viral mutations. ATV has the least effect
on lipids, although DRV is almost equivalent. As
mentioned, COB may replace RTV as the boosting
agent of choice in these regimens, although hopes
it would have less adverse reactions compared to
RTV have not necessarily been seen to date.
If virologic failure occurs on an initial first-line
regimen, a switch to a boosted PI-based regimen
is often recommended. Again, the boosted PI is
usually combined with 2 NRTIs. If PI mutations
occur in addition to resistance to other classes, a
boosted DRV- or TPV-based regimen is especially
recommended.16
Selection of INSTI
RAL is currently the preferred medication of
this class. The new COB-boosted EVG (as part
of Stribild) is an alternative regimen for treatmentnaïve patients.
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Antiretroviral Therapy in HIV Infection
ART Selection in MultiDrug-Resistant HIV
MDR-HIV can frequently be seen in patients
who have failed 2 or more standard ART regimens
and occasionally in patients newly diagnosed with
HIV. Treatment in these settings often requires a
nonstandard regimen. At least 2 active drugs, and
ideally 3 active drugs, should be administered,
and potency of the drugs is considered a more
important factor than the number of drugs administered. Typically, a boosted PI should be selected
based on genotypic resistance testing (data exists that DRV/r or TPV/r are most effective in this
setting51,52). ETR has been studied in the setting
of known NNRTI resistance in combination with
DRV/r and NRTIs and was found to confer benefit.53 In settings where no documented RAL resistance exists, it should be added as well because
there is evidence for significant efficacy in this setting31 (although special resistance testing to RAL
may be needed, especially if RAL has been used
in the past, as resistance attenuates benefit54).
MVC has shown effect in CCR5-tropic infections.25
NRTIs may continue to provide partial efficacy,
even in the face of known mutations.55 ENF can
be considered for salvage therapy, although it is
poorly tolerated because of the need for injections
and significant injection site reactions.
The presence of certain mutations to particular
drugs may lend credence to their addition when
these mutations decrease the fitness of the HIV
virus. For instance, the M184V mutation may significantly reduce the action of FTC and 3TC, but this
particular mutation confers a fitness disadvantage
to the HIV virus and makes AZT highly effective,
even in the presence of TAM mutations. Therefore,
FTC or 3TC may be continued in the face of such
a mutation. For patients with highly resistant virus,
including resistance to RAL or EVG, registration for
the experimental INSTI DTG may be considered.
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ART Selection in Patients with
Comorbidities
Cardiovascular Disease
ABC, LPV/r, and FPV/r have been associated
with some increased risk of cardiovascular disease, and alternatives should be considered in
patients at high risk.
Renal Disease
TDF, ATV/r, and LPV/r have been associated
with decline in renal function in some cases. Renal
function should be monitored while using these
agents, and they should be avoided, if possible, in
patients with baseline renal dysfunction. As mentioned previously, COB as well as RPV may cause
an artifactual increase in serum creatinine and
GFR that is not associated with true renal failure.
Since COB is frequently administered with TDF, it
may be difficult to distinguish true renal failure from
this artifact in patients who are co-administered the
2 drugs.
Osteoporosis
HIV infection alone is considered an independent risk factor for bone loss. Decreased bone
mineral density can generally be expected with
all ART regimens during the first year of therapy.
