Antivirals

metabolism associated
with host cell
low selectivity
toxicity

Antiviral agents: why do we need
them?
No antiviral agent inhibits totally viral replication
for now (with the exception possible - PI)
no effective vaccine against many diseases
- fast mutating (retroviruses)
problems with existing vaccines
- reassortment (influenza virus)
new viral infections
- no vaccine
development of new vaccines takes time
immunosuppressive diseases (AIDS, malignant
tumors, transplantations)
Antiviral agents: an ideal agent
YES
water-soluble
chemically and metabolically stable
good absorption
NO
toxicity
carcinogenicity
allergen
mutagen
teratogen
Antiviral agents

Most important problem - selectivity
Other problems
Toxicity
Poor absorption
Rapid metabolism
Rapid elimination


Antiviral agents
Therapeutic index (T.I.)=

Minimal toxic dose for cell
Minimal toxic dose for virus


Effective drug T.I. = 100 - 1000

A successful drug must interfere with:

A specific viral function e.g. enzyme necessary for
viral life cycle
A cellular function that the virus needs in order to
replicate
If interference with cellular function then it either:
is crucial for virus but not for the cell
or
only the virus-infected cells are killed
(activation of drug in the infected cell only?)

Strategies for antiviral therapy
use therapeutically
prophylactic use occasionally
any of the stages of viral replication can be a target
for antiviral intervention: attachment, uncoating the
viral genome, nucleic acid synthesis, assembly the
progeny virions
the requirements are: the process targeted be
essential for virus replication, the therapeutic agent
is active against the virus while having "acceptable
toxicity" to the host
Viral
RNA
Incorporated
into host
genome
reverse
transcriptase
HIV integrase
transcription
translation
Polyproteins
Final
structural
proteins
HIV protease
Drugs
NRTIs
NNRTIs
PIs
double helix
DNA
Antiviral agents: mechanisms of action
Entry inhibitors
Fusion inhibitors; CCR5 receptor antagonists
Inhibition of uncoating: Rimantadin, Amantadin, Pleconaril
Inhibition of RNA synthesis: Interferon, Ribavirin
Inhibition of genome replication
Inhibition of DNA polymerase or RT of virus:
Nucleosid/nucleotide analogs (acyclovir, AZT, lamivudin),
Non-nucleoside RTI
Inhibition of assembly of viruses: Protease inhibitors
Inhibition of viral release: Neuraminidase inhibitors

Most antiviral are nucleoside
analoges
Nucleoside e. N-glycoside
Nukleotide Nucleoside
Adenine Adenosine
Guanine Guanosine
Cytosine Cytidine
Uracil Uridine
Tymine dTymidine
purines
pyrimidines
Antiviral agents: history
1962 Idoxuridin
Pyrimidine analog
Toxic
Topical, herpetic keratitis
1983 Acyclovir
Purine analog
against herpesvirus
effective only in virus-infected cells
1990.ties Protease inhibitors

