870 SECTION VIII Chemotherapeutic Drugs
EXPERIMENTAL AGENTS
Brincidofovir is a nucleoside agent with activity against HSV,
CMV, adenovirus, BK virus, and poxvirus. It is currently under
clinical investigation for CMV and adenovirus infections.
■ ANTIRETROVIRAL AGENTS
Substantial advances have been made in antiretroviral therapy
since the introduction of the first agent, zidovudine, in 1987. Six
classes of antiretroviral agents are currently available for use: nucle-
oside/nucleotide reverse transcriptase inhibitors (NRTIs), non-
nucleoside reverse transcriptase inhibitors (NNRTIs), protease
inhibitors (PIs), fusion inhibitors, CCR5 co-receptor antagonists,
and integrase strand transfer inhibitors (INSTIs) (Table 49–3).
These agents inhibit HIV replication at different parts of the cycle
(Figure 49–3).
Knowledge of viral dynamics through the use of viral load and
resistance testing has made it clear that combination therapy with
maximally potent agents will reduce viral replication to the lowest
possible level, thereby reducing the number of cumulative muta-
tions and decreasing the likelihood of emergence of resistance.
Thus, administration of combination antiretroviral therapy, typi-
cally including at least three antiretroviral agents with differing
susceptibility patterns, has become the standard of care. Viral
susceptibility to specific agents varies among patients and may
change with time. Therefore, such combinations must be chosen
with care and tailored to the individual, as must changes to a given
regimen. In addition to potency and susceptibility, important
factors in the selection of agents for any given patient are toler-
ability, convenience, and optimization of adherence. New drugs
with high potency, low toxicity, and good tolerability increase the
feasibility of early, lifelong treatment. As new agents have become
available, several older ones have had diminished usage, because
of either suboptimal safety or inferior efficacy. Zalcitabine (ddC;
dideoxycytidine) is no longer marketed, and regimens containing
zidovudine (AZT; azidothymidine), ddI (didanosine), or stavu-
dine (d4T) are infrequently recommended as first-line regimens.
Decrease of the circulating viral load by antiretroviral therapy
is correlated with enhanced survival as well as decreased morbidity.
Also, the use of antiretroviral therapy strongly reduces the risk for
heterosexual and same-sex HIV transmission.
Discussion of antiretroviral agents in this chapter is specific to
HIV-1. Patterns of susceptibility of HIV-2 to these agents may
vary; however, there is innate resistance to the NNRTIs and enfu-
virtide as well as a lower barrier of resistance to NRTIs and PIs.
NUCLEOSIDE & NUCLEOTIDE
REVERSE TRANSCRIPTASE
INHIBITORS (NRTIs)
The NRTIs act by competitive inhibition of HIV-1 reverse tran-
scriptase; incorporation into the growing viral DNA chain causes
premature chain termination due to inhibition of binding with
the incoming nucleotide (Figure 49–3). Each agent requires intra-
cytoplasmic activation via phosphorylation by cellular enzymes to
the triphosphate form.
Typical resistance mutations include M184V, L74V, D67N,
and M41L. Lamivudine or emtricitabine therapy tends to select
rapidly for the M184V mutation in regimens that are not fully
suppressive. While the M184V mutation confers reduced suscep-
tibility to abacavir, didanosine, and zalcitabine, its presence may
restore phenotypic susceptibility to zidovudine. The K65R/N
mutation is associated with reduced susceptibility to tenofovir,
abacavir, lamivudine, and emtricitabine.
All NRTIs may be associated with mitochondrial toxicity,
which may manifest as peripheral neuropathy, pancreatitis, lipoat-
rophy, and hepatic steatosis. Less commonly, lactic acidosis may
occur, which can be fatal. NRTI treatment should be suspended
in the setting of rapidly rising aminotransferase levels, progressive
hepatomegaly, or metabolic acidosis of unknown cause. Lipoat-
rophy and insulin resistance may occur most frequently with use
of the thymidine analogs stavudine and zidovudine, and least
frequently with use of tenofovir, lamivudine, emtricitabine, and
abacavir.
ABACAVIR
Abacavir is a guanosine analog that is well absorbed following oral
administration (83%) and is unaffected by food. The serum half-
life is 1.5 hours. The drug undergoes hepatic glucuronidation and
carboxylation. Dosage reduction is recommended in mild hepatic
impairment; no data are available for patients with moderate or
severe liver disease. Since the drug is metabolized by alcohol dehy-
drogenase, serum levels of abacavir may be increased with concur-
rent alcohol (ie, ethanol) ingestion. Cerebrospinal fluid levels are
approximately one-third those of plasma. Abacavir is one of the
NRTI agents recommended for use in pregnancy (Table 49–5).
Hypersensitivity reactions, occasionally fatal, have been
reported in up to 8% of patients receiving abacavir and may be
more severe in association with once-daily dosing. Symptoms,
which generally occur within the first 6 weeks of therapy, include
fever, fatigue, nausea, vomiting, diarrhea, and abdominal pain.
Dyspnea, pharyngitis, and cough, and elevations in serum ami-
notransferase or creatine kinase levels may also be present, with
skin rash in ∼50% of patients. Rechallenge is contraindicated.
Screening for HLA-B*5701 before initiation of abacavir therapy is
important to identify patients with an increased risk for abacavir-
associated hypersensitivity reaction (see Table 5–4). Although the
positive predictive value of this test is only about 50%, it has a
negative predictive value approaching 100%.
Rash occurs in approximately 5% of patients, typically in
the first 6 weeks of treatment. Less frequent adverse events are
fever, nausea, vomiting, diarrhea, headache, dyspnea, fatigue,
and pancreatitis. In some studies but not in others, abacavir has
been associated with an increased risk of myocardial infarction.
The class effects of mitochondrial toxicity and disorders of lipid
metabolism seem to be less common with abacavir than with
other nucleoside analogs.
 TABLE 49–3 Currently available antiretroviral agents.
Administration Characteristic Adverse
Agent Class of Agent Recommended Adult Dosage Recommendation Effects Comments
1
Abacavir NRTI 300 mg bid or 600 mg qd Test to rule out the presence Rash, hypersensitivity Avoid alcohol.
of the HLA-B5701 allele prior reaction, nausea;
to initiation of therapy. possible increase in
myocardial infarction
Atazanavir PI2 400 mg qd or 300 mg qd with ritonavir Take with food. Avoid Nausea, rash, myalgia, See footnote 4. Avoid elvitegravir/
100 mg qd or cobicistat 150 mg qd; adjust concomitant antacids. indirect hyperbilirubinemia, cobicistat, etravirine, fosamprenavir,
dose in hepatic insufficiency Separate dosing acid- diarrhea, ↑ liver enzymes, nevirapine, tipranavir. Avoid in severe
reducing agents by ≥10 h. prolonged PR interval hepatic insufficiency. The oral powder
contains phenylalanine.
Darunavir PI2 Treatment-naïve: 800 mg qd with ritonavir Take with food. Diarrhea, headache, nausea, See footnote 4. Avoid elvitegravir/
100 mg qd or cobicistat 150 mg qd rash, hyperlipidemia, ↑ liver cobicistat and simeprevir. Avoid in
enzymes, ↑ serum amylase patients with sulfa allergy.
Treatment-experienced: 600 mg bid with
ritonavir 100 mg bid
Delavirdine NNRTI 400 mg tid Separate dosing from ddI or Rash, ↑ liver enzymes, head- See footnote 4. Avoid concurrent
antacids by ≥1 h. ache, nausea, diarrhea fosamprenavir. Teratogenic in rats.
Didanosine NRTI1 Tablets, 400 mg qd or 200 mg bid3 Take on an empty stomach. Peripheral neuropathy, pan- Avoid concurrent neuropathic drugs (eg,
(ddI) adjusted for weight creatitis, diarrhea. stavudine, zalcitabine, isoniazid), ribavirin,
or allopurinol. Chewable tablets contain
Buffered powder, 250 mg bid3 phenylalanine.
Dolutegravir INSTI INSTI-naïve: 50 mg qd Separate dosing from antac- Insomnia, headache, Avoid carbamazepine, dofetilide, nevirapine,
ids and polyvalent cations hypersensitivity reaction, phenobarbital, phenytoin.
If co-administered with efavirenz, fosam- by ≥2 h. ↑ liver enzymes
prenavir/ritonavir, tipranavir/ritonavir, or
rifampin or if certain INSTI mutations: 50
mg bid
Efavirenz NNRTI 600 mg qd Take on an empty stomach, Neuropsychiatric symptoms, See footnote 4. Avoid elvitegravir/
at bedtime. rash, ↑ liver enzymes, head- cobicistat, etravirine, indinavir, simeprevir.
ache, nausea Teratogenic in primates.
Elvitegravir INSTI Treatment-naïve: 150 mg qd with cobici- Take with food. Separate dos- Diarrhea, rash, ↑ liver See footnote 4. Avoid efavirenz and
stat 150, emtricitabine 200, and tenofovir ing from antacids by ≥2 h. enzymes nevirapine.
Treatment-experienced: 85 mg–150 mg qd
with a protease inhibitor
Emtricitabine NRTI1 200 mg qd3   Headache, diarrhea, nausea, Avoid concurrent lamivudine.
rash, hyperpigmentation

(continued)