In particular, TDF has been shown to be a strong
independent risk factor for bone density loss and
fracture,56 and should potentially be avoided in
postmenopausal women or those at high risk for
osteoporosis.57
Pregnancy
Pregnancy is a level AIa indication for initiation
of ART. Prevention of vertical transmission of HIV
from mother to fetus is the primary goal. HIV testing should be performed on all pregnant female
patients, and ART should be initiated as soon as
Infectious Diseases Volume 14, Part 3 19
Antiretroviral Therapy in HIV Infection
Table 7. Pregnancy Categories of Antiretroviral Medications
Drug
NRTI
3TC
AZT
FTC
TDF
ABC
ddI
d4T
NNRTI
NVP
EFV
ETR
RVP
PIs
LPV
RTV
ATV
DRV
SQV
IDV
NFV
FPV
TPV
INSTIs
RAL
Entry Inhibitors
ENF
MVC
Recommendation
Preferred
Preferred
Alternative
Alternative
Alternative
Third-line
Third-line
Preferred
Pregnancy category D, generally not
recommended
Insufficient data
Insufficient data
Preferred
Preferred for boosting
Alternative
Alternative
Alternative
Third-line
Third-line
Insufficient data
Insufficient data
Third-line
Insufficient data
Insufficient data
Information from AIDS Info. Guidelines for the use of antiretroviral
agents in HIV-1 infected adults and adolescents. aidsinfo.nih.gov/
guidelines/html/1/adult-and-adolescent-arv-guidelines/0/ Updated Mar
27, 2012. Accessed December 20, 2012.
INSTI = integrase strand transfer inhibitor; NNRTI = non-nucleoside reverse transcriptase inhibitor; NRTI = nucleoside reverse transcriptase
inhibitor; PI = protease inhibitor.
possible, even if diagnosis is made immediately before delivery. Pregnant patients with HIV should be
started on ART regardless of CD4 count. As with
20 Hospital Physician Board Review Manual
traditional ART, a 2-drug NRTI backbone should
generally be used in combination with a third active medication. Current guidelines list LPV/r plus
AZT/3TC as the preferred regimen in pregnancy,
given that it has the most historical data regarding
use in pregnant patients. However, the known toxicities associated with AZT compared with newer
agents make its choice less attractive, and in clinical practice less toxic regimens with newer ART
medications are frequently employed (Table 7).
Generally, all approved NRTI backbones can be
considered in pregnancy. Most boosted PI-based
regimens are considered to be reasonably safe
during pregnancy. With regard to NNRTI-based
regimens, EFV is the only Pregnancy Category
D ART medication and is generally avoided. Neural tube defects have been reported with the use
of EFV during pregnancy, especially in the first
trimester. However, the Antiretroviral Pregnancy
Registry has recorded no increase in the rate of
these congenital defects compared to the general
population with EFV or any other ART medications
(even with first-trimester exposure).58 There are insufficient data to recommend use of INSTI-based
regimens.
The PACTG 076 trial demonstrated the benefit
of intravenous AZT infusion starting 3 hours before
delivery in HIV-positive mothers with CD4 count
greater than 400 cells/μL,59 regardless of use of
antenatal ART. Intravenous AZT should also be
administered to all mothers newly diagnosed with
HIV immediately prior to delivery. Infants of mothers who did not receive ART during the antenatal
period should be administered a 2- or 3-drug AZTcontaining regimen for 6 weeks after birth.60 A regimen consisting of 6 weeks of AZT 8 to 12 mg twice
daily plus 3 doses of NVP 8 to 12 mg within the first
96 hours post-birth resulted in the best combination of efficacy and safety.
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Antiretroviral Therapy in HIV Infection
Mycobacterial Infections
Patients concurrently taking rifamycin antibiotics for mycobacterial infections are particularly
susceptible to drug-drug interactions. There are
guidelines for dose adjustments in such cases.
An EFV-based regimen is generally preferred in
patients taking a rifampin-based antimycobacterial regimen. Despite concern for a reduction in
EFV levels in this setting, this result is not felt to
be clinically significant.61–64 While package recommendations suggest the EFV dose should be
increased to 800 mg per day in patients weighing
more than 50 kg taking rifampin, the fixed-dose
formulation of 600 mg of EFV in Atripla has been
shown to produce reliable treatment of HIV regardless of weight.61,62,64,65 If EFV cannot be used,
rifampin should be switched to rifabutin and a PIbased regimen should be considered. PI-based
regimens have been shown to increase the drug
concentration of rifabutin, and therefore the dose
of rifabutin should be adjusted to 150 mg once
daily.66
RAL-based regimens have not been extensively
studied in the setting of antimycobacterial treatment. RAL levels are decreased in the setting of
rifampin, so either the dose of RAL should be increased to 800 mg twice daily, or rifabutin should
be substituted for rifampin.
