Drugs 2009; 69 (8): 1059-1075

ADIS DRUG EVALUATION 0012-6667/09/0008-1059/$55.55/0

ª 2009 Adis Data Information BV. All rights reserved.

Raltegravir
A Review of its Use in the Management of HIV Infection in
Treatment-Experienced Patients
Jamie D. Croxtall and Susan J. Keam
Wolters Kluwer Health | Adis, Auckland, New Zealand, an editorial office of Wolters Kluwer
Health, Philadelphia, Pennsylvania, USA

Various sections of the manuscript reviewed by:

F. Cainelli, School of Medicine, Faculty of Health Sciences, University of Botswana, Gaborone, Botswana;
B. Gazzard, St Stephen’s Centre, Chelsea and Westminster Hospital, London, UK; D.T. Jayaweera, Division of
Infectious Diseases, University of Miami School of Medicine, Miami, Florida, USA; M. Nelson, HIV Medicine,
Chelsea and Westminster Hospital, London, UK; R. Wood, Institute of Infectious Disease and Molecular
Medicine, University of Cape Town Faculty of Health Sciences, Cape Town, South Africa.

Data Selection
Sources: Medical literature published in any language since 1980 on ‘raltegravir’, identified using MEDLINE and EMBASE, supplemented
by AdisBase (a proprietary database of Wolters Kluwer Health | Adis). Additional references were identified from the reference lists of
published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing
the drug.
Search strategy: MEDLINE, EMBASE and AdisBase search term was ‘raltegravir’. Searches were last updated 20 May 2009.
Selection: Studies in patients with HIV infection who received raltegravir. Inclusion of studies was based mainly on the methods section of
the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic
and pharmacokinetic data are also included.
Index terms: Raltegravir, HIV infection, antiretroviral therapy, integrase inhibitor, pharmacodynamics, pharmacokinetics, therapeutic use,
tolerability.

Contents
Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1060
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1061
2. Pharmacodynamic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1061
2.1 Mechanism of Action. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1061
2.2 Antiretroviral Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1062
2.3 Resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1062
2.4 Other Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1063
3. Pharmacokinetic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1063
3.1 Absorption and Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1063
3.2 Metabolism and Elimination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1064
3.3 Special Populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1064
3.4 Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1065
4. Therapeutic Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1066
5. Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1069
6. Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1070
7. Place of Raltegravir in the Management of HIV Infection in Treatment-Experienced Patients. . . . . 1070
1060 Croxtall & Keam

Summary
Abstract Raltegravir (Isentress), an integrase inhibitor, inhibits the insertion of HIV-1
complementary DNA into the host genome. It is indicated in combination with
other antiretroviral therapy (ART) agents for the treatment of HIV-1 infection
in treatment-experienced adult patients who have evidence of viral replication
and HIV-1 strains resistant to multiple ART agents. It is the first of a new class
of ART agents to be approved that, as a result of a different mechanism of
action to other ART agents, has good activity against multidrug-resistant HIV-1
strains.

In clinical trials in treatment-experienced patients with HIV-1 infection and

evidence of viral replication, the addition of oral raltegravir to an optimized
background therapy (OBT) regimen improved virological and immunological
responses at 16 and 48 weeks to a greater extent than placebo plus OBT. Ralte-
gravir therapy was generally well tolerated, with a similar incidence of mild to
moderate adverse events in the treatment and placebo arms. The introduction of
integrase inhibitors extends the options available for managing treatment-
experienced patients with multiple-drug-resistant HIV-1 infection. Results to date
suggest that the combination of raltegravir and OBT will be a valuable treatment
option for this difficult-to-treat patient group.

Pharmacological Raltegravir is a selective inhibitor of integrase, an HIV-1-specific enzyme that

Properties is responsible for the insertion of viral complimentary DNA into the host
genome. In in vitro studies, the 95% inhibitory concentration (IC95) of raltegravir
in human T-lymphoid cells infected with a laboratory strain of HIV-1 was
31 nmol/L and ranged from 6 to 50 nmol/L in human peripheral blood mono-
nuclear cells, infected with clinical isolates of HIV-1, including strains resistant
to other classes of ART. Specific mutations within the HIV-1 integrase gene
(predominantly at Q148, N155 or Y143) are correlated with virological resistance
to raltegravir. Patients with higher baseline levels of HIV-1 RNA and less active
OBT regimens are at the highest risk of integrase mutations arising during
treatment.

Oral raltegravir is rapidly absorbed, with a mean maximum plasma con-

centration reached at a median time of »1 hour. The mean plasma concentration
of raltegravir at the end of a 12-hour dose administration interval after a 400 mg
dose exceeded the IC95 against HIV-1 in vitro. Raltegravir is metabolized in hu-
mans through uridine diphosphate-glucuronosyltransferase-mediated glucur-
onidation in the liver, and is eliminated in faeces and urine. The mean elimination
half-life of raltegravir is 7–12 hours. Raltegravir does not significantly affect the
activity of the cytochrome P450 system and therefore is not expected to interact
with other ART agents that are substrates for these enzymes.

Therapeutic Efficacy
In the two phase III BENCHMRK trials (n = 699), orally administered raltegravir
400 mg twice daily plus OBT improved both virological and immunological out-
comes in treatment-experienced patients with HIV-1 infection, evidence of viral
replication and HIV-1 strains resistant to multiple ART agents. At 16 weeks in the
individual trials and at 48 weeks in the combined analysis, raltegravir plus
OBT reduced HIV-1 RNA levels to <400 copies/mL (primary endpoint) and

ª 2009 Adis Data Information BV. All rights reserved. Drugs 2009; 69 (8)
Raltegravir: A Review 1061

<50 copies/mL in a significantly greater number of patients and significantly

increased CD4+ cell counts from baseline when compared with placebo plus OBT.
Moreover, prespecified subgroup analyses indicated that in the BENCHMRK
trials, the greater efficacy of raltegravir plus OBT compared with placebo plus
OBT was maintained in patients with baseline characteristics that typically pre-
dict a poor response to ART therapy, for example, higher HIV-1 RNA levels,
lower CD4+ cell counts and less active OBT regimens.

Tolerability Raltegravir was generally well tolerated when used in combination with OBT
regimens in treatment-experienced patients with HIV-1 infection in trials of up to
48 weeks’ duration. The majority of adverse events were mild to moderate in
severity, and of similar incidence in the raltegravir plus OBT and placebo plus
OBT treatment arms; treatment-related discontinuations were uncommon. The
most common drug-related adverse events reported were diarrhoea, headache,
nausea and fatigue.