871
872
TABLE 49–3 Currently available antiretroviral agents. (Continued)
Administration Characteristic Adverse
Agent Class of Agent Recommended Adult Dosage Recommendation Effects Comments

Enfuvirtide Fusion inhibitor 90 mg subcutaneously bid   Injection site reactions,  

hypersensitivity reaction,
insomnia, headache,
dizziness, nausea, eosinophilia;
possible increased bacterial
pneumonia
Etravirine NNRTI 200 mg bid Take with food. Rash, nausea, diarrhea See footnote 4. Avoid atazanavir, efavirenz,
elvitegravir/cobicistat, fosamprenavir,
indinavir, tipranavir.
Fosamprenavir PI2 1400 mg bid or 700 mg bid with ritonavir   Rash, diarrhea, nausea, head- See footnote 4. Avoid elvitegravir/
100 mg bid or 1400 mg daily with ritonavir ache, ↑ liver enzymes cobicistat, etravirine, lopinavir/ritonavir,
100–200 mg qd; adjust dose in hepatic nevirapine. Avoid in patients with sulfa
insufficiency allergy or severe hepatic insufficiency.
Avoid cimetidine, disulfiram, metronidazole,
vitamin E, ritonavir oral solution, and
alcohol with the oral solution.
Indinavir PI2 800 mg tid or 800 mg bid with ritonavir Best on an empty stomach. Nephrolithiasis, nausea, See footnote 4. Avoid efavirenz and
100–200 mg bid; adjust dose in cirrhosis Drink at least 48 oz liquid indirect hyperbilirubinemia, etravirine.
daily. Separate dosing from headache, diarrhea; pos-
ddI by ≥1 h. sible increase in myocardial
infarction
Lamivudine NRTI1 150 mg bid or 300 mg qd3   Nausea, headache, dizziness, Do not administer with emtricitabine or
fatigue zalcitabine.
Lopinavir/ PI/PI2 400/100 mg bid or 800/200 mg qd Separate dosing from ddI Diarrhea, nausea, hyper- See footnote 4. Avoid darunavir, elvitegravir/
ritonavir by 1 h. triglyceridemia, ↑ liver cobicistat, fosamprenavir, tipranavir. Avoid
enzymes; possible increase in disulfiram and metronidazole with oral
myocardial infarction solution.
Maraviroc CCR5 inhibitor 300 mg bid; 150 bid with CYP3A inhibitors;   Cough, muscle pain, diarrhea, See footnote 4. Do not administer in
600 mg bid with CYP3A inducers sleep disturbance, ↑ liver patients with severe renal dysfunction.
enzymes; possible increase in
myocardial infarction
Nelfinavir PI2 750 mg tid or 1250 mg bid Take with food. Diarrhea, nausea, flatulence See footnote 4. The oral powder contains
phenylalanine.
Nevirapine NNRTI 200 mg bid Dose-escalate from 200 mg Rash, hepatitis (occasionally See footnote 4. Avoid atazanavir, dolute-
daily over 14 days. fulminant), nausea, headache gravir, elvitegravir/cobicistat, fosampre-
navir. Contraindicated with moderate or
severe hepatic impairment.
Raltegravir INSTI 400 mg bid   Nausea, headache, fatigue, The chewable tablets contain
muscle aches, ↑ amylase phenylalanine.
levels, ↑ liver enzymes
Rilpivirine NNRTI 25 mg qd Take with food. Separate Headache, insomnia, depres- See footnote 4.
dosing from antacids or H2 sion, rash, ↑ liver enzymes
blockers by ≥4 h.
 Rilpivirine PI2 1000 mg bid with ritonavir 100 mg bid Take within 2 h of a full meal. Nausea, diarrhea, abdominal See footnote 4. Avoid darunavir, garlic
pain, dyspepsia, rash capsules, tipranavir and drugs that
increase the QT interval. Avoid in severe
hepatic insufficiency.
Stavudine NRTI1 30–40 mg bid, depending on weight3   Peripheral neuropathy, pan- Avoid zidovudine and neuropathic drugs
creatitis, rapidly progressive (eg, ddI, zalcitabine, isoniazid).
ascending neuromuscular
weakness (rare)
Tenofovir NRTI1 10 mg qd with emtricitabine plus   Gastrointestinal symptoms, Avoid inducers of p-glycoprotein
alafenamide elvitegravir/cobicistat; 25 mg qd with headache, ↑ creatinine, (rifampin, rifabutin, phenytoin,
emtricitabine ± rilpivirine proteinuria phenobarbital, St John’s Wort, tipranavir/
ritonavir). Also avoid in severe renal
insufficiency.
Tenofovir diso- NRTI1 300 mg qd3   Nausea, diarrhea, vomiting, Avoid atazanavir, didanosine, probenecid.
proxil fumarate flatulence, headache, renal
insufficiency
Tipranavir PI2 500 mg bid with ritonavir 200 mg bid Take with food. Separate Diarrhea, nausea, vomiting, See footnote 4. Avoid concurrent ata-
from ddI by ≥2 h. Avoid abdominal pain, rash, ↑ liver zanavir, elvitegravir/cobicistat, etravirine,
antacids. enzymes, hyperlipidemia fosamprenavir, lopinavir/ritonavir,
saquinavir. Avoid in patients with severe
hepatic insufficiency, who are at risk for
bleeding, or with sulfa allergy. Avoid vita-
min E with the oral solution.
Zidovudine NRTI1 200 mg tid or 300 mg bid3   Macrocytic anemia, neutro- Avoid concurrent stavudine and
penia, nausea, headache, myelosuppressive drugs (eg, ganciclovir,
insomnia, myopathy ribavirin).
1
All NRTI agents carry the risk of lactic acidosis with hepatic steatosis as a potential adverse event.
2
All PI agents carry the risk of hyperlipidemia, fat maldistribution, hyperglycemia, and insulin resistance as potential adverse events.
3
Adjust dose in renal insufficiency.
4
Because of altered systemic exposures, concurrent drugs that interact with the CYP3A4 system should be used with caution, including alfuzosin, amiodarone, aprepitant, artemether/lumefantrine, astemizole, atovaquone, benzodi-
azepines (diazepam, midazolam, triazolam), bexarotene, bepridil, bosentan, bupropion, calcium channel blockers (diltiazem, felodipine, nifedipine, nimodipine, verapamil), carbamazepine, ceritinib , cimetidine, cisapride, clopidogrel,
colchicine, conivaptan, corticosteroids, cyclosporine, dabrafenib, dapsone, desipramine, direct Factor Xa inhibitors (apixaban, rivaroxaban), disopyramide, dofetilide, dronedarone, enzalutamide, ergot alkaloid derivatives, ethinyl
estradiol/norethindrone acetate, flecainide, fluticasone, gestodene, idelalisib, irinotecan, ivacaftor, levodopa, lidocaine, lumacaftor, lurasidone, macrolide agents (clarithromycin, telithromycin), methadone, mitotane, nafcillin, PDE5
inhibitors, phenobarbital, phenytoin, pimozide, primidone, propafenone, protein pump inhibitors, quinidine, ranolazine, rifabutin, salmeterol, spironolactone, statin agents, St. John’s wort, tacrolimus, triazole antifungal agents (itra-
conazole ketoconazole, posaconazole, voriconazole), terfenadine, and warfarin.
INSTI, integrase strand transfer inhibitor; NNRTI, nonnucleoside reverse transcriptase inhibitor; NRTI, nucleoside/nucleotide reverse transcriptase inhibitor; PI, protease inhibitor.

873
874 SECTION VIII Chemotherapeutic Drugs

gp41
gp120

Blocked by CCR5
receptor antagonists

Host cell membrane

Binding

Chemokine receptors

CD4 Fusion and

Blocked by uncoating
fusion inhibitors

RNA

Blocked by Reverse
NRTIs, NNRTIs transcription

DNA
Integration
Blocked by integrase inhibitors

Transcription Translation

RNA Virion
assembly
Nucleus
Budding and
maturation
Blocked by protease
inhibitors

FIGURE 49–3 Life cycle of HIV. Binding of viral glycoproteins to host cell CD4 and chemokine receptors leads to fusion of the viral and host
cell membranes via gp41 and entry of the virion into the cell. After uncoating, reverse transcription copies the single-stranded HIV RNA genome
into double-stranded DNA, which is integrated into the host cell genome. Gene transcription by host cell enzymes produces messenger RNA,
which is translated into proteins that assemble into immature noninfectious virions that bud from the host cell membrane. Maturation into fully
infectious virions is through proteolytic cleavage. NNRTIs, nonnucleoside reverse transcriptase inhibitors; NRTIs, nucleoside/nucleotide reverse
transcriptase inhibitors.