Viruses, against which there are
antiviral agents
Herpesviruses
Herpes simplex virus
Varicella-zoster virus
Cytomegalovirus
Retroviruses
HIV
Other
Influenza A and B virus
RSV
Hepatitis B and C virus
1. Attachment to the cell
This phase of replication can be inhibited in two
ways:
Agents which mimic the viral attachment part
and bind to the cellular receptor
Agents which mimic the receptor and bind to
the viral attachment part
Ex: CCR-5 receptor antagonists, fusion
protein inhibitor
MARAVIROC approved for treatment
experienced HIV patients - By blocking
CCR-5 receptor and prevent entry of R5
tropic HIV into the cell
FUZEON (enfuvirtide) - inhibits fusion
protein gp41, prevents fusion of the HIV
into host cell
Treatment of HIV infection
2. Penetration / Uncoating the viral
genome
It is difficult to specifically target these stages of the life cycle
Uncoating in particular is largely mediated by cellular enzymes,
although like penetration, is often influenced by one or more
virus proteins.
PLECONARIL:
- is a broad spectrum anti-picorna virus agent.
- it is orally and topical (nasal spray) bioavailable
- it is a small cyclic drug which binds to a canyon pore of the
virus blocking attachment and uncoating of the viral particle.
- Not approved by FDA
AMANTADINE / RIMANTADINE
influenza A prophylaxis and treatment
inhibit penetration or uncoating of the virus
Prophylactic / treatment dosage of amantadine: 100mg bid (14-
64yr) or 100mg/d (>64yr) for the duration of the epidemic or
until immunity from the vaccine develops (typically 2 wk after
administration) or 1 to 2 days after symptoms resolve.
Amantadine is renal excreted, and dosage must be adjusted for
the elderly and for patients with renal impairment.
Amantadine is not recommended for influenza due to
resistance
Rimantadine is primarily metabolized in the liver
neurotoxicity
2. Penetration / Uncoating the viral
genome
3. Genome Replication
virus polymerases provide a target for a specific
antiviral agent, and this method has produced the
majority of the specific antiviral drugs currently in
use.
drugs function as polymerase substrate, i.e.
nucleoside / nucleotide analogues.
The toxicity of these drugs varies considerably: well
tolerated (e.g. acyclovir) to highly toxic (e.g. IdU /
TFT / AZT).
short serum half lives of 1- 4h.
Nucleoside analogues are in fact pro-drugs, since
they need to be phosphorylated before becoming
effective.
Genome Replication
Idoxuridine (IDU)
acts by irreversibly replacing thymidine in newly
synthesized DNA and producing an abnormal and
essentially nonfunctional DNA molecule.
No specificity - is highly toxic to host cells. (limited to
topical therapy of herpes simplex kerato-
conjunctivitis in US and also for herpes labialis and
genitalis in Europe).
Adverse reaction: irritation, pain, itching, and
inflammation or edema of the eyelids; rare allergic
reactions and photophobia
Genome Replication
Vidarabine (adenine arabinoside, ara-A)
interferes with viral DNA synthesis
is effective in the treatment of HSV infections.
less susceptible to the development of drug-resistant
viral strains than IDU, and IDU-resistant infections
often respond to vidarabine.
Ophthalmic preparations of vidarabine are effective
for acute keratoconjunctivitis and recurrent
superficial keratitis caused by HSV-1 and HSV-2.
Adverse effects: tearing, irritation, pain, photophobia,
and superficial punctate keratitis.
Genome Replication
Trifluridine (trifluorothymidine)
a thymidine analog, interferes with DNA synthesis and
is effective in treating primary keratoconjunctivitis and
recurrent keratitis caused by HSV-1 and HSV-2.
as effective as vidarabine and may be effective in
patients who have not responded to IDU or vidarabine.
The marrow-suppressive effect of trifluridine precludes
systemic use.
Adverse effects: burning or stinging in the eye,
palpebral edema, punctate keratopathy and
hypersensitivity reactions.
Genome Replication
Acyclovir
a purine nucleoside analog with activity against herpes
viruses (in order of potency): HSV-1, HSV-2, VZV,
Epstein-Barr virus (EBV), cytomegalovirus (CMV).
low bioavailability
Acyclovir Viral thymidine kinase Acyclovir
monophosphate Cellular thymidine kinase
Acyclovir triphosphate
Acyclovir triphosphate (chain terminator) competitively inhibits
deoxyguanosine triphosphate for viral DNA polymerase.
may develop resistance via a mutation in the viral thymidine kinase.
Oral acyclovir: 2- 4g /d, 5td, 10mg/bw tid, 7d
- primary and recurrent genital and labial HSV (more
than six outbreaks of genital HSV a year), varicella in
immunocompetent adults or immunocompromised
patients, herpes zoster.
- adverse effects: nausea, vomiting, diarrhea,
headache, and rashes
IV acyclovir: 500mg tid or 10mg/bw tid
in herpes encephalitis
Adverse effects: phlebitis, rash, and neurotoxicity
resulting in lethargy, confusion, seizures, or coma.
Genome Replication
Genome Replication
Valacyclovir
is an ester of acyclovir.
is converted to acyclovir by first-pass intestinal and
hepatic metabolism;
the bioavailability of valacyclovir after conversion is