1. Introduction Integrase is an HIV-1-specific enzyme essential

The 2008 Joint United Nations Programme on
HIV/AIDS report on the global AIDS epidemic
estimates that in 2007 there were 33 million peo-
ple infected with HIV type-1 (HIV-1) world-
wide.[1] There were 2.7 million new infections
occurring in 2007, which is lower than in previous
years and, as a consequence, the epidemic ap-
pears to be stabilizing;[1] however, the prevalence
of infection remains unacceptably high.[1-3]
Although antiretroviral therapy (ART) regi-
mens have significantly reduced the morbidity and
mortality associated with HIV-1 infections, there is
currently no cure for the disease. Moreover, for all
ART regimens, the emergence of both evolved and
transmitted resistance presents a significant com-
promise for effective long-term treatment suc-
cess.[2,4,5] Indeed, estimates suggest that as many as
76% of treatment-experienced patients who are
viraemic harbour viruses that exhibit resistance,[6]
with a prevalence of three-class drug resistance of
more than 13% in viraemic treatment-experienced
patients in the US.[6]
Treatment successes cannot be sustained with-
out reducing the incidence of new infections,
reducing drug toxicities and tackling the problem
of ART resistance.[2,4,5] Therefore, there remains
an ongoing need for the development of new
treatment modalities for patients with HIV-1
infection.
for viral replication. It catalyses the insertion of
viral complementary DNA (cDNA) into the
genome of host cells.[7] Inhibition of this novel
target may be of value in patients with HIV-1
variants that exhibit resistance to conventional
ART agents.
Raltegravir (Isentress) is the first ART in-
tegrase inhibitor to be approved for use in the
treatment of HIV-1 infection. This article reviews
the pharmacological properties of raltegravir,
and its clinical efficacy and tolerability profile in
treatment-experienced patients with HIV-1 infec-
tions resistant to other ART agents.
2. Pharmacodynamic Properties
The pharmacodynamic properties of raltegravir
have been reviewed previously in detail.[7-10] There-
fore, this section provides an overview of these and
more recently published data,[11-17] supplemented,
where appropriate, by the manufacturer’s pre-
scribing information.[18,19]
2.1 Mechanism of Action
Raltegravir is a hydroxypyrimidinone carbox-
amide that shares the b-hydroxy ketone struc-
tural motif of the diketo acid class of compounds
(figure 1). This motif is a defining moiety of the
integrase inhibitor class. Raltegravir prevents