DIDANOSINE The drug is eliminated by both cellular metabolism and renal

Didanosine (ddI) is a synthetic analog of deoxyadenosine. Oral
bioavailability is approximately 40%. Buffered or enteric-coated
formulations are necessary to prevent inactivation by gastric acid.
Cerebrospinal fluid concentrations of the drug are approximately
20% of serum concentrations. Serum half-life is 1.5 hours, but the
intracellular half-life of the activated compound is 20–24 hours.
excretion.
The major clinical toxicities associated with didanosine therapy
are peripheral distal sensory neuropathy and dose-dependent pan-
creatitis. Therefore, co-administration with drugs or conditions that
increase the risk of either (eg, alcohol abuse, hypertriglyceridemia,
pregnancy, zalcitabine, stavudine, isoniazid, vincristine, ribavirin,
and hydroxyurea), should be avoided. Other reported adverse effects

include diarrhea (particularly with the buffered formulation), hepa-
titis, esophageal ulceration, cardiomyopathy, central nervous system
toxicity (headache, irritability, insomnia), and hypertriglyceridemia.
Concurrent stavudine increases the risk of lactic acidosis. Reports of
retinal changes and optic neuritis in patients receiving didanosine,
particularly in adults receiving high doses and in children, mandate
periodic retinal examinations.
Increased levels of didanosine when administered with tenofo-
vir necessitate dose reduction. Concurrent allopurinol or ribavirin
is contraindicated. The buffer in didanosine tablets interferes with
the absorption of delavirdine and nelfinavir, necessitating separa-
tion in time. The chewable tablets contain phenylalanine, which
can be harmful to patients with phenylketonuria.
EMTRICITABINE
Emtricitabine (FTC) is a fluorinated analog of lamivudine with
a long intracellular half-life (>24 hours), allowing for once-daily
dosing. Oral bioavailability of the capsules is 93% and is unaf-
fected by food, but penetration into the cerebrospinal fluid is low.
Elimination is by both glomerular filtration and active tubular
secretion. The serum half-life is about 10 hours.
Emtricitabine is one of the NRTI agents recommended for
use in pregnancy (Table 49–5). The combination of tenofovir
and emtricitabine is recommended as pre-exposure prophylaxis to
reduce HIV acquisition in high-risk persons.
Both emtricitabine and lamivudine may select for the M184V/I
mutation and therefore should not be used together.
The most common adverse effects observed in patients
receiving emtricitabine are headache, diarrhea, nausea, and rash.
Hyperpigmentation of the palms or soles may be observed (∼ 3%),
particularly in African Americans (up to 13%). Clinically signifi-
cant drug-drug interactions involving emtricitabine have not been
identified. Due to its activity against HBV, exacerbation of HBV
may occur if therapy is interrupted or discontinued in patients
co-infected with HIV.
LAMIVUDINE
Lamivudine (3TC) is a cytosine analog with in vitro activity
against both HIV-1 and HBV.
Oral bioavailability exceeds 80% and is not food-dependent.
The mean cerebrospinal fluid:plasma ratio of lamivudine is
0.1–0.2. Serum half-life is 2.5 hours, whereas the intracellular
half-life of the triphosphorylated compound is 11–14 hours.
Lamivudine is predominantly eliminated in the urine by active
organic cation secretion.
Lamivudine is one of the recommended NRTI agents for use
in pregnant women (Table 49–5).
Adverse effects are uncommon but include headache, dizziness,
insomnia, fatigue, dry mouth, and gastrointestinal discomfort.
Due to its activity against HBV, exacerbation of HBV may occur if
therapy is interrupted or discontinued in patients co-infected with
HIV and HBV. Since both emtricitabine and lamivudine may
select for the M184V/I mutation, these agents should not be used
CHAPTER 49 Antiviral Agents 875
together. Levels of lamivudine may increase when administered
with trimethoprim-sulfamethoxazole. Lamivudine and zalcitabine
may inhibit the intracellular phosphorylation of one another;
therefore, their concurrent use should be avoided if possible.
STAVUDINE
The thymidine analog stavudine (d4T) has high oral bioavail-
ability (86%) that is not food-dependent. The serum half-life is
1.1 hours, the intracellular half-life is 3.0–3.5 hours, and mean
cerebrospinal fluid concentrations are 55% of those of plasma.
Excretion is by active tubular secretion and glomerular filtration.
The major toxicity is a dose-related peripheral sensory neu-
ropathy; incidence may be increased with concomitant neurotoxic
drugs such as didanosine, vincristine, isoniazid, or ribavirin, or
in patients with advanced immunosuppression. Other potential
adverse effects are pancreatitis, arthralgias, and elevation in serum
aminotransferases. Caution is advised in patients with liver dys-
function. A rare adverse effect is a rapidly progressive ascending
neuromuscular weakness. Lactic acidosis with hepatic steatosis, as
well as lipodystrophy, appear to occur more frequently in patients
receiving stavudine than in those receiving other NRTI agents.
Stavudine should not be administered with didanosine due to
increased risk of both lactic acidosis and pancreatitis. This com-
bination has been implicated in several deaths in HIV-infected
pregnant women. Since zidovudine may reduce the intracellular
phosphorylation of stavudine, these two drugs should not be used
together.
TENOFOVIR DISOPROXIL FUMARATE
Tenofovir is an acyclic nucleoside phosphonate (ie, nucleotide)
analog of adenosine with activity against HIV and HBV. Like
the nucleoside analogs, tenofovir competitively inhibits HIV
reverse transcriptase and causes chain termination after incorpo-
ration into DNA. However, only two rather than three intracel-
lular phosphorylations are required for active inhibition of DNA
synthesis.
Tenofovir disoproxil fumarate is a water-soluble prodrug of
active tenofovir. The oral bioavailability increases from 25% in
the fasted state to 39% after a high-fat meal. The prolonged serum
(12–17 hours) and intracellular half-lives allow once-daily dos-
ing. Elimination occurs by both glomerular filtration and active
tubular secretion, and dosage adjustment in patients with renal
insufficiency is recommended.
Tenofovir disoproxil fumarate is one of the NRTI agents rec-
ommended for use in pregnancy (Table 49–5). The combination
of tenofovir and emtricitabine is recommended as pre-exposure
prophylaxis to reduce HIV acquisition in high-risk persons.
Gastrointestinal complaints (eg, nausea, diarrhea, vomiting,
flatulence) are the most common adverse effects but rarely require
discontinuation. Since tenofovir is formulated with lactose, these
may occur more frequently in patients with lactose intolerance.
Cumulative loss of renal function has been observed, possibly
increased with concurrent use of boosted PI regimens. Acute renal
876 SECTION VIII Chemotherapeutic Drugs
failure and Fanconi’s syndrome have also been reported. For this
reason, tenofovir should be used with caution in patients at risk
for renal dysfunction. Serum creatinine levels should be monitored
during therapy and tenofovir discontinued for new proteinuria,
glycosuria, or calculated glomerular filtration rate <30 mL/min.
Tenofovir-associated proximal renal tubulopathy causes excessive
renal phosphate and calcium losses and 1-hydroxylation defects
of vitamin D; loss of bone mineral density and osteomalacia have
been reported. Tenofovir may compete with other drugs that are
actively secreted by the kidneys, such as cidofovir, acyclovir, and
ganciclovir. Concurrent use of probenecid is contraindicated.
Tenofovir levels may increase, and levels of telaprevir decrease,
when these agents are co-administered. Due to its activity against
HBV, exacerbation of HBV may occur if therapy is interrupted or
discontinued in patients co-infected with HIV and HBV.
TENOFOVIR ALAFENAMIDE
Tenofovir alafenamide is a phosphonoamidate prodrug of
tenofovir that is currently available in co-formulation with
other antiretroviral agents (with emtricitabine, with elvitegra-
vir plus cobicistat plus emtricitabine, and with rilpivirine plus
emtricitabine). Plasma levels of active tenofovir in plasma are
approximately 90% lower with tenofovir alafenamide than with
tenofovir disoproxil, since metabolism occurs in lymphocytes
and macrophages (as well as hepatocytes and some other cells)
rather than blood.
Tenofovir alafenamide is a substrate of P-glycoprotein, and
levels of tenofovir can be affected by inhibitors or inducers of
P-glycoprotein. Ritonavir and cobicistat can increase plasma con-
centrations of tenofovir, while darunavir can decrease tenofovir
concentrations.
Tenofovir alafenamide appears to have less renal and bone tox-
icity than tenofovir disoproxil fumarate; however this is still under
investigation. It does not require dose adjustment in patients with
creatinine clearance >30 mL/min.
Tenofovir alafenamide is a substrate of P-glycoprotein, and
levels of tenofovir can be affected by inhibitors or inducers of
P-glycoprotein. Ritonavir and cobicistat can increase plasma con-
centrations of tenofovir, while darunavir can decrease tenofovir
concentrations.
Adverse effects appear to be uncommon but may include
gastrointestinal symptoms or headache. Tenofovir alafenamide is
active against hepatitis B and has been approved for treatment of
HBV infection.
ZIDOVUDINE
Zidovudine (azidothymidine; AZT) is a deoxythymidine analog
that is well absorbed (63%) and distributed to most body tissues
and fluids, including the cerebrospinal fluid, where drug levels
are 60–65% of those in serum. Although the serum half-life
averages 1 hour, the intracellular half-life of the phosphorylated
compound is 3–4 hours, allowing twice-daily dosing. Zidovudine
is eliminated primarily by renal excretion following glucuronida-
tion in the liver.
Zidovudine was the first antiretroviral agent to be approved
and has been well studied. Studies evaluating the use of zidovu-
dine during pregnancy, labor, and postpartum showed significant
reductions in the rate of vertical transmission, and zidovudine
remains one of the NRTI agents recommended for use in preg-
nant women (Table 49–5). Zidovudine is also recommended as
an option for postexposure prophylaxis in individuals exposed to
HIV.
The most common adverse effects of zidovudine are macro-
cytic anemia (1–4%) and neutropenia (2–8%). Gastrointestinal
intolerance, headaches, and insomnia may occur but tend to
resolve during therapy. A symptomatic myopathy may occur
with prolonged use. Lipoatrophy appears to be more common in
patients receiving zidovudine or other thymidine analogs. High
doses can cause anxiety, confusion, and tremulousness.
Induction or inhibition of glucuronidation may alter serum
levels of zidovudine when co-administered with atovaquone,
lopinavir/ritonavir, probenecid, or valproic acid. Concurrent
stavudine is contraindicated due to competitive inhibition of
intracellular phosphorylation.
NONNUCLEOSIDE REVERSE
TRANSCRIPTASE INHIBITORS
(NNRTIs)
The NNRTIs bind directly to HIV-1 reverse transcriptase
(Figure 49–3), resulting in allosteric inhibition of RNA- and
DNA-dependent DNA polymerase activity. The binding site of
NNRTIs is near to but distinct from that of NRTIs. Unlike the
NRTI agents, NNRTIs neither compete with nucleoside triphos-
phates nor require phosphorylation to be active.
The second-generation NNRTIs (etravirine, rilpivirine) have
higher potency, longer half-lives and reduced side-effect profiles
compared with older NNRTIs (delavirdine, efavirenz, nevirapine).
Baseline genotypic testing is recommended prior to initiating
NNRTI treatment because primary resistance rates range from
approximately 2% to 8%. NNRTI resistance occurs rapidly with
monotherapy and can result from a single mutation. The K103N
and Y181C mutations confer resistance to the first-generation
NNRTIs, but not to etravirine or rilpivirine. Other mutations (eg,
L100I, Y188C, G190A) may also confer cross-resistance among
the NNRTI class. However, there is no cross-resistance between
the NNRTIs and the NRTIs; in fact, some nucleoside-resistant
viruses display hypersusceptibility to NNRTIs.
As a class, NNRTI agents tend to be associated with varying
levels of gastrointestinal intolerance and skin rash, the latter of
which may infrequently be serious (eg, Stevens-Johnson syn-
drome). A further limitation to use of NNRTI agents as a compo-
nent of antiretroviral therapy is their metabolism by the CYP450
system, leading to innumerable potential drug-drug interactions
(Tables 49–3 and 49–4). All NNRTI agents are substrates for
CYP3A4 and can act as inducers (nevirapine), inhibitors (dela-
virdine), or mixed inducers and inhibitors (efavirenz, etravirine).
 CHAPTER 49 Antiviral Agents 877