54%, which is three to five times higher than that of
oral acyclovir.
Doze: 500mg tid, 7 days
Adverse effects are similar to those of acyclovir.
Penciclovir
is a guanosine analog that is phosphorylated by the viral thymidine
kinase and by cellular kinases to a triphosphate form which inhibits
viral DNA polymerase.
inhibits HSV-1 and HSV-2, VZV.
Penciclovir 1% cream is used to treat recurrent orolabial HSV in
adults.
Famciclovir
is a pro-drug of the active antiviral penciclovir.
It inhibits HSV-1, HSV-2, and VZV, it reduces HBV viral load in
patients with chronic B hepatitis
Famciclovir is 77% bioavailable and is rapidly converted to
penciclovir in the intestine and liver.
Genome Replication
Genome Replication
Ganciclovir
is a nucleoside analog that differs from acyclovir by an
additional hydroxymethyl group on the side chain
it has in vitro activity against all herpes viruses, including
CMV.
It is phosphorylated by viral thymidine kinase of HSV or
VZV and by a kinase unique to CMV.
HSV resistant to acyclovir is cross-resistant to ganciclovir
Adverse effect: bone marrow suppression, particularly
neutropenia, anemia, rash, fever, azotemia, liver function
abnormalities, nausea, and vomiting.
Oral ganciclovir has very low bioavailability (6 to 9%).
- dose of 1 g tid,
- for primary prophylaxis of CMV disease in bone marrow
transplant recipients during the initial profound immune
suppressive period.
IV ganciclovir with immune globulin
- Initial: 5 mg/kg IV over 1 hour every 12 hours for 7 to 14 days
- Maintenance: 5 mg/kg IV once a day, 7 days/week or 6 mg/kg
IV once a day, 5 days/week.
- CMV pneumonitis in bone marrow transplant patients and
CMV retinitis in HIV.
Intravitreal injections are used for patients with CMV retinitis
who are resistant to IV or who cannot tolerate the IV formula
Genome Replication
Foscarnet, iv
is an organic analog of pyrophosphate.
It selectively inhibits virus-specific DNA polymerase and
reverse transcriptase.
It is not phosphorylated by viral thymidine kinase and
therefore is active against acyclovir-resistant HSV/VZV
strains and ganciclovir-resistant CMV
Adverse effects: nephrotoxicity, symptomatic
hypocalcemia, hypomagnesemia, phosphatemia,
hypokalemia, and CNS effects.
Genome Replication
Ribavirin
is a guanosine analog that inhibits the
replication of many RNA and DNA viruses.
inhibit messenger RNA formation.
activity in vitro against respiratory syncytial
virus (RSV), influenza A and B, HSV-1, HSV-2,
and many other viruses (HCV, Hantavirus,
Lassa fever virus)
Genome Replication
Aerosolized drug: in high-risk infants, young
children, and immuno-compromised adults with
severe lower respiratory tract infection due to RSV.
is mutagenic to mammalian cells in culture; thus
appropriate measures to protect health care workers
from the aerosolized drug are necessary.
Oral Ribavirin 1200 mg/d in association with
interferon is the treatment of choice for chronic C
hepatitis.
IV ribavirin: in severe Lassa fever, hantavirus
pulmonary syndrome, for SARS
A significant adverse effect of the IV formula is
haemolysis
Genome Replication
Cidofovir (cytosine)
is a nucleotide analog and contains a phosphonate group
that does not require virus-dependent phosphorylation.
Cellular enzymes convert cidofovir to the active
diphosphate form, which has a long intracellular half-life.
in vitro activity against a broad spectrum of viruses,
including HSV-1, HSV-2, VZV, CMV, EBV, adenovirus,
human papillomavirus (HPV), and human polyomavirus.
It is used to treat CMV retinitis in patients with HIV.
adverse effects: renal failure.
Iv, topical, intravitreal injection
Genome Replication
Lamivudine (3TC, Epivir, Zefix)
is a synthetic nucleoside analog that is phosphorylated
to the active compound 5-triphosphate metabolite,
which inhibits HIV reverse transcriptase, and also been
shown to suppress HBV DNA in patients with chronic
active hepatitis B.
The dose for HIV: 150mg bid or 300 mg once daily
The dose for hepatitis: 100 mg po bid.
Adverse effects: GI upset, headache, fatigue, and rash
Genome Replication
Hepsera (adefovir dipivoxil)
Tablets for the treatment of chronic hepatitis B in
adults (>12 years)
Dose: 10 mg, once daily, taken orally, without regard
to food.
The major adverse events: severe, acute
exacerbation of hepatitis B after discontinuation of
Hepsera and kidney toxicity.
Genome Replication
Entecavir (Baraclude):
Nucleoside analogue reverse transcriptase inhibitor.
Has selective anti-hepatitis B virus (HBV) activity.
Dose: 0.5 mg tablet once-daily for chronic hepatitis B patients
beginning treatment for the first time (nucleoside-nave patients), and
a single 1 mg tablet once-daily for patients experiencing resistance to
lamivudine.
Cross resistance has been observed among HBV nucleoside
analogues.
Adverse Events: lactic acidosis and severe hepatomegaly with
steatosis, severe acute exacerbations of hepatitis B have been
reported in patients who have discontinued anti-hepatitis B therapy,
headache, abdominal pain, diarrhea, fatigue, and dizziness.