A recently approved 3-month, once-weekly regimen of isoniazid and rifapentine for the treatment
of latent tuberculosis infection should not be used
in patients on ART, and generally should be avoided in patients with HIV.67
Liver Disease
All ART medications have some degree of hepatic metabolism, and caution should be exercised
with their use in patients with liver disease or cirrhosis (although patients with Pugh score A can
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still tolerate most medications). The NNRTI NVP is
especially concerning with regard to hepatic failure
and should be avoided if possible in this patient
population.
Chronic Hepatitis B
Interferon-based hepatitis B–treatment regimens
have not been extensively studied in the setting of
HIV. Therefore, an NRTI-based approach is generally employed. Usually, a typical 3-drug HIV ART
regimen is selected that includes an NRTI backbone with 2 active NRTIs against hepatitis B virus
(HBV) and 2 active NRTIs against HIV. TDF and
either FTC or 3TC are recommend, as all of these
agents are active against both HBV and HIV.
NRTI backbones where FTC or 3TC is the only
active medication against HBV are not recommended.68,69 Therefore, in cases where significant
contraindications to TDF exist, entecavir can be
used for HBV treatment. Since entecavir is only
partially active against HIV, adding another fully
active anti-HIV NRTI, such as ABC, is required, or
selection of the M184V HIV RT mutation might result.70 Since 3TC has full activity against both HIV
and HBV, its use counts towards each virus.
Chronic Hepatitis C
Peginterferon alfa and ribavirin have typically
been used for treatment of hepatitis C virus (HCV)
infection in patients co-infected with HCV and HIV.
Co-administration of the NRTIs ddl or AZT should
be avoided with ribavirin. The addition of the PIs
telaprevir and boceprevir to peginterferon alfa and
ribavirin has been demonstrated to improve treatment response in patients with lone HCV genotype
1 infection.71,72 Phase II and III trials suggest similar efficacy in patients with HCV/HIV co-infection
as well. Limited data exists regarding drug-drug
interactions between telaprevir or boceprevir with
Infectious Diseases Volume 14, Part 3 21
Antiretroviral Therapy in HIV Infection
current ART medications, but it is currently felt
that RAL-based regimens may be safely used in
combination with either telaprevir and boceprevir,
and that ATV/r- and EFV-based regimens may
additionally be used with telaprevir. Telaprevir and
boceprevir are not considered to be acceptable
therapies for HIV.
Laboratory Testing
With the expanded role of ART in patients with
less-advanced disease, a new diagnosis of HIV in
any patient should prompt a panel of blood tests
to evaluate the appropriateness of offering such
therapy. Similarly, patients with a known diagnosis
of HIV who are not taking ART should have studies
performed at regular intervals to continuously reevaluate disease status. If not performed recently,
lab testing should be performed immediately prior to
therapy initiation. Testing should continue at regular
intervals during treatment to monitor for virologic
failure, HIV-related or unrelated organ dysfunction,
and medication side effects. Relevant lab tests to
be performed before and after initiation of ART are
listed in Table 8; this list does not include additional
tests that may also be indicated to screen for chronic coinfections or malignancy (eg, syphilis serology,
cervical cancer screening, tuberculin skin test).
In general, a follow-up lab panel consisting of
CD4 count, HIV viral load, complete blood count
with differential, and complete metabolic panel
should be performed every 3 months from the
time of diagnosis, with or without therapy. For a
patient with reliable adherence to an ART regimen with CD4 ≥350 cells/μL and undetectable
viral load for greater than 1 year, it may be reasonable to extend this monitoring interval to every
6 months.16 Fasting lipids and urinalysis should
be repeated every 12 months (unless significant
abnormalities exist or there is concern for HIV22 Hospital Physician Board Review Manual
associated nephropathy, where biannual testing
may be appropriate). CD4 count and HIV viral
load should also be reassessed 2 to 8 weeks after
initiation of a new ART regimen.