TABLE 49–4 Clinically significant drug-drug interactions pertaining to two-drug antiretroviral combinations.1
Agent Drugs That Increase Its Serum Levels Drugs That Decrease Its Serum Levels

Atazanavir Ritonavir Didanosine, efavirenz, elvitegravir/cobicistat, etravirine,

fosamprenavir, nevirapine, stavudine, tenofovir, tipranavir
Darunavir Indinavir Efavirenz, lopinavir/ritonavir, saquinavir
2
Delavirdine   Didanosine, fosamprenavir
Didanosine Tenofovir Atazanavir, ritonavir
Dolutegravir   Efavirenz, etravirine, nevirapine
2
Efavirenz Darunavir  
Elvitegravir3 Ritonavir Efavirenz, nevirapine
Etravirine Atazanavir, delavirdine, indinavir, lopinavir/ritonavir Efavirenz, nevirapine, ritonavir, saquinavir, tipranavir
Fosamprenavir Atazanavir, delavirdine, etravirine, ritonavir Didanosine, efavirenz, lopinavir/ritonavir, maraviroc, nevirapine,
tipranavir
Indinavir Darunavir, delavirdine, nelfinavir, ritonavir Didanosine, efavirenz, etravirine, nevirapine
Lopinavir/ritonavir Darunavir Didanosine, efavirenz, fosamprenavir, nelfinavir, nevirapine,
tipranavir
Maraviroc Atazanavir, darunavir, lopinavir/ritonavir, nevirapine, Efavirenz, etravirine, tipranavir
saquinavir, ritonavir
Nelfinavir Delavirdine, indinavir, ritonavir, saquinavir  
2
Nevirapine Fosamprenavir  
Raltegravir Atazanavir Etravirine, tipranavir
Rilpivirine2 Darunavir, lopinavir/ritonavir  
Saquinavir Atazanavir, delavirdine, indinavir, lopinavir/ritonavir, Efavirenz, etravirine, nevirapine, tipranavir
nelfinavir, ritonavir
Tenofovir alafenamide Ritonavir Darunavir
Tenofovir disoproxil Atazanavir  
fumarate
Tipranavir   Efavirenz
1
Dose adjustment may be necessary if co-administered.
2
NNRTI-NNRTI drug-drug interactions are not listed.
3
Drug-drug interactions are rare with elvitegravir as a single agent but multiple if co-administered with either cobicistat or ritonavir.

Given the large number of non-HIV medications that are also
metabolized by this pathway (see Chapter 4), drug-drug interac-
tions must be expected and looked for; dosage adjustments are
frequently required and some combinations are contraindicated.
DELAVIRDINE
Delavirdine has an oral bioavailability of about 85%, but this
is reduced by antacids or H2-blockers. It is extensively bound
(∼98%) to plasma proteins and has correspondingly low cerebro-
spinal fluid levels. Serum half-life is approximately 6 hours.
Skin rash occurs in up to 38% of patients receiving delavir-
dine; it typically occurs during the first 1–3 weeks of therapy
and does not preclude rechallenge. However, severe rash such
as erythema multiforme and Stevens-Johnson syndrome have
rarely been reported. Other possible adverse effects are headache,
fatigue, nausea, diarrhea, and increased serum aminotransferase
levels. Delavirdine has been shown to be teratogenic in rats, caus-
ing ventricular septal defects and other malformations at dosages
not unlike those achieved in humans. Thus, pregnancy should be
avoided when taking delavirdine.
Delavirdine is extensively metabolized by CYP3A and CYP2D6
enzymes. Therefore, there are numerous potential drug-drug
interactions to consider (Tables 49–3 and 49–4). The concur-
rent use of delavirdine with fosamprenavir is not recommended
because of bidirectional interactions. Co-administration of dela-
virdine with indinavir or saquinavir prolongs the elimination
half-life of the latter agents, thus allowing them to be dosed twice
rather than thrice daily.
EFAVIRENZ
Efavirenz can be given once daily because of its long half-life
(40–55 hours). It is moderately well absorbed following oral
administration (45%). Since toxicity may increase owing to
increased bioavailability after a high-fat meal, efavirenz should be
taken on an empty stomach. Efavirenz is principally metabolized
by CYP3A4 and CYP2B6 to inactive hydroxylated metabolites;
878 SECTION VIII Chemotherapeutic Drugs