Genome Replication
4.Inhibition of viral release:
Neuraminidase inhibitors
Oseltamivir / Zanamavir
Influenza contains an enzyme neuraminidase which is
essential for the replication of the virus.
Neuraminidase inhibitors prevent the release of new
virions and their spread from cell to cell. These are effective
against both types of influenza A and B.
Do not interfere with immune response to influenza vaccine.
Can be used for both prophylaxis and treatment.
Oseltamivir is orally administered.
Zanamavir is given intranasal.
Risk of bronchospasm with zanamavir
Immune Globulins

Hyperimmune CMV immunoglobulin has
attenuated CMV disease associated with
kidney transplantation, but it has not proved
useful in preventing CMV disease in HIV-
infected persons.
Interferons

Interferons are natural cellular products released from infected
host cells in response to viral or other foreign nucleic acids.
They are detectable as early as 2 h after infection.
Their complex mechanism of action has not been fully
established, but interferon selectively blocks translation and
transcription of viral RNA, stopping viral replication without
disturbing normal host cell function.(Charles E. Samuel.
Antiviral Actions of Interferons.Clin. Microbiol. Rev. 2001,
14(4):778.)
A recombinant form of endogenous interferon- is being studied
in selected patients with hairy cell leukemia, Kaposi sarcoma,
human papilloma virus, and respiratory viruses.
They are used primarily for hepatitis B and C. Patients with
active HBV or HCV with detectable viral loads and abnormal
liver function tests may benefit from therapy.
Classified on the basis of the cell types from
which they were derived:
Interferon type leukocyte
Interferon type fibroblast
Interferon type immune cell

Interferons

Three known enzymes are induced by interferons:
A protein kinase that leads to phosphorylation of
elongation factor 2, resulting in inhibition of peptide chain
initiation;
Oligoisoadenylate synthase, which leads to activation of a
ribonuclease (RNA) and degradation of viral mRNA;
A phosphodiesterase that can degrade the terminal
nucleotides of tRNA, inhibiting peptide elongation.
Interferons