ª 2009 Adis Data Information BV. All rights reserved. Drugs 2009; 69 (8)
1062
O protease inhibitors (PIs) and a fusion inhibitor,
N H3C O–K+
N N
H3C H H
O N
N
N HIV-2 exhibits inherent resistance to NNRTIs
O H3C CH3 O
Fig. 1. Chemical structure of raltegravir.
covalent insertion of viral HIV-1 cDNA into the
host cell genome.[9-11,20-22] Importantly, host cells
do not express integrase activity; thus, raltegravir
is unlikely to affect normal cell activity.[7-9]
Like other integrase inhibitors, raltegravir
selectively blocks the strand-transfer activity of
integrase at nanomolar concentrations (appar-
ent 50% inhibitory concentration [IC50] of
2–7 nmol/L).[11,22] Integrase inhibition prevents
the insertion of linear HIV-1 cDNA into the host
cell genome. Consequently, the formation of HIV-1
provirus, which is necessary for the production of
progeny virus and infection of new cells, is
prevented.[7-9] By contrast, other human phos-
phoryltransferases, such as the polymerase and
ribonuclease H activities of HIV-1 reverse tran-
scriptase and DNA polymerase a, b and g, are not
significantly inhibited by raltegravir in vitro.[9]
2.2 Antiretroviral Activity
Raltegravir is a potent inhibitor of viral repli-
cation in vitro, including ART-resistant strains.[18,19]
In studies in human T-lymphoid cell cultures in-
fected with a laboratory strain of HIV-1 (variant
H9IIIB), the 95% inhibitory concentration (IC95)
of raltegravir was 31 nmol/L.[18,19] In mitogen-
activated human peripheral blood mononuclear
cells (PBMCs) infected with a variety of HIV-1
clinical isolates, including strains resistant to
ARTs of other classes, raltegravir IC95 values
ranged from 6 to 50 nmol/L.[18] Mean IC95 values
did not differ between B subtype and non-B
subtype HIV-1 clinical isolates assessed in human
PBMC replication assays (14 and 21 nmol/L).[12]
Additive-to-synergistic activity was evident
in vitro when raltegravir was used in combination
with other ART agents, including non-nucleoside
reverse transcriptase inhibitors (NNRTIs), nu-
cleoside reverse transcriptase inhibitors (NRTIs),
ª 2009 Adis Data Information BV. All rights reserved.
Croxtall & Keam
F against human T-lymphoid cells infected with
HIV-1 variant H9IIIB.[18]
and fusion inhibitors, and is less sensitive than
HIV-1 to several PIs in vitro.[23] However, ralte-
gravir showed good in vitro inhibitory activity
against 14 clinical isolates of HIV-2 (median IC50
and IC95 values of 2.4 and 12.5 nmol/L) in human
PBMC assays[13] and in an isolate of HIV-2 in
CEMx174 cells (T-cell/B-cell hybrid cell line)
[IC95 6 nmol/L].[18]
2.3 Resistance
Virological failure of raltegravir in patients
with HIV-1 infection appears to be correlated
with specific mutations at several key sites
within the integrase gene.[18,19,24] Several stu-
dies[14-16,18,19,24] have indicated that mutations
that result in amino acid substitutions at one of
three signature sites, including Q148 (changed to
H, K or R; i.e. Q148H/K/R), N155H or
Y143C/H/R, together with one or more addi-
tional substitutions (L74I/M/R, E92Q, T97A,
E138A/K, G140A/S, V151I, G163R, H183P,
Y226D/F/H, S230R, D232N, T66A and
E157Q[15,16,18,19,24]), play a crucial role in the
development of resistance to raltegravir. A small
study (n = 9) in treatment-experienced patients
receiving salvage therapy (which included ralte-
gravir) who subsequently developed virological
failure to raltegravir showed that the E92Q,
G140S and Q148H substitutions of HIV-1 in-
tegrase were associated with a 7- to 8-fold
decrease in susceptibility to raltegravir in vitro,
and the N155H substitution was associated with
a 14-fold decrease.[16]
In the ongoing phase III BENCHMRK
(Blocking integrase in treatment Experienced
patients with a Novel Compound against HIV:
MeRcK) trials (see section 4 for trial design de-
tails), 105 of 462 raltegravir recipients (23%) ex-
hibited virological failure at an interim assess-
ment time of 48 weeks.[14] Genotyping of HIV-1
integrase in 94 of these patients showed that 64
had a mutation known to confer raltegravir re-
sistance, with 54 having amino acid substitutions
Drugs 2009; 69 (8)
Raltegravir: A Review
at either Q148, N155 or Y143.[14] Of the remain-
ing 30 patients, 25 had no amino acid changes
from baseline sequence and five had changes of
unknown phenotypic effect.[14] In addition, most
(48 of 64) patients with resistance had two or
more mutations associated with resistance. Sub-
group analyses of the combined BENCHMRK
trials (n = 699) showed that patients with higher
baseline HIV-1 RNA levels or genotypic or phe-
notypic scores for optimized background therapy
(OBT) of 0 had an increased risk of HIV-1 in-
tegrase mutations arising during treatment.[14]
On the other hand, clade-specific polymorph-
isms of the HIV-1 integrase gene do not appear to
contribute to reduced susceptibility to raltegravir.[17]
The emergence of mutations Q148K/R and
N155H have been identified in the integrase gene
of HIV-2 infected patients with raltegravir re-
sistance,[13,25] suggesting a common pathway to
integrase inhibitor resistance with HIV-1.
2.4 Other Effects
Oral raltegravir 400 mg twice daily for
48 weeks had little effect on fasting serum lipids
in the BENCHMRK trials, as evidenced by non-
significant changes relative to placebo in total
cholesterol (increased by 7.4%) and low-density
lipoprotein (LDL) cholesterol (increased by
6.2%).[26] Unlike many other ART agents, ralte-
gravir does not appear to be associated with the
development of clinically relevant dyslipidaemia
or hypercholesterolaemia.[19]
Furthermore, a single supratherapeutic oral
dose (1600 mg) of raltegravir did not prolong the
corrected QT (Fridericia method) [QTcF] inter-
val in healthy volunteers in a thorough QT/QTc
study (n = 31).[27]
3. Pharmacokinetic Properties
This section reviews the pharmacokinetic
properties of raltegravir in healthy volunteers
(n = 6–57)[28-35] and treatment-naive patients with
HIV-1 infection (n = 6),[36] focusing, where possi-
ble, on data using the approved dosage of 400 mg
twice daily. Additional information from the
ª 2009 Adis Data Information BV. All rights reserved.
1063
manufacturer’s prescribing information[18,19] is
also included.
3.1 Absorption and Distribution
The absolute bioavailability of raltegravir has
not been established. The pharmacokinetic para-
meters of orally administered raltegravir (400 mg
single dose or 400 mg twice daily for 10 days) in
healthy volunteers and treatment-naive patients
with HIV-1 infection are summarized in table I.
In a single-dose escalation study in fasted healthy
male volunteers, the mean maximum plasma con-
centration (Cmax), the mean plasma concentra-
tion at 12 hours post-dose (C12) and the mean
area under the plasma concentration-time curve
(AUC) from time zero to infinity (AUC¥) of or-
ally administered raltegravir increased approxi-
mately proportionally with doses of 10–1200 mg,
and slightly less than proportionally in doses
up to 1600 mg.[30] Absorption was rapid, with
a median time to Cmax (tmax) of approximately
1 hour.[30] Systemic exposure to single-dose ral-
tegravir 400 mg was similar in fasted healthy male
and female volunteers, as assessed by the
AUC¥.[30] The rate, but not the extent, of ralte-
gravir absorption was slowed when administered
with a high-fat meal in healthy volunteers.[29]
These effects, and the associated small increase
in systemic exposure, were not considered to
be clinically meaningful, and raltegravir can be
administered with or without food.[18,19]
Following multiple-dose administration of oral
raltegravir 100–800 mg twice daily for 10 days in
healthy male volunteers, both the AUC during a
dose administration interval (0–12 hours) and the
Cmax increased approximately proportionally with
dose, and steady-state raltegravir concentrations
were achieved within 2 days.[30] C12 values in-
creased slightly less than proportionally with
dose;[30] however, at all dosages the C12 values for
raltegravir were higher than 33 nmol/L, thus ex-
ceeding the raltegravir IC95 against most strains
of HIV-1 in vitro (section 2.2).
In treatment-naive patients with HIV-1 infec-
tion, Cmax, C12 and AUC¥ values increased pro-
portionally with raltegravir 100–400 mg twice
daily after 10 days of treatment, with no further
Drugs 2009; 69 (8)
1064 Croxtall & Keam

Table I. Mean pharmacokinetic values for single- (400 mg)[30] or multiple-dose (400 mg twice daily for 10 days)[30,36] orally administered
raltegravir as monotherapy in randomized, double-blind, placebo-controlled trials in healthy volunteers[30] and treatment-naive patients with
HIV-1 infection[36]
Parameter Healthy male volunteers[30]a Treatment-naive patients[36]
single dose (n = 6)b multiple dose (n = 8)c multiple dose (n = 6)c
Cmax (mmol/L) 10.6 11.2 4.5
tmax (h) 1.0d 1.0d 1.7

C12 (nmol/L) 81.3 200.6 142
AUC (mmol h/L) 24.6e 28.7f 14.2f
t1/2a (h) 1.1 1.1
t1/2b (h) 6.9 10.7
CLR (L/h) 3.6 3.6
a Lactose formulation of raltegravir.
b Fasted state.
c Steady-state values at day 10.
d Median value.
e From time zero to infinity.
f From 0 to 12 hours.
AUC = area under the plasma concentration-time curve; C12 = plasma concentration at the end of the dose administration interval (12 h);
CLR = renal clearance; Cmax = maximum plasma concentration; tmax = time to reach Cmax; t1/2 = elimination half-life of the initial (a) or terminal (b)
phases.