the remainder is eliminated in the feces as unchanged drug. It is cobicistat, fosamprenavir, indinavir, and tipranavir. In addition,
highly bound to albumin (∼ 99%), and cerebrospinal fluid levels co-administration with clarithromycin or with the antimalarial
range from 0.3% to 1.2% of plasma levels. agent artemether/lumefantrine should be avoided if possible.
The principal adverse effects of efavirenz involve the central
nervous system. Dizziness, drowsiness, insomnia, nightmares,
and headache tend to diminish with continued therapy; dosing at
NEVIRAPINE
bedtime may also be helpful. Psychiatric symptoms such as depres-
The oral bioavailability of nevirapine is excellent (>90%) and is
sion, mania, and psychosis have been observed in the weeks fol-
not food-dependent. The drug is highly lipophilic and achieves
lowing initiation and may necessitate discontinuation. Skin rash
cerebrospinal fluid levels that are 45% of those in plasma. Serum
has been reported early in therapy in up to 28% of patients; the
half-life is 25–30 hours. It is extensively metabolized by the
rash is usually mild to moderate in severity and typically resolves
CYP3A isoform to hydroxylated metabolites and then excreted,
despite continuation. Rarely, rash has been severe or life-threat-
primarily in the urine.
ening. Other potential adverse reactions are nausea, vomiting,
A single dose of nevirapine (200 mg) is effective in the pre-
diarrhea, crystalluria, elevated liver enzymes, and an increase in
vention of transmission of HIV from mother to newborn when
total serum cholesterol by 10–20%. High rates of fetal abnormali-
administered at the onset of labor and followed by a 2-mg/kg dose
ties, such as neural tube defects, occurred in pregnant monkeys
to the neonate within 3 days of delivery. However, nevirapine is no
exposed to efavirenz in doses roughly equivalent to the human
longer recommended for use in pregnancy due to the potential for
dosage; several cases of congenital anomalies have been reported
adverse events and low barrier to resistance.
in humans. Efavirenz is one of the NNRTI agents recommended
Rash, usually a maculopapular eruption that spares the palms
for use in pregnancy (Table 49–5), but should be initiated after
and soles, occurs in up to 20% of patients, usually in the first
the first 8 weeks due to birth defects observed in a primate study.
4–6 weeks of therapy. Although typically mild and self-limited,
As both an inducer and an inhibitor of CYP3A4, efavirenz
rash is dose-limiting in about 7% of patients. Women appear to
induces its own metabolism and interacts with the metabolism
have an increased incidence of rash. When initiating therapy, grad-
of many other drugs (Tables 49–3 and 49–4). Co-administration
ual dose escalation over 14 days is recommended to decrease the
with boceprevir, elvitegravir/cobicistat, etravirine, indinavir, itra-
incidence of rash. Severe and life-threatening skin rashes, includ-
conazole, ketoconazole, and simeprevir is contraindicated. Levels
ing Stevens-Johnson syndrome and toxic epidermal necrolysis, are
of efavirenz may be reduced by concomitant nevirapine. Levels of
rare but are more common than with other NNRTIs. Nevirapine
lopinavir/ritonavir, maraviroc, methadone, and telaprevir may be
therapy should be immediately discontinued in patients with
reduced when administered with efavirenz.
severe rash and in those with accompanying constitutional symp-
toms; since rash may accompany hepatotoxicity, liver tests should
be assessed. Symptomatic liver toxicity may occur in up to 4% of
ETRAVIRINE patients, may be severe, and is more frequent in those with higher
pretherapy CD4 cell counts (ie, >250 cells/mm3 in women and
Etravirine, a diarylpyrimidine, was designed to be effective against
>400 cells/mm3 in men), in women, and in those with HBV or
strains of HIV that had developed resistance to first-generation
HCV co-infection. Fulminant, life-threatening hepatitis has been
NNRTIs due to mutations such as K103N and Y181C. Although
reported, typically within the first 18 weeks of therapy. Other
etravirine has a higher genetic barrier to resistance than the other
adverse effects include fever, nausea, headache, and somnolence.
NNRTIs, mutations selected by etravirine usually are associated
Nevirapine is a moderate inducer of CYP3A metabolism,
with resistance to efavirenz, nevirapine, and delavirdine.
resulting in numerous potential drug-drug interactions (see
Etravirine should be taken with a meal to increase systemic
Tables 49–3 and 49–4). Co-administration of artemether/lume-
exposure. It is highly protein-bound and is primarily metabolized
fantrine, atazanavir, dolutegravir, elvitegravir/cobicistat, fosampre-
by the liver. Mean terminal half-life is ∼41 hours.
navir, ketoconazole, and rifampin should be avoided.
The most common adverse effects of etravirine are rash, nau-
sea, and diarrhea. The rash is typically mild and usually resolves
after 1–2 weeks without discontinuation of therapy. Rarely, rash RILPIVIRINE
has been severe or life-threatening. Laboratory abnormalities
include elevations in serum cholesterol, triglyceride, glucose, and Rilpivirine, a diarylpyrimidine, must be administered with a
hepatic aminotransferase levels. Aminotransferase elevations are meal (preferably high fat or >400 kcal). Its oral bioavailability is
more common in patients with HBV or HCV co-infection. dependent on an acid gastric environment for optimal absorption;
Etravirine is a substrate as well as an inducer of CYP3A4 and thus antacids and H2-receptor antagonists should be separated in
an inhibitor of CYP2C9 and CYP2C19 and thus has potential time and proton pump inhibitors are contraindicated. The drug
for numerous drug-drug interactions (Tables 49–3 and 49–4). is highly protein bound and the terminal elimination half-life is
Some of the interactions are difficult to predict. For example, 50 hours.
etravirine may decrease itraconazole and ketoconazole concentra- Rilpivirine is one of the NNRTI agents recommended for use
tions but increase voriconazole concentrations. Etravirine should in pregnancy (Table 49–5). Rilpivirine is primarily metabolized
not be given with atazanavir, clopidogrel, efavirenz, elvitegravir/ by CYP3A4, and drugs that induce or inhibit CYP3A4 may thus

TABLE 49–5 The use of antiretroviral agents in
pregnancy.
Recommended Agents Alternate Agents
Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)
Abacavir, emtricitabine, lamivudine,
tenofovir disoproxil fumarate, zidovudine
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Efavirenz Rilpivirine
Protease inhibitors (PIs)
Atazanavir/ritonavir, darunavir/ritonavir Lopinavir/ritonavir
Integrase inhibitors
Raltegravir  
affect the clearance of rilpivirine (see Table 49–3). However, clini-
cally significant drug-drug interactions with other antiretroviral
agents have not been identified to date.
The most common adverse effects associated with rilpivirine
therapy are rash, depression, headache, insomnia, and increased
serum aminotransferases. Increased serum cholesterol, and fat
redistribution syndrome have also been reported. Higher doses
have been associated with QTc prolongation. Inhibition of renal
tubular secretion of creatinine causes a reversible elevation in
serum creatinine, but glomerular filtration rate is not affected.
PROTEASE INHIBITORS (PIs)
During the later stages of the HIV growth cycle, the gag and
gag-pol gene products are translated into polyproteins, and
these become immature budding particles. The HIV protease is
responsible for cleaving these precursor molecules to produce the
final structural proteins of the mature virion core. By preventing
post-translational cleavage of the Gag-Pol polyprotein, protease
inhibitors (PIs) prevent the processing of viral proteins into func-
tional conformations, resulting in the production of immature,
noninfectious viral particles (Figure 49–3). Unlike the NRTIs, PIs
do not need intracellular activation.
Specific genotypic alterations that confer phenotypic resistance
are fairly common with these agents, thus contraindicating mono-
therapy. Some of the most common mutations conferring broad
resistance to PIs are substitutions at the 10, 46, 54, 82, 84, and 90
codons; the number of mutations may predict the level of pheno-
typic resistance. The I50L substitution emerging during atazanavir
therapy has been associated with increased susceptibility to other
PIs. Darunavir and tipranavir appear to have improved virologic
activity in patients harboring HIV-1 resistant to other PIs.
As a class, PIs are associated with gastrointestinal intolerance,
which may be dose-limiting, and lipodystrophy, which includes
both metabolic (hyperglycemia, hyperlipidemia) and morphologic
(lipoatrophy, fat deposition) derangements. A syndrome of redis-
tribution and accumulation of body fat that results in central obe-
sity, dorsocervical fat enlargement (buffalo hump), peripheral and
facial wasting, breast enlargement, and a cushingoid appearance
has been observed, least commonly with atazanavir. PIs may be
CHAPTER 49 Antiviral Agents 879
associated with cardiac conduction abnormalities, including PR
and QT interval prolongation. A baseline electrocardiogram and
avoidance of other agents causing prolonged PR or QT intervals
should be considered. Abacavir, lopinavir/ritonavir, and fosam-
prenavir/ritonavir have been associated with an increased risk of
cardiovascular disease in some, but not all, studies. Drug-induced
hepatitis and rare severe hepatotoxicity have been reported to
varying degrees with all PIs; the frequency of hepatic events is
higher with tipranavir/ritonavir than with other PIs. Unconju-
gated hyperbilirubinemia may occur with atazanavir or indinavir.
Whether PI agents are associated with bone loss and osteoporosis
after long-term use is under investigation. PIs have been associated
with increased spontaneous bleeding in patients with hemophilia
A or B; an increased risk of intracranial hemorrhage has been
reported in patients receiving tipranavir/ritonavir. Darunavir,
amprenavir, fosamprenavir, and tipranavir are sulfonamides; cau-
tion should be used in patients with a history of sulfa allergy.
All of the antiretroviral PIs are extensively metabolized by
CYP3A4, with ritonavir having the most pronounced inhibitory
effect and saquinavir the least. Some PI agents, such as amprena-
vir and ritonavir, are also inducers of specific CYP isoforms. As
a result, there is enormous potential for drug-drug interactions
with other antiretroviral agents and other commonly used medi-
cations (Tables 49–3 and 49–4). Expert resources about drug-
drug interactions should be consulted, as dosage adjustments are
frequently required and some combinations are contraindicated.
It is noteworthy that the potent CYP3A4 inhibitory properties of
ritonavir are used to clinical advantage by having it “boost” the
levels of other PI agents when given in combination, thus acting
as a pharmacokinetic enhancer rather than an antiretroviral agent.
Ritonavir boosting increases drug exposure, thereby prolonging
the drug’s half-life and allowing reduction in frequency; in addi-
tion, the genetic barrier to resistance is raised.
ATAZANAVIR
Atazanavir is an azapeptide PI with a pharmacokinetic profile that
allows once-daily dosing. Atazanavir requires an acidic medium
for absorption and exhibits pH-dependent aqueous solubility;
therefore, it should be taken with meals. Separation of ingestion
from acid-reducing agents by at least 12 hours is recommended
and concurrent proton pump inhibitors are contraindicated.
Atazanavir is able to penetrate both the cerebrospinal and semi-
nal fluids. The plasma half-life is 6–7 hours, which increases to
approximately 11 hours when co-administered with ritonavir. The
primary route of elimination is biliary; atazanavir should not be
given to patients with severe hepatic insufficiency.
Boosted atazanavir is one of the recommended PI agents for
use in pregnant women (Table 49–5).
The most common adverse effects in patients receiving
atazanavir are diarrhea and nausea; vomiting, abdominal pain,
headache, and peripheral neuropathy may also occur. Skin rash,
reported in ∼20% of patients, is generally mild; however severe
rash and Stevens Johnson syndrome have been reported. As with
indinavir, indirect hyperbilirubinemia with overt jaundice may
880 SECTION VIII Chemotherapeutic Drugs
occur in approximately 10% of patients, owing to inhibition of
the UGT1A1 glucuronidation enzyme. Elevation of serum ami-
notransferases has separately been observed, usually in patients
with underlying HBV or HCV co-infection. Kidney stones,
gallstones, PR prolongation, and decreased bone mineral density
have also been reported. In contrast to the other PIs, atazanavir
does not appear to be associated with dyslipidemia or hypergly-
cemia. The oral powder contains phenylalanine, which can be
harmful to patients with phenylketonuria.
As an inhibitor of CYP3A4, CYP2C9, and UGT1A1, the
potential for drug-drug interactions with atazanavir is great
(Tables 49–3 and 49–4). Due to decreased atazanavir levels, ata-
zanavir should not be administered with bosentan, elvitegravir/
cobicistat, etravirine, fosamprenavir, nevirapine, proton pump
inhibitors, or tipranavir. Tenofovir and efavirenz should not be
co-administered with atazanavir unless ritonavir is added to boost
levels. In addition, co-administration of atazanavir with other
drugs that inhibit UGT1A1, such as irinotecan, may increase its
levels. Atovaquone and voriconazole levels may be decreased with
coadministration, and levels of maraviroc and ranolazine may be
increased.
DARUNAVIR
Darunavir must be co-administered with ritonavir or cobicistat.
Darunavir should be taken with meals to improve bioavailability.
It is highly protein-bound and primarily metabolized by the liver.
Boosted darunavir is one of the PI agents recommended for use
in pregnancy (Table 49–5).
Adverse effects include diarrhea, nausea, headache, and
increases in amylase and hepatic aminotransferase levels. Rash
occurs in 2–7% of patients and may occasionally be severe. Liver
toxicity, including severe hepatitis, has been reported, such that
liver function tests should be monitored; the risk may be higher
for persons with HBV, HCV, or other chronic liver disease.
Darunavir contains a sulfonamide moiety and may cause a hyper-
sensitivity reaction, particularly in patients with sulfa allergy.
Darunavir both inhibits and is metabolized by the CYP3A
enzyme system, conferring many possible drug-drug interac-
tions (Tables 49–3 and 49–4). In addition, the co-administered
ritonavir is a potent inhibitor of CYP3A and CYP2D6, and an
inducer of other hepatic enzyme systems. Co-administration with
elvitegravir/cobicistat or simeprevir is contraindicated due to
bidirectional drug-drug interactions. Levels of cyclophosphamide,
digoxin, and simeprevir may be increased when administered
with darunavir, and levels of paroxetine and sertraline may be
decreased.
FOSAMPRENAVIR
Fosamprenavir is a prodrug of amprenavir that is rapidly hydro-
lyzed by enzymes in the intestinal epithelium. Because of its
significantly lower daily pill burden, fosamprenavir tablets have
replaced amprenavir capsules for adults. Fosamprenavir is most
often administered in combination with low-dose ritonavir.
After hydrolysis of fosamprenavir, amprenavir is rapidly
absorbed from the gastrointestinal tract, and its prodrug can be
taken with or without food. However, high-fat meals decrease
absorption and thus should be avoided. The plasma half-life is
relatively long (7–11 hours). Amprenavir is metabolized in the
liver and should be used with caution in the setting of hepatic
insufficiency.
The most common adverse effects of fosamprenavir are
headache, nausea, diarrhea, perioral paresthesias, depression.
Fosamprenavir contains a sulfa moiety and may cause a rash in
up to 19% of patients, sometimes severe enough to warrant drug
discontinuation.
Amprenavir is both an inducer and an inhibitor of CYP3A4
(Tables 49–3 and 49–4). Co-administration of elvitegravir/cobi-
cistat, etravirine, lopinavir/ritonavir, nevirapine, posaconazole, or
ranolazine is contraindicated. The oral suspension, which contains
propylene glycol, is contraindicated in young children, pregnant
women, patients with renal or hepatic failure, and those using
metronidazole or disulfiram. Also, the oral solutions of ampre-
navir and ritonavir should not be co-administered because the
propylene glycol in one and the ethanol in the other may compete
for the same metabolic pathway, leading to accumulation of either.
Because the oral solution contains vitamin E at several times the
recommended daily dosage, supplemental vitamin E should be
avoided.
INDINAVIR
Indinavir requires an acidic environment for optimum solubil-
ity and therefore must be consumed on an empty stomach or
with a small, low-fat, low-protein meal for maximal absorption
(60–65%). The serum half-life is 1.5–2 hours, protein binding is
∼60%, and the drug has a high level of cerebrospinal fluid pen-
etration (up to 76% of serum levels). Excretion is primarily fecal.
An increase in AUC by 60% and in half-life to 2.8 hours in the
setting of hepatic insufficiency necessitates dose reduction.
The most common adverse effects of indinavir are uncon-
jugated hyperbilirubinemia and nephrolithiasis due to urinary
crystallization of the drug. Nephrolithiasis can occur within days
after initiating therapy, with an estimated incidence of approxi-
mately 10%. Acute renal failure and interstitial fibrosis have also
been reported. Consumption of at least 48 ounces of water daily is
important to maintain adequate hydration, and serum creatinine
levels should be monitored. Nausea, diarrhea, sicca syndrome,
headache, blurred vision, and elevations of serum aminotransfer-
ase levels have also been reported. Insulin resistance may be more
common with indinavir than with the other PIs, occurring in
3–5% of patients. In some studies but not in others, indinavir has
been associated with a higher risk of myocardial infarction. There
have also been rare cases of acute hemolytic anemia.
Since indinavir is an inhibitor of CYP3A4, numerous and
complex drug interactions can occur (Tables 49–3 and 49–4).
Boosting with ritonavir allows for twice-daily rather than thrice-
daily dosing and eliminates the food restriction associated with
use of indinavir. However, there is potential for an increase in