In patients with HBV who fit appropriate criteria, 2.5 to 5 million U
sc or IM 3times/ week for 4 to 6 mo can induce clearance of HBV
DNA and the hepatitis B e antigen (HBeAg) from serum and
improve liver function test abnormalities and liver histology in 25
to 40% of patients.
For chronic delta hepatitis, higher doses in the range of 9 to 10
million U 3 times/wk are required, and relapse is very common.
For HCV, 3 to 6 million U 3 times/wk for 6 to 12 mo typically
decreases HCV RNA level and improves liver function tests and
liver histology in 10 to 25%.
Adverse effects include: fever, chills, weakness, and myalgia
(influenza like syndrome) typically starting 7 to 12 h after first
injection and lasting up to 12 h (treatment with acetaminophen),
allergy, thyroiditis.
Addition of ribavirin to interferon for HCV.
Interferons

Peginterferon alfa 2a and 2b (polyethylene glycol conjugated
"pegylated" interferon)
Is alpha interferon that has been modified chemically by the addition of
a large inert molecule of polyethylene glycol.
Has been evaluated alone and in combination with ribavirin as
treatment for hepatitis C. Studies suggest that peginterferon may have
greater efficacy than standard interferon. Pegylation changes the
uptake, distribution, and excretion of interferon, prolonging its half-life.
Peginterferon can be given once weekly and provides a constant level
of interferon in the blood, whereas standard interferon must be given
several times weekly and provides intermittent and fluctuating levels.
In addition, peginterferon is more active than standard interferon in
inhibiting HCV and yields higher sustained response rates with similar
side effects.
Because of its ease of administration and better efficacy, peginterferon
has replaced standard interferon both as monotherapy and as
combination therapy for hepatitis C.
Interferons

New ARV
Fusion / Entry Inhibition
Maraviroc
Non-Nucleoside Reverse Transcriptase
Inhibition
Etravirine
Integrase Inhibition
Raltegravir
Protease Inhibition
Darunavir

Chemical Structures
Etravirine
Maraviroc
Raltegravir
Darunavir
Life Cycle
Maraviroc (Selzentry)
August 6, 2007 FDA accelerated
approval
First CCR5 co-receptor inhibitor
Approved for treatment-experienced
patients over 16 years of age with CCR5-
tropic virus
Has NOT shown efficacy in those with
mixed or dual virus tropism
Chemokines
Maraviroc - Pharmacokinetics
Peak plasma concentration 0.5-4 hours

Metabolized by CYP450 system
Renal clearance of 25%

Terminal half-life at steady state 14-18 hours

76% protein bound

Pregnancy category B
Maraviroc
No food restrictions
Available forms: 150 mg, 300 mg film-coated tablets
Dosage: 300 mg po BID usual dose:
300 mg BID all NRTIs, nevirapine, tipranavir,
enfuvirtide
150 mg BID CYP3A inhibitors (with or without with a
strong CYP3A inducer): protease inhibitors (other than
tipranavir), delavirdine
600 mg BID CYP3A inducer (if used without a strong
CYP3A inhibitor [see above]): efavirenz, etravirine
Motivate 1 & 2
Trial design
474 patients were randomized 1:2:2 to placebo or
maraviroc 150 mg once daily (qd) or maraviroc (mvc)
twice daily (bid), all 3 groups along with OBT,
optimized therapy background.


MOTIVATE 1 & 2
Patient characteristics

MOTIVATE 1 & 2
Viral Load Results
MOTIVATE 1 & 2
CD4 Results
MOTIVATE 1 & 2
Adverse effects seen at week
24:
< 5% stopped medication due
to ADEs
No increase in mortality,
malignancy, hepatotoxicity
Increased incidence of
Candida, herpes, and influenza
infections
Most common: cough, fever,
URI, rash, musculoskeletal
symptoms, abdominal pain,
dizziness
Serious adverse events in <
2%: angina, heart failure, MI,
hepatic cirrhosis or failure,
jaundice, viral meningitis,
pneumonia, myositis,
osteonecrosis, rhabdomyolysis
Grade 3-4 lab abnormalities in
at least 2%: increase in
bilirubin, amylase, lipase, AST,
ALT
At week 48: diarrhea, nausea,
fatigue, headache same as in
OBT groups.