increase for the 600 mg dosage.[36] Absorption
was rapid, with a mean tmax of 1.3–2 hours. Mean
C12 values at all raltegravir dosages at day 10
exceeded 33 nmol/L.[36]
Approximately 83% of the drug is bound to
human plasma protein over the concentration
range 2–10 mmol/L.[18]
3.2 Metabolism and Elimination
Raltegravir is metabolized in humans pri-
marily through uridine diphosphate-glucuronosyl-
transferase (UGT)-mediated glucuronidation in
the liver, predominantly via UGT1A1.[31] Ap-
proximately 33% of raltegravir recovered in the
plasma of healthy volunteers was found to be the
glucuronide derivative, with the remainder ac-
counted for by the parent compound.[31] There
was no evidence for oxidative metabolism of
raltegravir in isolated human liver microsomes
and the drug did not interact with cytochrome
P450 (CYP).[31]
Plasma concentrations of orally administered
raltegravir declined rapidly in healthy volun-
teers following a single 200 mg dose and were
undetectable after 24 hours.[31] The appa-
rent mean terminal elimination half-life after
single or repeated administration of raltegravir
10–1600 mg was 6–12 hours, but there is also a
shorter half-life initial phase (»1 hour) which
accounts for most of the AUC.[18,19,30]
The renal clearance rate of raltegravir was
3.6 L/h for healthy volunteers receiving the recom-
mended dosage of 400 mg twice daily (table I).[30]
Raltegravir was eliminated in the faeces (51%)
and urine (32%) of healthy volunteers following
oral administration of the 14C-labelled drug.[31]
The glucuronide metabolite of raltegravir ac-
counted for 23% of the label recovered in urine,
whereas only the parent compound was found in
the faecal fraction.[31]
3.3 Special Populations
Age, sex, race, moderate hepatic impairment
and severe renal impairment had no appreciable
effect on the pharmacokinetic profile of ralte-
gravir, and dosage adjustments are not necessary
in these patient groups.[18,19,37] However, the
pharmacokinetics of raltegravir in children and in

ª 2009 Adis Data Information BV. All rights reserved. Drugs 2009; 69 (8)
Raltegravir: A Review 1065

patients with severe hepatic impairment have not
been determined. The extent to which raltegravir is
dialyzable is unknown; therefore, administration
prior to a dialysis session is not recommended.[18,19]
Following a single 400 mg dose, plasma con-
centrations of raltegravir were slightly higher for
individuals with the UGT1A1*28/*28 genotype
compared with the normal UGT1A1*1/*1 geno-
type, when matched for age, sex, race and body
mass index.[28] The geometric mean ratio
(UGT1A1*28/*28 : UGT1A1*1/*1) for AUC¥ was
1.41, for Cmax was 1.40 and for C12 was 1.91;
however, tmax and elimination half-life values were
similar for both genotypes.[28] These differences
are not considered to be clinically significant and
dosage adjustments are not required in individuals
with the UGT1A1*28/*28 polymorphism.[18,19]
3.4 Drug Interactions
Several studies have investigated the pharma-
cokinetic interactions between commonly co-
administered agents and raltegravir in healthy
volunteers, and these are summarized in table
II,[32-35,38,39] together with recommendations
for dosage adjustment for patients with HIV-1
infection.[18,19] There are no drug interaction
studies of raltegravir with darunavir.[40]
Raltegravir does not significantly affect the ac-
tivity of the CYP isoenzymes, including CYP3A4,
nor does it inhibit UGT1A1 and UGT2B7 activity
and P-glycoprotein-mediated transport in vitro.[18,19]
Therefore, raltegravir is not expected to interact
with agents that are substrates of these enzymes,
including PIs, NNRTIs, methadone, opioid an-
algesics, statins, azole antifungals, oral contracep-
tives, proton pump inhibitors and anti-erectile
dysfunction agents.[18,19]
This is largely confirmed in the studies pre-
sented in table II. However, coadministration
with the proton pump inhibitor omeprazole re-
sulted in an increase in plasma levels of ralte-
gravir.[35] As a consequence, coadministration of
raltegravir with agents that increase gastric pH is

Table II. Pharmacokinetic interactions between raltegravir (RAL) and other coadministered drugs in healthy subjects and recommended
dosage adjustments. The manufacturer’s prescribing information[18,19] should be consulted for further information on drug interactions
Dosage regimen (dose in mg) [frequency] No. of Ratio with : without coadministered drug Recommended dosage
Coadministered drug RAL subjects Cmax AUC C12 adjustment[18,19]
Effect of coadministered drug on the mean pharmacokinetic parameters of RAL
ATA 300 + RIT 100 [od][32] 400 [bid] 10 1.24 1.41a 1.77 None required
EFA 600 [od][33] 400 [sd] 9 0.64 0.64b 0.79 None required
OME 20 [sd][35] 400 [sd] NR 4.15 3.12b 1.46 Coadministration not
recommended
RIF 600 [od][38] 400 [sd] 9 0.62 0.60b 0.39 Caution required
RIT 100 [bid][33] 400 [sd] 10 0.76 0.84b 0.99 None required
TEN 300 [od][18] 400 [bid] 9 1.64 1.49c 1.03 None required
TIP 500 + RIT 200 [bid][39] 400 [bid] 18 0.82 0.76b 0.45 None required
Effect of RAL on the mean pharmacokinetic parameters of coadministered drug
ETH [NR][19] 400 [bid] NR 1.01 0.98c NR None required
MID 2 [sd] [34]
400 [bid] 10 1.03 0.92b NR None required
NOR [NR][19] 400 [bid] NR 1.29 1.14c NR None required
TEN 300 [od][19] 400 [bid] 9 0.67 0.9c 0.87 None required
a From 0 to 12 hours.
b From 0 to ¥.
c Interval not defined.
ATA = atazanavir; AUC = area under the plasma concentration-time curve; bid = twice daily; C12 = plasma concentration at the end of the
dose administration interval (12 h); Cmax = maximum plasma concentration; EFA = efavirenz; ETH = ethinyl estradiol; MID = midazolam;
NOR = norelgestromin; NR = not reported; od = once daily OME = omeprazole; RIF = rifampicin; RIT = ritonavir; sd = single dose;
TEN = tenofovir; TIP = tipranavir.