CD4 counts estimate an HIV patient’s immune
status. These counts are monitored prior to initiation of ART to ascertain the need to begin therapy
and/or prophylaxis for OIs. They are also monitored
after therapy initiation to roughly assess the immune
response to ART and to reevaluate need for prophylaxis for OIs. Generally, the CD4 count should
increase by at least 50 to 150 cells/μL in the first
year of therapy and an additional 50 to 100 cells/
μL in the second year.73,74 A lower CD4 count at the
time of therapy initiation correlates to a lower potential CD4 count ceiling once therapy stability has
been achieved. Patients with CD4 counts less than
200 cells/μL at ART initiation rarely achieve counts
greater than 500 cells/μL after 4 years of therapy.73
Immunologic failure is the inability to appropriately
mount a CD4 response to ART treatment. There
is currently no known benefit to changing therapy
based on immunologic failure, however.36,75–77
The HIV viral load is the gold-standard measurement of ART effectiveness. An undetectable
HIV viral load is the major goal of treatment. The
viral load should be expected to drop by a factor
of log10 copies/mL 4 weeks after therapy initiation.
The viral load should then be reasonably expected to become undetectable by 16 to 24 weeks of
therapy.1 During this initial time frame, it is advisable to monitor HIV viral load every 4 to 8 weeks
(instead of the usual 3- to 6-month follow-up interval) to assess for virologic failure. Virologic failure
is the inability to achieve an appropriately undetectable viral load despite administration of ART.
Once a patient has achieved an undetectable
viral load, an elevation in the viral load during repeat testing could represent 1 of 2 scenarios. A
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Antiretroviral Therapy in HIV Infection
Table 8. Relevant Laboratory Studies Before and After Initiation of Antiretroviral Therapy in HIV Patients
Test
At Diagnosis
Before ART Initiation
At ART Initiation
ART Follow-up
Virologic Failure
CD4 Count
HIV viral load
+
+
+ (3-mo intervals)
+ (3-mo intervals)
+ (and 2-–8 wk later)
+ (and 2–8 wk later)
+
+
HIV genotype* , †
Complete blood count/
differential
Complete metabolic
panel
Fasting lipid panel
Pregnancy test
Serologies for HAV,
HBV, HCV
Electrocardiogram
+
+
–
+ (3-mo intervals)
+
+
+ (3-mo intervals)
+ (every 4–8 wk until
undetectable, then
at 3-mo intervals)
–
+ (3-mo intervals)
+
+ (3-mo intervals)
+
+ (3-mo intervals)
–
+
–
+
+ (12-mo intervals)
–
–
+
+
–
+ (12-mo intervals)
–
–
–
–
–
–
–
–
–
HLA-B5701‡
–
–
–
–
Urinalysis
+
+ (12-mo intervals)
+/– (if considering
SQV or ATV)
+/– (if considering
ABC)
+
+ (12-mo intervals)
–
+
–
HAV = hepatitis A virus; HBV = hepatitis B virus; HCV = hepatitis C virus.
* In patients with virologic failure, genotypic testing preferably should be performed while the patient is still taking the failing ART regimen.
† A minimum viral load of 1000 copies/mL is recommended to ensure accuracy of genotypic testing.
‡ Patients positive for the HLA-B5701 allele should not be started on ABC therapy due to concern regarding severe hypersensitivity reaction.
temporary increase in the viral load from undetectable to 50 to 1000 copies/mL likely represents a
“blip.” Blips do not represent virologic failure, and
the patient should be continued on the current
regimen without changes.78,79 Blips should prompt
an assessment of patient compliance with ART,
as omitted therapy may sometimes account for a
blip. A blip should also be confirmed with repeat
viral load testing in 2 to 4 weeks.16 Virologic failure
represents a sustained elevation in the viral load in
previously undetectable patients, or the inability to
fully suppress the viral load at 24 to 48 weeks of
ART treatment. Virologic failure should prompt HIV
resistance testing and consideration of a different
ART regimen.