Hepatotoxicity - Maraviroc
One case in healthy volunteer of possible drug-
induced hepatotoxicity with allergy

Evidence of allergic reaction include: pruritic
rash, eosinophilia, increased IgE levels

Immediate evaluation and possible
discontinuation of agent suggested if signs or
symptoms of systemic rash reactions of
hepatotoxicity develop
Life Cycle
Borrowed from www.gladstone.ucsf.edu
Etravirine (Intelence)
FDA approval on 1-18-2008

First of the Second Generation NNRTIs

Approved for treatment-experienced
patients
Etravirine - Pharmacokinetics
Bioavailability in current formulation improved
compared to early formulations with decreased
pill burden

Metabolism: metabolized by CYP liver enzymes
and primarily excreted in feces

Pregnancy Category: B but not studied in
pregnancy

Inducer of CYP3A4
Etravirine - Efficacy
TMC125-C207
10 HIV+ men with 10-500 fold resistance to
Efavirenz
7 day treatment with TMC125
Median decrease in viral load slightly less than 10-
fold with 44% over 10-fold
No relationship between response and genotype
or phenotype results
Etravirine - Efficacy
TMC125-C223 Trial
199 HIV+ patients with NNRTI and PI-resistance
assigned to OBT + either 400 mg or 800 mg
TMC125 BID or standard-of-care regimen
Week 24: VL decreased >90% in the two
treatment arms compared to 50% in the SOC arm
Week 48: mean VL drop 0.88 for 400 mg, 1.01 for
800 mg, 0.14 for SOC arm
DUET 1 & 2
Study Design:
N= 1203 total
DUET 1 & 2
DUET 1 & 2
VL < 50 copies/ml
DUET 1 & 2
Etravirine Adverse Effects
HCV and HBV co-infected patients had a
worsening of hepatitis-related symptoms

Nausea and rash (15%) most commonly reported
ADEs; rash may require discontinuation;
reported cases of Stevens-Johnson Syndrome

Others: abdominal pain, fatigue, peripheral
neuropathy, headache, hypertension
Etravirine - Dosing
Standard dose: 2 100 mg po BID

Take after a meal

Intelence should not be combined with the following: Norvir
(ritonavir)-boosted Aptivus (tipranavir), Norvir-boosted Lexiva
(fosamprenavir) or Norvir-boosted Reyataz (atazanavir); any
protease inhibitors given without a boosting dose of Norvir; or
any of the other approved NNRTIs.

Etravirine Resistance
Mutations:
K103N no effect
Worst responders had
V179F*, Y181V*, Y106I,
and V179O

* Also seen with EFV and
NVP, always found
together
Life Cycle
Borrowed from www.gladstone.ucsf.edu
Raltegravir (Isentress)
FDA approval on 10-12-2007

First of the Integrase Inhibitors

Approved for treatment-experienced
patients
Raltegravir - Pharmacokinetics
Inhibits catalytic activity of HIV-1 integrase

Cmax in fasted state at 3 hours; delayed after a
high fat meal

83% protein bound

Metabolism: 51% excreted in feces, 32% in urine

Pregnancy Category: C
Raltegravir - Efficacy
198 treatment-nave patients:
(Raltegravir at varying doses ranging from 100-600 mg po BID or
Efavirenz 600 mg po qHS) + tenofovir + 3TC








Changes in CD4 counts similar
Raltegravir - Efficacy
179 treatment-experienced patients with
VL > 5000 and resistance to at least one
drug in each anti-HIV class
Raltegravir 200, 400, or 600 BID or placebo
with optimized background tx
Week 24: mean viral load decreases from
baseline of 99% for raltegravir groups
versus 50% for placebo group
BENCHMRK 2
Methods: Pts failing ART with
triple-class resistant HIV were
randomized 2:1 to oral BID RAL
400 mg or placebo (PBO). All pts
received OBT.
Groups:
Baseline characteristics were
similar in the RAL and PBO groups.
At baseline, median CD4 counts
were 102 and 132 cells/mm3, and
geometric mean viral loads were 4.7
and 4.7 log10 copies/mL in the RAL
and PBO groups, respectively.
Genotyping demonstrated that OBT
contained <1 active drug (sensitivity
score = 0) in 20% and 27% of pts in
the RAL and PBO groups,
respectively.