ª 2009 Adis Data Information BV. All rights reserved. Drugs 2009; 69 (8)
1066
not recommended unless this is unavoidable.[19]
Additionally, because raltegravir is metabolized
by UGT-mediated glucuronidation, agents such
as rifampicin (rifampin), which are strong in-
ducers of UGT enzymes, should be coadminis-
tered with caution and modification in raltegravir
dosage may be required (section 6).[18,19]
4. Therapeutic Efficacy
The therapeutic efficacy of raltegravir in com-
bination with other antiretroviral agents has been
evaluated in patients with HIV-1 infection who are
treatment-naive[36,41,42] or treatment-experienced
with multidrug ART resistance.[14,26,43] However,
raltegravir is not approved for use in treatment-
naive patients and this section reviews clinical trial
data in treatment-experienced patients only.
Clinical data reviewed in this section in pa-
tients (aged ‡16 years) with ART-resistant HIV-1
receiving oral raltegravir 400 mg twice daily (the
recommended dosage; see section 6) are primarily
derived from two BENCHMRK trials.[14,26]
BENCHMRK-1 and BENCHMRK-2 (MK-0518
protocols 018 and 019) are identically designed,
ongoing (scheduled to run at least 156 weeks),
randomized, double-blind, placebo-controlled,
multicentre, phase III trials in ART-experienced
patients with virological failure (HIV-1 RNA
levels >1000 copies/mL) when receiving ART ther-
apy, and documented phenotypic or genotypic
resistance to at least one drug in each of three
approved classes of oral ART drugs (NRTIs,
NNRTIs, PIs).[14,26] BENCHMRK-1 is being
conducted in Europe, Asia/Pacific and Peru,
whereas BENCHMRK-2 is being conducted in
North, Central and South America.[14,26]
The BENCHMRK clinical trial data are sup-
ported by a phase II, randomized, double-blind,
dose-finding trial in ART-experienced patients
with HIV-1 infection (protocol 005)[44] that esta-
blished raltegravir 400 mg twice daily as the
optimum dosage regimen. This study has been
reviewed previously in detail[9] and is not dis-
cussed further. A noncomparative, open-label,
multicentre, ongoing, phase II French study
(ANRS 139 TRIO)[45] in patients with ART-
resistant HIV-1 (n = 103) indicated the efficacy of
ª 2009 Adis Data Information BV. All rights reserved.
Croxtall & Keam
a raltegravir 400 mg twice daily plus etravirine and
darunavir/ritonavir regimen, and is not discussed
further. Furthermore, a small (n = 35) switching
trial suggested that all patients not tolerating en-
fuvirtide could replace enfuvirtide with raltegravir
in the combined ART regimen without loss of
viral suppression for up to a median time of
7 months (except one patient with a detectable, but
transient, viral load after 5 months).[46] Similarly,
a randomized, noninferiority, switching trial in
highly treatment-experienced patients (n = 170)
indicated that raltegravir plus OBT was non-
inferior to enfuvirtide plus OBT in terms of viral
suppression.[47] These trials are also not discussed
further.
Patients presented with similar baseline char-
acteristics in both BENCHMRK trials: with a
median age range of 43–47 years, median plasma
HIV-1 RNA levels of 4.6–4.8 log10 copies/mL,
median CD4+ cell counts of 102–140 cells/mm3,
median duration of prior ART use of 10–11 years,
median number of ART drugs in OBT of four, a
history of AIDS in 89–93.5%, a co-infection of
hepatitis B and/or C in 7.6–22.9% and a geno-
typic or phenotypic score of 0 in 10.4–30.2%;
84.1–91.3% were male.[26] Randomization of pa-
tients to receive either raltegravir 400 mg twice
daily plus OBT (n = 232 or 230) or placebo twice
daily plus OBT (n = 118 or 119) was stratified
according to the extent of resistance to prior PI
treatment and the inclusion of enfuvirtide in the
OBT.[26] In addition to prior ART treatment,
both genotypic and phenotypic resistance testing
of patients determined the selection of OBT be-
fore randomization.[26]
Patients with renal insufficiency (serum crea-
tinine levels more than 2 · the upper limit of
normal [ULN]) or acute or decompensated
chronic hepatitis were excluded from the study.
Patients with stable chronic hepatitis B or hepa-
titis C were permitted if their serum aminotrans-
ferase levels were <5 · the ULN, and patients
with active cancer were enrolled if they did not
require chemotherapy and the cancer was un-
likely to affect the study outcome.[26]
In both BENCHMRK studies, the prespeci-
fied primary outcome measure was defined as the
proportion of patients achieving suppression of
Drugs 2009; 69 (8)
Raltegravir: A Review
HIV-1 RNA levels to <400 copies/mL after 16
weeks of treatment.[26] Prespecified secondary
outcome measures were defined as the proportion
of patients with HIV-1 RNA levels <50
copies/mL and the change from baseline in CD4+
cell counts at weeks 16 and 48.[26] A combined
analysis of both BENCHMRK trials was also
prespecified to provide precise estimates of viro-
logical response rates. Logistic regression analy-
sis showed that as a result of the consistency of
efficacy between treatment groups, exploratory
subgroup analyses of pooled data were fea-
sible.[14,26]
All treated patients were included in the final
efficacy analysis. Missing data were analysed in
the following three ways: the primary efficacy
analysis counted treatment-related discontinua-
tions as treatment failures at subsequent time-
points; a second, worst-case approach counted
noncompletion for any reason as treatment fail-
ure; and a third, observed-failure approach
counted discontinuation due to a lack of efficacy
as treatment failure.[26]
Prespecified subgroup analyses of combined
data from the two BENCHMRK trials were
conducted at week 48 according to demographic
characteristics, baseline HIV-1 RNA levels,
CD4+ counts, the inclusion of active PIs in the
OBT and genotypic/phenotypic testing for HIV-1
resistance; however, the analysis of enfuvirtide
plus darunavir in OBT was specified after
unblinding.[14]
Orally administered raltegravir 400 mg twice
daily plus OBT significantly improved virological
and immunological outcomes in treatment-
experienced patients with HIV-1 infection and
triple class resistance compared with placebo
twice daily plus OBT in the BENCHMRK
trials.[26]
The proportion of patients achieving HIV-1
RNA levels of <400 copies/mL, with treatment-
related discontinuations counted as virological
failure, was significantly greater in the raltegravir
plus OBT treatment group than in the placebo
plus OBT treatment group in both
BENCHMRK-1 and BENCHMRK-2 trials at
week 16 (primary endpoint; table III).[26] In both
trials, 78% of raltegravir plus OBT recipients
ª 2009 Adis Data Information BV. All rights reserved.
1067
achieved this endpoint, compared with just over
40% of those receiving placebo plus OBT (both
p < 0.001). Furthermore, HIV-1 RNA levels were
suppressed to <50 copies/mL in a significantly
greater number of raltegravir plus OBT than in
placebo plus OBT recipients (table III).[26] These
results were confirmed when the more stringent
criterion of patient noncompletion counted as
treatment failure was used in the individual stu-
dies and the combined analysis (78% vs 42% for
patients achieving HIV-1 RNA levels <400
copies/mL and 62% vs 35% for patients achieving
HIV-1 RNA levels <50 copies/mL).[26]
The greater efficacy of raltegravir plus OBT
over placebo plus OBT in the BENCHMRK
trials was maintained following 48 weeks’ treat-
ment (table III).[26] At least 72% of raltegravir
plus OBT recipients in the combined analysis had
plasma HIV-1 RNA levels of <400 copies/mL and
62% achieved levels of <50 copies/mL. By con-
trast, only 37% and 33% of those receiving pla-
cebo plus OBT achieved these endpoints.[26]
Moreover, the proportion of patients with HIV-1
RNA levels of <50 copies/mL for recipients of
raltegravir plus OBT or placebo plus OBT was
little changed between week 16 using treatment-
related discontinuation as virological failure data
(62–63% vs 33–36%) and week 48 using patient
noncompletion as virological failure data
(60–65% vs 31–35%) [table III].[26]
CD4+ cell counts rose from baseline (102–140
cells/mm3) by a mean of 83 cells/mm3 in
BENCHMRK 1 and 86 cells/mm3 in BENCHMRK
2 following 16 weeks’ treatment with raltegravir
plus OBT compared with 31 and 40 cells/mm3
for recipients of placebo plus OBT (values esti-
mated from a graph; significance not reported)
[table III].[26] The increase from baseline in CD4+
cell counts was maintained through to 48 weeks in
both BENCHMRK trials. In the combined analy-
sis using observed lack of efficacy as virological
failure data, CD4+ cell counts increased from
baseline by a mean of 109 cells/mm3 for recipients
of raltegravir plus OBT versus 45 cells/mm3 for
those receiving placebo plus OBT (p < 0.001) at
week 48 (table III).[26]
Using an observed lack of efficacy as treat-
ment failure analysis, the mean change from
Drugs 2009; 69 (8)
1068 Croxtall & Keam