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Viral load monitoring should always be the true
metric of ART treatment success. Judging the success of an ART regimen by CD4 count or clinical
outcome alone may mask subclinical incomplete
viral suppression. This incomplete viral suppression can lead to significant viral resistance, as
this implies that the virus may be replicating in the
presence of drug. Clinicians who administer ART
should be especially mindful of viral resistance in
patients who were previously treated in the developing world, where frequent viral load monitoring
may be unavailable or unaffordable.
A recommendation to check a patient’s coreceptor status (CCR5 or CXCR4) with a tropism
assay is not included in Table 8. In general, this
Infectious Diseases Volume 14, Part 3 23
Antiretroviral Therapy in HIV Infection
Table 9. Occupational Postexposure Prophylaxis (PEP) Recommendations
Exposure Severity
HIV-Negative Source
Percutaneous Injuries
Mild *
Severe†
No PEP
No PEP
Mucous Membrane and Open Skin Exposures
Small-volume§
No PEP
Large-volume¶
No PEP
HIV-Positive Source,
VL <1500 Copies/mL
HIV-Positive Source,
VL ≥1500 Copies/mL
HIV Source Status
Unknown
2-drug PEP
3-drug PEP
3-drug PEP
3-drug PEP
Consider 2-drug PEP‡
Consider 2-drug PEP‡
Consider 2-drug PEP
2-drug PEP
2-drug PEP
3-drug PEP
No PEP
Consider 2-drug PEP#
Information from Panlilio AL, Cardo DM, Grohskopf LA; U.S. Public Health Service. Updated U.S. Public Health Service guidelines for the management of occupational exposures to HIV and recommendations for postexposure prophylaxis. MMWR Recomm Rep 2005;54 (RR-9):1–17.
Available at aidsinfo.nih.gov/contentfiles/HealthCareOccupExpoGL.pdf. Accessed December 20, 2012.
VL = viral load.
* Superficial injury, solid needles.
† Deep injuries, large-bore hollow needles, visible blood on penetrating object, use of object in patient’s vein or artery.
‡ Based on patient preference after careful discussion with treating physician.
§ A few drops.
¶ A large splash.
# Based on patient preference after careful discussion with treating physician.
test should only be performed when MVC therapy
is being considered. As mentioned above, MVC is
generally not a medication that is used to construct
an ART regimen for treatment-naïve patients. There
is little utility to performing this tropism assay at the
time of HIV diagnosis, as a patient’s co-receptor
status can change over time. If MVC is being considered, an HIV viral load of at least 1000 copies/mL
is recommended to ensure accuracy of most available tropism assays. Most patients will develop at
least a small subpopulation of CXCR4-using viruses
5 years after initial diagnosis.29,59,80,81 As mentioned
previously, MVC has not been shown to confer benefit to patients with CXCR4 viral populations.
POSTEXPOSURE PROPHYLAXIS
Percutaneous or mucous membrane exposure
to HIV-contaminated bodily fluids does confer a
24 Hospital Physician Board Review Manual
respective 0.3% to 0.09% risk of infection.82,83 Exposures in the health care workplace are generally
related to blood and are often caused by contact
with sharp objects or accidental splashes to the
facial area. Nonoccupational exposures generally
occur through voluntary or forced sexual contact
and intravenous drug use. Expert consensus
guides the usage of antiretroviral therapy for postexposure prophylaxis (PEP), as no randomized
prospective trials have been conducted in this
area. For occupational exposures, the HIV status of
the reference patient and the severity of the exposure must be considered (Table 9 and Table 10).
When treatment is indicated, it should ideally be
initiated within 4 hours of exposure. Duration of
therapy should be 28 days.83 PEP is generally not
indicated beyond 72 hours of exposure.
PEP in the setting of a nonoccupational exposure (nPEP) is recommended within 72 hours of
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Antiretroviral Therapy in HIV Infection
exposure to bodily fluids such as blood, semen,
vaginal or rectal secretions, or breast milk from
a known HIV-positive contact. It may also be indicated on a case-by-case basis when the HIV
status of the assailant is unknown, such as for
victims of sexual assault. Again, treatment should
begin promptly and continue for a 28-day course.