BENCHMRK 2
BENCHMRK 1
& 2
Raltegravir - Dosing
Recommended dose 400 mg tablet po
BID

No significant drug-drug interaction with
other ARVs

Use with caution when administered with
strong inducers of UGT, such as rifampin,
which may lead to low levels
Raltegravir Adverse Drug Effects
Most commonly reported adverse effects:
Diarrhea, nausea, headache, dizziness, itching
Others: constipation, flatulence, sweating
All above similar to incidence in the placebo
groups
Grade 2 to 4 elevations in creatine kinase
seen
Life Cycle
Borrowed from www.gladstone.ucsf.edu
Darunavir (Prezista)
Approved by FDA 6-23-2006

Approved for use by treatment-
experienced patients; may also be very
effective in nave patients

Second generation PI
Darunavir - Pharmacokinetics
Inhibits cleavage of HIV-encoded Gag-Pol polyproteins

Cmax approximately 30% higher when taken after a meal
compared to fasting

95% protein bound

Metabolism: extensively by CYP enzymes, predominantly
CYP3A

Pregnancy Category: B

Darunavir - Efficacy
TMC114-C202 + TMC114-C213 Trials
N=319 + 318; all with baseline VL > 1000 and
previous treatment with 3 classes of meds and
had at least one primary PI mutation
Darunavir/r or investigator-selected PI with
optimized background
Results at 24 weeks:
63% versus 19% had VL <400 copies/ml
CD4 increase 92 versus 17 cells/mm3.
POWER 1 and 2
Phase IIb trials in treatment-experienced
patients
Week 48:
61% on darunavir/r had at least a 90% reduction
in viral load compared to 15% in control PI arm
Viral load < 50 copies/ml: 45% versus 10%
TITAN
Tx-experienced patients nave to
lopinavir and darunavir N=595
Virologic failure:
10.4% on darunavir compared
22% on lopinavir.
Among people with virologic
failure:
proportionately fewer in the
darunavir arm with new
mutations conferring PI
resistance (21% versus 36%)

fewer with darunavir failure had
new nucleoside-related
mutations (14% versus 27%).

ARTEMIS
689 tx-nave
patients
Assigned to
TDF/FTC plus
either:
once daily
darunavir/r 800/100
mg
or lopinavir/r given
once or twice daily

Darunavir Dosing
Usual dosing: 600 mg + 100 mg ritonavir po BID
New formulation approved by FDA of 600 mg

Darunavir may be given with atazanavir but not other
protease inhibitors. Maraviroc must be decreased when
given with darunavir.

Should not be used with carbamazepine, phenobarbital,
phenytoin, St. Johns wort, and rifampin
Use cautiously with azoles preferably not more than 200
mg po daily
Darunavir - Adverse Drug Effects
Most common ADEs: diarrhea, nausea, headache,
nasopharyngitis

Severe skin reactions, including erythema multiforme and
Stevens-Johnson Syndrome, reported

Also reported: high lipids, decreased WBCs, fever,
elevated transaminases (25% incidence of grade 3 or 4 lab
abnormalities)

Not well studied yet in patients with chronic hepatitis
Darunavir - Resistance
Cross-resistance with other PIs seen
DRV-resistant viruses not susceptible to AMP,
ATV, IND, LPV, NLF, RTV, SQV
Limited cross-reactivity with tipranavir

Decreased response:
6-21 fold decrease if 3 of the following mutations
present: S37N/D, R41E/S/T, K55Q, K70E, A71T,
T74S, V77I, I85V
Summation
Maraviroc:
Must have CCR5-tropic virus on Trofile testing
Etravirine
Still active with NNRTI-resistant strains with K103N
Raltegravir
Minimal drug-drug interactions, active against resistant
organisms
Darunavir
Good activity in deeply experienced patients; use cautiously in
patients with chronic hepatitis.