Table III. Efficacy of oral raltegravir (RAL) 400 mg twice daily in adult patients (pts) with HIV type-1 (HIV-1) infection who have evidence of
viral replication and HIV-1 strains resistant to three classes of antiretroviral therapy (ART). Results from the pre-planned 16- and 48-week
analyses of all evaluable pts in the BENCHMRK trials. BENCHMRK-1 and BENCHMRK-2 are identically designed, ongoing, randomized,
double-blind, placebo (PL)-controlled, multicentre, phase III trials in pts with ART-resistant HIV-1 receiving RAL 400 mg twice daily plus
optimized background therapy (OBT) or PL twice daily plus OBT[26]
Study Treatment No. of Pts (%) with plasma HIV-1 RNA levelsa Mean change from baseline inb
regimen pts c
<400 <50 CD4+ cell counts plasma viral load
(copies/mL) (copies/mL)d (cells/mm3)d,e (log10 copies/mL)f
Results at 16 weeks
BENCHMRK 1 RAL + OBT 227 78*g 62* 83h -1.8h
PL + OBT 117 41 g
33 31 h
-0.8h
*g *
BENCHMRK 2 RAL + OBT 226 78 63 86 h
-1.9h
PL + OBT 118 43 g
36 40 h
-1.1h
Results at 48 weeks
BENCHMRK 1 RAL + OBT 227–231 74* 65* 120* -1.7*
PL + OBT 114–118 36 31 49 -0.8
BENCHMRK 2 RAL + OBT 216–228 71* 60* 98* -1.7*
PL + OBT 114–119 38 35 40 -0.8
BENCHMRK 1 and 2 RAL + OBT 439–459 72* 62* 109* -1.7*
PL + OBT 228–237 37 33 45 -0.8
a Treatment-related discontinuations at 16 weeks and pt noncompletion at 48 weeks were counted as virological failures. Pts were deemed
to have virological failure if HIV-1 RNA levels at or after week 16 were: (i) not reduced to <400 copies/mL or by >1 log10/mL from baseline;
(ii) increased by >1 log10/mL from the lower of two consecutive measurements; or (iii) ‡400 copies/mL on two consecutive measurements
following a prior level of <400 copies/mL.
b Observed lack of efficacy at 16 and 48 weeks counted as virological failure; data for treatment-related discontinuations and pt
noncompletion not reported.
c A total of 462 pts were randomized to RAL plus OBT and 237 to PL plus OBT in BENCHMRK 1 and 2. Where evaluable pt numbers varied
according to the statistical approach used for analysis, values are presented as a range.
d Secondary endpoint.
e Baseline values ranged from 102 to 140 cell/mm3.
f Baseline values ranged from 4.6 to 4.8 log10 copies/mL.
g Primary endpoint.
h Value estimated from a graph.
*
p < 0.001.

baseline in HIV-1 plasma viral load was -1.7
log10 copies/mL for raltegravir plus OBT versus
-0.8 log10 copies/mL for placebo plus OBT re-
cipients, for both studies individually and the
combined analysis, at week 48 (table III).[26]
Preliminary data indicate that the anti-
retroviral efficacy of raltegravir was maintained
at 96 weeks in both BENCHMRK trials (avail-
able as an abstract).[43] Pooled data from both
studies showed that after 96 weeks, HIV-1 RNA
levels were reduced to <50 copies/mL in 58% of
recipients of raltegravir plus OBT (n = 462) versus
33% of recipients of placebo plus OBT (n = 237),
with patient non-completion counted as viro-
logical failure; CD4+ cell counts increased by
123 cells/mm3 versus 49 cells/mm3 (statistical
significance not reported).[43]
Prespecified subgroup analyses for potential
prognostic factors (using the observed lack of effi-
cacy as virological failure approach) suggested that
the efficacy of raltegravir plus OBT was not affected
by baseline viral load (including HIV-1 RNA levels
>100 000 copies/mL) and CD4+ cell counts (inclu-
ding counts of <50 cells/mm3), various demographic
variables and viral subtypes.[14] However, a
greater efficacy of raltegravir plus OBT over