A 3-drug regimen is used for nPEP. See Table 11
for recommended regimens for nPEP.
PREEXPOSURE PROPHYLAXIS
Preexposure prophylaxis (PrEP) is the administration of ART to an HIV-negative patient who is
sexually active with a known HIV-positive partner
or with partners at high risk for HIV disease. While
minimizing the viral load in the HIV-positive patient
is protective, patients with undetectable plasma
HIV RNA levels may still harbor viral RNA in significant quantity in the genital region.84 Compared
to the plasma viral load, the genital viral RNA
concentration is a more important risk factor for
transmission, yet testing for this metric is not widely
available. Therefore, PrEP has been considered as
an adjunct to condom use to minimize HIV transmission to the uninfected patient who partakes in
high-risk sexual situations.
Several clinical trials to assess use of PrEP are
either currently underway or in the preliminary
stages.85–88 In general, these studies employ daily
single-drug TDF or a TDF/FTC oral combination
and/or the use of a topical TDF gel. The data have
been mixed, and current guidelines suggest that
the cautious use of PrEP may be a reasonable
consideration. Strict adherence must be stressed,
as data suggests that failure of PrEP is most likely
related to noncompliance.
Major concerns do exist, especially with regard
to possible acquisition of a new undetected HIV
infection by a previously uninfected patient taking
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Table 10. Recommendations for Two-Drug and Three-Drug
Occupational Postexposure Prophylaxis Regimens
Recommendation
Two-Drug Regimen
Preferred
Preferred
Preferred
Preferred
Alternative
Alternative
Alternative
Alternative
Recommendation
Preferred
Alternative
Alternative
Alternative
Alternative
Alternative
Alternative
AZT/3TC
AZT/FTC
TDF/3TC
TDF/FTC
d4T/3TC
d4T/FTC
ddI/3TC
ddI/FTC
Three-Drug Regimen*
LPV/r
ATV/r
FPV/r
IDV/r
SQV/r
NFV
EFV
Information from Panlilio AL, Cardo DM, Grohskopf LA; U.S. Public
Health Service. Updated U.S. Public Health Service guidelines for the
management of occupational exposures to HIV and recommendations for postexposure prophylaxis. MMWR Recomm Rep 2005;54
(RR-9):1–17. Available at aidsinfo.nih.gov/contentfiles/HealthCareOccupExpoGL.pdf. Accessed December 20, 2012.
*In addition to a 2-drug regimen.
PrEP. As mentioned, the PrEP regimen is not a
full 3-drug ART regimen, and viral resistance may
quickly develop in this setting should a new infection go undetected. The HIV status of uninfected
patients must therefore be confirmed prior to PrEP
initiation and should be monitored frequently throughout therapy, as a new positive result should prompt
full 3-drug ART therapy. The potential for developing
an undetected new HIV infection with subsequent
resistance while taking an inadequate regimen is a
major drawback of PrEP, both to the patient and to
the community in general (if the patient were to infect
others in the community with their resistant strain).
Infectious Diseases Volume 14, Part 3 25
Antiretroviral Therapy in HIV Infection
Table 11. Recommendations for Nonoccupational Exposure
Prophylaxis Regimens
Recommendation
Preferred
Preferred
Alternative
Alternative
Alternative
Alternative
Alternative
Alternative
Alternative
Alternative
Third-line
Regimen
EFV + (TDF or AZT)/
(FTC or 3TC)
LPV/r + AZT/(FTC or 3TC)
EFV + (ABC or ddI or d4T) +
(FTC or 3TC)
ATV + (FTC or 3TC) + [(AZT or
d4T or ABC) or (TDF/r)]
FPV + (FTC or 3TC) + [(AZT or
d4T) or (ABC or TDF or ddI)]
FPV/r + (FTC or 3TC) + (TDF or
ABC or ddI or d4T)
IDV/r + (FTC or 3TC) + (TDF or
ABC or ddI or d4T)
LPV/r + (FTC or 3TC) + (TDF or
ABC or ddI or d4T)
NFV + (FTC or 3TC) + (TDF or
AZT or ddI or d4T)
SQV/r + (FTC or 3TC) + (TDF or
ABC or AZT or ddI or d4T)
ABC + 3TC + AZT
Information from Panlilio AL, Cardo DM, Grohskopf LA; U.S. Public
Health Service. Updated U.S. Public Health Service guidelines for the
management of occupational exposures to HIV and recommendations for postexposure prophylaxis. MMWR Recomm Rep 2005;54
(RR-9):1–17. Available at aidsinfo.nih.gov/contentfiles/HealthCareOccupExpoGL.pdf. Accessed December 20, 2012.