nephrolithiasis with this combination compared with indinavir
alone; thus, a high fluid intake (1.5–2 L/d) is advised. Indinavir
should not be co-administered with astemizole, cerivastatin, efavi-
renz, ergotamine, etravirine, lovastatin, pimozide, rifampin, simv-
astatin, terfenadine, or triazolam. Levels of amlodipine, levodopa,
and trazodone may be increased with concurrent administration
of indinavir.
LOPINAVIR
Lopinavir is available only in combination with low-dose rito-
navir as a pharmacologic “booster” via inhibition of its CYP3A-
mediated metabolism, resulting in increased exposure and a
reduced pill burden.
Lopinavir is highly protein bound (98–99%), and its half-life is
5–6 hours. It is extensively metabolized by CYP3A, which is inhib-
ited by ritonavir. Lopinavir/ritonavir is one of the recommended
antiretroviral agents for use in pregnant women (Table 49–5).
The most common adverse effects of lopinavir are diarrhea,
nausea, vomiting, increased serum lipids, and increased serum
aminotransferases (more common in patients with HBV or HCV
co-infection). Prolongation of the PR and/or QT interval may
occur. In some studies but not in others, lopinavir/ritonavir has
been associated with a higher risk of myocardial infarction. Pan-
creatitis has rarely been reported. Ritonavir-boosted lopinavir may
be more commonly associated with gastrointestinal adverse events
than other PIs.
Potential drug-drug interactions are extensive (Tables 49–3
and 49–4). Levels of lamotrigine and methadone may be reduced
with co-administration, and levels of bosentan may be increased.
Concurrent use of darunavir, elvitegravir/cobicistat, fosamprena-
vir, and tipranavir is contraindicated. Since the oral solution of
lopinavir/ritonavir contains alcohol, concurrent disulfiram and
metronidazole are contraindicated. The oral solution also contains
propylene glycol, contraindicating the co-administration of other
drugs containing propylene glycol.
NELFINAVIR
Nelfinavir has high absorption in the fed state (70–80%), under-
goes metabolism by CYP3A, and is excreted primarily in the feces.
The plasma half-life in humans is 3.5–5 hours, and the drug is
more than 98% protein-bound.
The most common adverse effects associated with nelfinavir
(10–30%) are diarrhea and flatulence. Diarrhea responds to
anti-diarrheal medications but may be dose-limiting. Nelfinavir
is an inhibitor of the CYP3A system, and multiple drug interac-
tions may occur (Tables 49–3 and 49–4). An increased dosage
of nelfinavir is recommended when co-administered with rifabu-
tin (with a decreased dose of rifabutin), whereas a decrease in
saquinavir dose is suggested with concurrent nelfinavir. Do not
co-administer with astemizole, cerivastatin, cisapride, ergotamine,
lovastatin, omeprazole, pimozide, quinidine, rifampin, simvas-
tatin, or terfenadine. The oral powder contains phenylalanine,
which can be harmful to patients with phenylketonuria.
CHAPTER 49 Antiviral Agents 881
RITONAVIR
Ritonavir has a high bioavailability (∼75%) that increases with
food. It is 98% protein-bound and has a serum half-life of
3–5 hours. Metabolism to an active metabolite occurs via the
CYP3A and CYP2D6 isoforms; excretion is primarily in the feces.
Ritonavir as a pharmacologic “booster” is one of the recommended
antiretroviral agents for use in pregnant women (Table 49–5).
Adverse effects of full-dose ritonavir include asthenia, gastroin-
testinal disturbances, and hepatitis; these are greatly reduced with
the lower doses used for boosting. Dose escalation over 1–2 weeks
decreases these side effects. Other potential adverse effects include
altered taste, paresthesias (circumoral or peripheral), elevated
serum aminotransferase and lipid levels, headache, elevations in
serum creatine kinase, and pancreatitis. Inhibition of renal tubular
secretion of creatinine causes a reversible elevation in serum creati-
nine, but glomerular filtration rate is not affected.
Ritonavir is a potent inhibitor of CYP3A4, resulting in many
potential drug interactions (Tables 49–3 and 49–4). However,
this characteristic has been used to great advantage when ritonavir
is administered in low doses (100–200 mg twice daily) in com-
bination with any of the other PI agents, to permit lower or less
frequent dosing (or both) with greater tolerability as well as the
potential for greater efficacy against resistant virus. Therapeutic
levels of digoxin and theophylline should be monitored when
co-administered with ritonavir. The concurrent use of saquinavir
and ritonavir is contraindicated due to an increased risk of QT
prolongation (with torsades de pointes arrhythmia) and PR inter-
val prolongation. Concurrent simeprevir is also contraindicated.
SAQUINAVIR
In its original formulation as a hard gel capsule, oral saquinavir
was poorly bioavailable (∼4% after food). However, reformulation
of saquinavir for once-daily dosing in combination with low-dose
ritonavir has both improved antiviral efficacy and decreased gas-
trointestinal adverse effects. A previous formulation of saquinavir
in soft gel capsules is no longer available.
Saquinavir should be taken within 2 hours after a fatty meal for
enhanced absorption. Saquinavir is 97% protein-bound, and serum
half-life is approximately 2 hours. Saquinavir has a large volume of
distribution, but penetration into the cerebrospinal fluid is negligible.
Excretion is primarily in the feces. Gastrointestinal discomfort (nau-
sea, diarrhea, abdominal discomfort, dyspepsia) may occur. When
administered in combination with low-dose ritonavir, there appears
to be less dyslipidemia or gastrointestinal toxicity than with some of
the other boosted PI regimens. Since prolongation of the QT interval
and torsades de pointes have rarely been reported, saquinavir should
not be used in patients with congenital long QT syndrome, AV block,
refractory hypokalemia or hypomagnesemia, or in combination with
drugs that both increase saquinavir plasma concentrations and pro-
long the QT interval. The concurrent use of saquinavir and ritonavir
may confer an increased risk of QT or PR prolongation.
Saquinavir is subject to extensive first-pass metabolism by
CYP3A4 and functions as a CYP3A4 inhibitor as well as a
882 SECTION VIII Chemotherapeutic Drugs