ª 2009 Adis Data Information BV. All rights reserved. Drugs 2009; 69 (8)
Raltegravir: A Review 1069

placebo plus OBT was observed in patients with 9 RAL + OBT

PL + OBT
genotypic and phenotypic scores of 0–2. Posthoc 8
analysis indicated that the inclusion or non- 7
inclusion of darunavir and/or enfuvirtide as part 6

Patients (%)
of OBT had no effect on the improvement in 5
efficacy of raltegravir plus OBT over placebo plus 4
OBT, although there was an additional benefit 3
from the inclusion of these agents in both treat- 2
ment arms.[14] 1
0

es

ed n
se
nt
l

T
e ol

nc phi T
ro
as

i
ub
AL

AS
ou
id

r
5. Tolerability

la
ce Ele ste
e

n
er

y
ea st

El bilir
lc
ki

m
d
e
le
yc

ne ate

a
ol
o

at
cl

tin

l
ch

ta
ic
ed ch

ro

ev
tri

at

to
ut
L
The tolerability profile of raltegravir has been

l
ed

re
a

LD
cr

ed
o t
at

at
ed
reviewed previously.[9] This section provides an
ev

pa
ed

ev
at
El

at
at

El
ev

ed
u
ev
ev

ed
El
overview of the tolerability of raltegravir in com-

at
El
El

bination with OBT in treatment-experienced
patients with HIV-1 infection in the ongoing
BENCHMRK trials described in section 4,[26] with
additional supporting information provided from
the manufacturer’s prescribing information.[18,19]
In general, raltegravir was well tolerated, with
the majority of adverse events being of mild to
moderate severity.[26] Moreover, adverse event-
related discontinuations were uncommon, with
2% of patients receiving raltegravir plus OBT
discontinuing treatment for this reason versus 3%
of recipients of placebo plus OBT.[18,19]
5 RAL + OBT
PL + OBT
4
Patients (%)
ev
El
Fig. 3. Tolerability profile of raltegravir (RAL). Combined analysis
of the most frequent (incidence of >3% in either treatment arm)
laboratory abnormalities of grade 3 or 4 up to week 48 in the
BENCHMRK (Blocking integrase in treatment Experienced patients
with a Novel Compound against HIV: MeRcK) trials.[26] See table III
for trial design details. Patients were treated with raltegravir (RAL)
400 mg twice daily plus optimized background therapy (OBT)
[n = 462] or placebo (PL) twice daily plus OBT (n = 237). LDL = low-
density lipoprotein.
The most commonly reported adverse events
regardless of causality for recipients of raltegravir
400 mg twice daily plus OBT (n = 507) versus
placebo twice daily plus OBT (n = 282) were
diarrhoea (17.6% vs 20.6%), nausea (11.2% vs
15.2%), headache (10.1% vs 12.4%) and pyrexia
(6.3% vs 11%) based on pooled safety data from
three randomized clinical trials.[19]

3 Similarly, data from the combined BENCHMRK

2
studies showed that the most common drug-
related clinical adverse events of moderate to
1 severe intensity at 48 weeks were diarrhoea,
0 headache, nausea and fatigue, which were not
significantly different between the raltegravir
n

in
a

he

ea

ue
tio
oe

pa
c

ig
ac

plus OBT and placebo plus OBT treatment

da

au
rrh

ite
Fa
re

ea

N
ia

s
D

n-

groups (figure 2).[26] Injection-site reactions were

ite

io
s
n-

ct
je
io

considered to be related to the enfuvirtide com-

In
ct
je

ponent of OBT.[26]
In

Fig. 2. Tolerability profile of raltegravir (RAL). Combined analysis of
common treatment-related adverse events of moderate to severe
intensity up to week 48 in the BENCHMRK (Blocking integrase in
treatment Experienced patients with a Novel Compound against HIV:
MeRcK) trials.[26] See table III for trial design details. Patients were
treated with RAL 400 mg twice daily plus optimized background
therapy (OBT) [n = 462] or placebo (PL) twice daily plus OBT
(n = 237).
Triglyceride elevation was the most common
treatment-related laboratory abnormality in ral-
tegravir plus OBT recipients, followed by in-
creased total cholesterol, creatine kinase, LDL
cholesterol and ALT levels, reduced neutrophil
count, and increased pancreatic amylase, total

ª 2009 Adis Data Information BV. All rights reserved. Drugs 2009; 69 (8)
1070 Croxtall & Keam