Other considerations should be made as well.
A patient’s HBV status should be assessed. Patients who are unwilling to undergo frequent lab
testing probably should not be offered PrEP. Females taking PrEP who may become or recently
became pregnant should have risks and benefits
to the fetus clearly discussed. Ideally, uninfected
females taking PrEP who become pregnant should
abstain from further high-risk sexual contact to
fully minimize their risk of contracting HIV during
their pregnancy. Since TDF is a primary medication in this regimen, PrEP should not be offered to
26 Hospital Physician Board Review Manual
patients with renal dysfunction. There are no data
available for the use of PrEP in the setting where a
monogamous HIV-positive partner is currently taking ART therapy.
IMMUNE RECONSTITUTION INFLAMMATORY
SYNDROME
HIV-positive patients who are initiated on ART
at a low baseline CD4 count may be at risk for
immune reconstitution inflammatory syndrome
(IRIS; often when the initial baseline CD4 count is
less than 100 cells/μL). In this patient population,
OIs may exist subclinically, as the host is unable
to mount an appropriate immune inflammatory
defense response due to a virally impaired immune system. As the immune system is restored
with ART treatment, these subclinical infections
can stimulate an aggressive inflammatory reaction. This reaction usually involves infected organ
systems, and is generally more common and profound in patients with disseminated OIs and high
titers of pathogen. Autoimmune IRIS reactions
that are unrelated to a known OI have also been
described.1
IRIS is a clinical diagnosis that may be difficult to
discern from a true new infection or drug reaction.
Once IRIS is considered the most likely possibility, nonsteroidal anti-inflammatory or corticosteroid
medications may be considered depending on
severity.
Some controversy exists with regard to the
timing of ART initiation in newly diagnosed AIDS
patients with active OIs. A concern has been that
starting ART in the setting of a known OI might
provoke an IRIS response that could compromise
the health of the patient. Limited data suggests
that ART therapy should be initiated earlier rather
than later in these patients1 (Table 5), although
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Antiretroviral Therapy in HIV Infection
care should be taken in certain special situations.
For example, caution should be taken with patients with cryptococcal meningitis. A randomized
clinical trial from Zimbabwe in patients with cryptococcal meningitis compared ART administration
in a group 72 hours after diagnosis and in a second group after 10 weeks of fluconazole administration. The early-treatment group had over 2.5
times the risk of death.89 Therefore, the general
recommendation is to delay ART for patients with
cryptococcal meningitis until they have received
at least 2 to 10 weeks of antifungal therapy.1
Patients with most OIs or active tuberculosis
and CD4 count <50 cells/μL should be started on
ART within 2 weeks of OI diagnosis or initiation
of anti-tuberculosis treatment. Patients with active
tuberculosis infection and CD4 count ≥50 cells/μL
should be started on ART within 8 to 10 weeks of
anti-tuberculosis treatment initiation. Timing of ART
initiation in patients with tuberculosis meningitis is
less certain. A Vietnamese study demonstrated
no significant outcome improvement and more adverse effects in patients started on immediate ART
in this setting versus patients started on 2-month
delayed ART (tuberculosis treatment was started
immediately in both groups).90 However, because
of better patient monitoring in the United States,
a grade CIII recommendation exists to initiate patients with tuberculosis meningitis and HIV on ART
immediately.
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