substrate; thus, there are many potential drug-drug interactions
(Tables 49–3 and 49–4). Increased saquinavir levels when co-
administered with omeprazole necessitate close monitoring for
toxicities. Digoxin levels should be monitored. Liver tests should
be monitored if saquinavir is co-administered with delavirdine or
rifampin. Concurrent darunavir or tipranavir is contraindicated.
TIPRANAVIR
Tipranavir is a newer PI indicated for use in treatment-experienced
patients who harbor strains resistant to other PI agents. It is used
in combination with ritonavir to achieve effective serum levels.
Bioavailability is poor but is increased when taken with a high-
fat meal. The drug is metabolized by the liver microsomal system
and is contraindicated in patients with hepatic insufficiency.
Tipranavir contains a sulfonamide moiety and should not be
administered to patients with known sulfa allergy.
The most common adverse effects of tipranavir are diarrhea,
nausea, vomiting, and abdominal pain. An urticarial or maculo-
papular rash occurs in 10–14%, and may be more common with
co-administered ethinyl estradiol. Liver toxicity, including life-threat-
ening hepatic decompensation, has been observed and may be more
common than with other PIs, particularly in patients with chronic
HBV or HCV infection. Because of an increased risk for intracranial
hemorrhage in patients receiving tipranavir/ritonavir, the drug should
be avoided in patients with head trauma or bleeding diathesis. Other
potential adverse effects include depression, elevation in serum amy-
lase, increased serum lipids, and decreased white blood cell count.
Tipranavir both inhibits and induces the CYP3A4 system.
When used in combination with ritonavir, its net effect is inhibi-
tion. Tipranavir also induces the P-glycoprotein transporter and
thus may alter the disposition of many other drugs (Tables 49–3
and 49–4). Concurrent use with atazanavir, elvitegravir/cobici-
stat, etravirine, fosamprenavir, lopinavir/ritonavir and saquinavir
should be avoided. Supplemental vitamin E is contraindicated in
patients receiving the oral solution.
FUSION INHIBITORS
The process of HIV-1 entry into host cells is complex; each step
presents a potential target for inhibition. Viral attachment to the
host cell entails binding of the viral envelope glycoprotein com-
plex gp160 (consisting of gp120 and gp41) to its cellular receptor
CD4. This binding induces conformational changes in gp120 that
enable access to the chemokine receptors CCR5 or CXCR4. Che-
mokine receptor binding induces further conformational changes
in gp120, allowing exposure to gp41 and leading to fusion of the
viral envelope with the host cell membrane and subsequent entry
of the viral core into the cellular cytoplasm.
ENFUVIRTIDE
Enfuvirtide is a synthetic 36-amino-acid peptide fusion inhibitor
that blocks HIV entry into the cell (Figure 49–3). Enfuvirtide
binds to the gp41 subunit of the viral envelope glycoprotein,
preventing the conformational changes required for the fusion of
the viral and cellular membranes.
Enfuvirtide, which must be administered by subcutaneous
injection, is the only parenterally administered antiretroviral
agent. Metabolism appears to be by proteolytic hydrolysis with-
out involvement of the CYP450 system. Elimination half-life is
3.8 hours.
Resistance to enfuvirtide can result from mutations in gp41;
the frequency and significance of this phenomenon are being
investigated. However, enfuvirtide lacks cross-resistance with the
other currently approved antiretroviral drug classes.
The most common adverse effects are local injection site reac-
tions, consisting of painful erythematous nodules. Although fre-
quent, these are typically mild-to-moderate in severity and rarely
lead to discontinuation. Other potential side effects include insom-
nia, headache, dizziness, and nausea. Hypersensitivity reactions may
rarely occur, are of varying severity, and may recur on rechallenge.
Eosinophilia is the primary laboratory abnormality seen with enfu-
virtide administration. In Phase 3 studies, bacterial pneumonia was
seen at a higher rate in patients who received enfuvirtide than in
those who did not receive enfuvirtide. No drug-drug interactions
have been identified that would require the alteration of the dosage
of concomitant antiretroviral or other drugs.
ENTRY INHIBITORS
MARAVIROC
Maraviroc is approved for use in combination with other antiret-
roviral agents in adult patients infected only with CCR5-tropic
HIV-1. Maraviroc binds specifically and selectively to the host
protein CCR5, one of two chemokine receptors necessary for
entrance of HIV into CD4+ cells. Since maraviroc is active against
HIV that uses the CCR5 co-receptor exclusively, and not against
HIV strains with CXCR4, dual, or mixed tropism, co-receptor
tropism should be determined by specific testing before maraviroc
is started. Substantial proportions of patients, particularly those
with advanced HIV infection, are likely to have virus that is not
exclusively CCR5-tropic.
The absorption of maraviroc is rapid but variable, with the
time to maximum absorption generally 1–4 hours after inges-
tion of the drug. Most of the drug (≥ 75%) is excreted in the
feces, whereas approximately 20% is excreted in urine. The
recommended dose of maraviroc varies according to renal func-
tion and the concomitant use of CYP3A inducers or inhibitors
(Table 49–3). Maraviroc is contraindicated in patients with severe
or end-stage renal impairment and caution is advised when used
in patients with preexisting hepatic impairment and in those co-
infected with HBV or HCV. Maraviroc has excellent penetration
into the cervicovaginal fluid, with levels almost four times higher
than the corresponding concentrations in blood plasma.
Resistance to maraviroc is associated with one or more
mutations in the V3 loop of gp120. However, emergence of
CXCR4 virus (either previously undetected or newly developed)
appears to be a more common cause of virologic failure than the
development of resistance mutations. There appears to be no

cross-resistance with drugs from any other class, including the
fusion inhibitor enfuvirtide.
Maraviroc is a substrate for CYP3A4 and therefore requires
adjustment in the presence of drugs that interact with these enzymes
(Tables 49–3 and 49–4). It is also a substrate for P-glycoprotein,
which limits intracellular concentrations of the drug. The dosage
of maraviroc must be decreased if it is co-administered with strong
CYP3A inhibitors (eg, delavirdine, ketoconazole, itraconazole,
clarithromycin, or any protease inhibitor other than tipranavir)
and must be increased if co-administered with CYP3A inducers
(eg, efavirenz, etravirine, carbamazepine, phenytoin, or St. John’s
wort). Concurrent use of rifampin is contraindicated.
Potential adverse effects of maraviroc include upper respiratory
tract infection, cough, pyrexia, rash, dizziness, muscle and joint
pain, diarrhea, sleep disturbance, and elevations in serum ami-
notransferases. Hepatotoxicity has been reported, which may be
preceded by a systemic allergic reaction (ie, pruritic rash, eosino-
philia, or elevated IgE); discontinuation of maraviroc should be
prompt if this constellation occurs. Myocardial ischemia and
infarction have been observed in patients receiving maraviroc;
therefore caution is advised in patients at increased cardiovascular
risk. There is an increased risk of postural hypotension in patients
with severe renal impairment.
There has been concern that blockade of the chemokine CCR5
receptor—a human protein—may result in decreased immune
surveillance, with a subsequent increased risk of malignancy or
infection. To date, however, there has been no evidence of an
increased risk of either malignancy or infection in patients receiv-
ing maraviroc.
INTEGRASE STRAND TRANSFER
INHIBITORS (INSTIs)
This class of agents binds integrase, a viral enzyme essential to the
replication of both HIV-1 and HIV-2. By doing so, it inhibits
strand transfer, the third and final step of provirus integration,
thus interfering with the integration of reverse-transcribed HIV
DNA into the chromosomes of host cells (Figure 49–3). As a
class, these agents tend to be well tolerated, with headache and
gastrointestinal effects the most commonly reported adverse
events. Their use in combination antiretroviral regimens or with
cobicistat (ie, elvitegravir) means that additional adverse events
and/or drug-drug interactions need to be considered as well. The
available data suggest that effects upon lipid metabolism are favor-
able compared with efavirenz and PIs. Rare severe events include
systemic hypersensitivity reactions and rhabdomyolysis.
DOLUTEGRAVIR
The frequency of dosing of dolutegravir depends on the presence
or absence of integrase inhibitor-associated resistance mutations
and the concurrent use of efavirenz, fosamprenavir/ritonavir,
tipranavir/ritonavir, or rifampin. Dolutegravir should be taken
2 hours before or 6 hours after cation-containing antacids or laxa-
tives, sucralfate, oral iron supplements, oral calcium supplements,
CHAPTER 49 Antiviral Agents 883
or buffered medications. Peak plasma concentrations occur within
2–3 hours of ingestion. Dolutegravir is highly protein bound
(99%). The terminal half-life is ∼14 hours. Serum levels may be
reduced in patients with severe renal insufficiency.
Adverse effects of dolutegravir are infrequent but may include
insomnia, headache, increased serum aminotransferase levels,
and, rarely, rash. A hypersensitivity reaction, including rash and
systemic symptoms, has been reported; the drug should be dis-
continued immediately if this occurs and not restarted. Dolute-
gravir increases serum creatinine by inhibiting tubular secretion
of creatinine but has no effect on actual glomerular filtration rate.
Dolutegravir is primarily metabolized via UGT1A1 with
some contribution from CYP3A. Therefore, multiple drug-
drug interactions may occur (Table 49–3 and 49–4). Levels of
dolutegravir may decrease when co-administered with efavirenz,
etravirine, nevirapine, rifampin, or rifapentine, in some instances
necessitating increased doses of dolutegravir or boosting or both.
Co-administration with the metabolic inducers oxcarbazepine,
phenytoin, phenobarbital, carbamazepine, and St. John’s wort
should be avoided. Dolutegravir inhibits the renal organic cation
transporter OCT2, thereby increasing plasma concentrations of
drugs eliminated via OCT2 such as dofetilide and metformin. For
this reason, co-administration with dofetilide is contraindicated
and close monitoring, with potential for dose adjustment, is rec-
ommended for co-administration with metformin.
ELVITEGRAVIR
Elvitegravir should be taken with food, and it should be taken
2 hours before or 6 hours after cation-containing antacids or laxa-
tives, sucralfate, oral iron supplements, oral calcium supplements,
or buffered medications. Peak levels occur within 4 hours of inges-
tion; elvitegravir is highly protein bound (>98%).
Elvitegravir requires boosting with an additional drug, such as
cobicistat (a pharmacokinetic enhancer that inhibits CYP3A4 as
well as certain intestinal transport proteins) or ritonavir. Cobici-
stat inhibits renal tubular secretion of creatinine; therefore, fixed-
dose combinations need to be adjusted for renal function.
There appear to be few adverse effects associated with elvitegra-
vir per se but may include diarrhea, rash, and elevation in hepatic
aminotransferases.
Elvitegravir is primarily metabolized by CYP3A enzymes, so
drugs that induce or inhibit the action of CYP3A may affect serum
levels of elvitegravir (Table 49–3 and 49–4). In addition, cobicistat
and ritonavir strongly inhibit CYP3A. Elvitegravir levels may be
lowered by concurrent efavirenz or nevirapine, rifampin, rifabutin,
carbamazepine, phenytoin, or St. John’s wort. Concurrent use of
azole antifungal drugs is contraindicated due to a potential increase
in elvitegravir levels; rifabutin levels may also be increased by con-
current elvitegravir. Elvitegravir also induces CYP2D9 and may
lower concentrations of substrates of this enzyme. With the fixed
dose combination, concurrent alfuzosin or atazanavir, cisapride,
darunavir, efavirenz, etravirine, fosamprenavir, ledipasvir, lopinavir/
ritonavir, methylprednisolone, midazolam, nevirapine, pimozide,
prednisolone, rifampin, rifabutin are contraindicated.
884 SECTION VIII Chemotherapeutic Drugs

RALTEGRAVIR presence of decompensated cirrhosis and hypersplenism, thyroid

Absolute bioavailability of the pyrimidinone analog raltegravir has
not been established but does not appear to be food-dependent.
Terminal half-life is ∼ 9 hours. The drug does not interact with
the cytochrome P450 system but is metabolized by glucuronida-
tion, particularly UGT1A1. Therefore, concurrent use of inducers
or inhibitors of UGT1A1 such as rifampin and rifapentine may
necessitate dosage adjustment of raltegravir. The chewable tablets
contain phenylalanine, which can be harmful to patients with
phenylketonuria.
Raltegravir is one of the antiretroviral agents recommended for
use in pregnancy (Table 49–5).
Adverse effects of raltegravir are uncommon but include nau-
sea, headache, fatigue, muscle aches, and increased serum amylase
and aminotransferase levels. Severe, potentially life-threatening
and fatal skin reactions have been reported, including Stevens-
Johnson syndrome, hypersensitivity reaction, and toxic epidermal
necrolysis.
■ ANTIHEPATITIS AGENTS
The advantages of nucleoside/nucleotide analogs (NA) therapy
of hepatitis over interferons (IFN) include fewer adverse effects
and a one-pill-a-day oral administration. The main advantages
of IFN over NAs are the absence of resistance, and achieve-
ment of higher rates of viral agglutinin reduction. However, the
disadvantages of IFN are that less than 50% of persons treated
will respond, its high cost, administration by injection, and com-
mon adverse effects, which preclude its use in many persons,
particularly in resource-limited settings. A number of relative and
absolute contraindications to IFN also exist, which include the
disease, autoimmune diseases, severe coronary artery disease, renal
transplant disease, pregnancy, seizures and psychiatric illness, con-
comitant use of certain drugs, retinopathy, thrombocytopenia and
leucopenia. IFN also cannot be used in infants less than 1 year and
in pregnant women.
INTERFERON ALFA
Interferons are host cytokines that exert complex antiviral, immu-
nomodulatory, and antiproliferative actions (see Chapter 55).
Interferon alfa appears to function by induction of intracellular
signals following binding to specific cell membrane receptors,
resulting in inhibition of viral penetration, translation, tran-
scription, protein processing, maturation, and release, as well as
increased host expression of major histocompatibility complex
antigens, enhanced phagocytic activity of macrophages, and aug-
mentation of the proliferation and survival of cytotoxic T cells.
Interferon alfa-2b is licensed for the treatment for chronic
HBV infection; interferon alfa-2a, interferon alfa-2b, and
interferon alfacon-1 are licensed for treatment of chronic HCV
infection (Table 49–6). Interferon alfa-2a and interferon alfa-2b
may be administered either subcutaneously or intramuscularly;
half-life is 2–5 hours, depending on the route of administra-
tion. Alfa interferons are filtered at the glomerulus and undergo
rapid proteolytic degradation during tubular reabsorption, such
that detection in the systemic circulation is negligible. Liver
metabolism and subsequent biliary excretion are considered
minor pathways.
Pegylation (the attachment of polyethylene glycol to a pro-
tein) reduces the rate of absorption following subcutaneous
injection, reduces renal and cellular clearance, and decreases

TABLE 49–6 Drugs used to treat chronic hepatitis B virus infection.

Agent Recommended Adult Dosage Potential Adverse Effects

Nucleoside/nucleotide analogs
Entecavir1 500 or 1000 mg qd orally Headache, fatigue, upper abdominal pain; lactic acidosis
Tenofovir alafenamide 25 mg qd orally Nausea, abdominal pain, diarrhea, dizziness, fatigue, nephropathy, lactic
fumarate acidosis
Tenofovir disoproxil1 300 mg qd orally Nausea, abdominal pain, diarrhea, dizziness, fatigue, nephropathy, lactic
acidosis
Adefovir dipivoxil1 10 mg qd orally Renal dysfunction, lactic acidosis
Lamivudine1 100 mg qd orally Headache, nausea, diarrhea, dizziness, myalgia, and malaise, lactic acidosis
Telbivudine1 600 mg qd orally Fatigue, headache, cough, nausea, diarrhea, myopathy, peripheral neuropathy,
lactic acidosis
Interferon alfa-2b 5 million IU/d or 10 million IU three Flu-like symptoms, fatigue, mood disturbances, cytopenias, autoimmune
times weekly subcutaneously or disorders
intramuscularly
Pegylated interferon 180 mcg once weekly subcutaneously Flu-like symptoms, fatigue, mood disturbances, cytopenias, autoimmune
alfa-2a1 disorders
1
Dose must be reduced in patients with renal insufficiency.
IU, international units.