bilirubin and AST levels which were not signi- Postmarketing surveillance has indicated a
ficantly different from the placebo plus OBT risk of depression and suicidal behaviours in pa-
treatment arm (figure 3).[26] Elevated creatine tients with pre-existing psychiatric illness. How-
kinase levels was the third most common labo- ever, the frequency of these events in relation to
ratory abnormality in raltegravir plus OBT re- raltegravir exposure is not clear.[18]
cipients and, although instances of myopathy and
rhabdomyolysis have been reported, the rela-
tionship of raltegravir treatment to these events 6. Dosage and Administration
is not known.[18,19]
Raltegravir is indicated in combination with
Following 48 weeks’ treatment in the com-
other ART agents for the treatment of HIV-1
bined BENCHMRK trials, 16 of the 462 ralte-
infection in treatment-experienced adult patients
gravir plus OBT recipients (3.5%) and 4 of the
who have evidence of viral replication and HIV-1
237 placebo plus OBT recipients (1.7%) had a
strains resistant to multiple ART agents.[18,19]
diagnosis of new, recurrent or progressive can-
The recommended dosage of raltegravir is 400 mg
cer.[26] The relative risk of cancer in the ralte-
twice daily administered orally with or without
gravir treatment arms was 1.54 (95% CI 0.50,
food.[18,19] Caution should be used when coad-
6.34) compared with the placebo arms.[26]
ministering raltegravir with strong inducers of
The types of cancer (Kaposi’s sarcoma, non-
UGT1A1 (e.g. rifampicin), as reduced plasma
Hodgkin’s lymphoma, anal squamous-cell carci-
concentrations of raltegravir may ensue (section
noma, rectal adenocarcinoma, hepatocellular
3.4). In the EU, a doubling of the dose of ralte-
carcinoma, skin cancer and laryngeal squamous-
gravir may be required if coadministration with
cell carcinoma) are those expected in patients
rifampicin cannot be avoided[19] and in the US,
with severe immunodeficiency, papillomavirus
the recommended raltegravir dosage is 800 mg
or active hepatitis B infection, and ongoing sur-
twice daily.[18] In the EU, coadministration of
veillance may be advisable. However, a recent
raltegravir with agents that increase gastric pH is
review of 1039 recipients of raltegravir plus
not recommended unless this is unavoidable.[19]
OBT pooled from several trials suggests that
Raltegravir should be used during pregnancy
malignancy rates associated with raltegravir
only if the potential maternal benefits outweigh
treatment are not significantly different from
fetal risk and is not recommended for breast-
that of comparator ART agents (available as an
feeding mothers.[18,19] Caution is advised when
abstract).[48]
administering raltegravir to patients with an in-
The tolerability profile of raltegravir plus OBT
creased risk of myopathy or rhabdomyolysis be-
was similar in treatment-experienced patients
cause of elevated creatine kinase levels, although
with HIV-1 infection and chronic active hepatitis
no direct link has been shown. Local prescribing
B and/or hepatitis C co-infections in the
information should be consulted for other con-
BENCHMRK trials.[18,19] However, worsening
traindications, warnings or recommendations.
from baseline of AST, ALT or total bilirubin
levels was 2- to 4-fold higher in raltegravir plus
OBT recipients with hepatitis co-infections than 7. Place of Raltegravir in the
in those without co-infections.[18,19] Management of HIV Infection in
When commencing combination ART, pa- Treatment-Experienced Patients
tients with severe immunodeficiency may develop
an inflammatory response to opportunistic in- The overall aim of the management of patients
fections (such as Mycobacterium avium complex, with HIV-1 infection is maximal suppression of
cytomegalovirus, pneumonia, tuberculosis or re- HIV-1 replication, preservation of immunological
activation of varicella zoster virus) when re- function and prevention of vertical transmis-
sponding to the initial phase of treatment, and sion.[5,49-51] Moreover, in patients with prior
these may require further intervention.[18] treatment experience exhibiting ART resistance,

ª 2009 Adis Data Information BV. All rights reserved. Drugs 2009; 69 (8)
Raltegravir: A Review
the prevention of further selection of resistance
mutations is highly desirable.[49]
Currently, first-line treatment regimens re-
commended for HIV-1-infected patients consist
of three or more drugs from four classes of
ART agents, which include NRTIs, NNRTIs,
PIs and fusion inhibitors.[49-52] The implemen-
tation of these combination regimens has, in
large part, been responsible for stabilizing the
morbidity and mortality associated with HIV-1
infections.[53]
However, these ART regimens are inherently
complex and have considerable adverse effects,
which presents difficulties for patient adherence
resulting in suboptimal drug exposure and,
thereby, an increased risk of the development of
viral resistance.[5] Drug-susceptibility profiles not
only play a crucial role in the selection of ART
regimen employed,[52] but also have a direct
bearing on efficacy outcomes in both ART-naive
and ART-experienced patients.[54] Indeed, the
British HIV Association specifically recommends
individualized ART regimens ‘‘in order to achieve
maximum potency, durability, adherence, and
tolerability and to avoid long-term toxicities and
any likely drug interactions’’.[51]
For treatment-experienced patients with
multiple-drug virological failure, the selection of
ART combination regimens that combine two or
three fully active drugs has, up until now, been
compromised by the number of drug classes
available and the degree of intraclass cross-
resistance that exists among these agents.[54]
The availability of novel ART agents from
alternative drug classes presents new oppor-
tunities for managing patients with HIV-1
infection, particularly those with evidence of
multiple-drug resistance.[55] Furthermore, these
newer ART agents may provide an impetus
for redefining treatment guidelines for the man-
agement of HIV-1 infections.[55] Indeed, the
International AIDS Society USA panel now
recommends the addition of either an integrase
inhibitor or a chemokine (C-C motif) receptor 5
antagonist to combination therapy for HIV-1-
infected patients with first-line failure of NNRTI-
based regimens and multidrug resistance.[50]
ª 2009 Adis Data Information BV. All rights reserved.
1071
Raltegravir is the first drug to be approved in
the new class of ART integrase inhibitors. It is
indicated in combination with other ART agents
for the treatment of HIV-1 infection in treatment-
experienced adult patients who have evidence of
viral replication and HIV-1 strains resistant to
multiple ART agents (section 6). One other in-
tegrase inhibitor, elvite- gravir, has been filed for
regulatory approval, and additional integrase
inhibitors are in development.[8]
As the first integrase inhibitor, raltegravir
presents several advantages over other ART
agents for treatment-experienced patients with
multiple-drug resistant HIV-1 infection. The
novel mechanism of action of raltegravir (section
2.1) means that the potential for cross-resistance
with ART agents from other classes is much re-
duced. Indeed, pharmacodynamic studies show
that antiviral activity is maintained in human
cells in culture infected with a broad range of
HIV-1 clinical isolates, including primary isolates
from a variety of subtypes and isolates resistant
to other ART agents (section 2.2). Moreover,
raltegravir inhibits integrase activity at nano-
molar concentrations in vitro, and this activity
is enhanced additively or synergistically when
ART agents from other classes are used in
combination.
Well designed, ongoing, phase III clinical
trials in adults (BENCHMRK-1 and -2) showed
ralte- gravir to be effective in the management of
treatment-experienced patients with HIV-1 infec-
tion resistant to multiple ART agents (section 4).
When added to an OBT regimen, raltegravir
400 mg twice daily reduced HIV-1 RNA levels to
<400 copies/mL and <50 copies/mL in a signi-
ficantly greater number of patients than placebo
plus OBT after 48 weeks of treatment. Further-
more, mean CD4+ cell counts were increased by a
significantly greater amount from baseline in re-
cipients of raltegravir plus OBT compared with
patients receiving placebo plus OBT. These trials
are scheduled to continue for at least 156 weeks.
As many as two-thirds of patients with HIV-1
infection have CD4+ cell counts of <200 cells/mm3
at baseline,[51] which, typically, is predictive of a
much poorer long-term prognosis.[5,49-51] How-
ever, subgroup analysis of the BENCHMRK
Drugs 2009; 69 (8)
1072
trials indicated that the greater efficacy of ralte-
gravir over placebo as part of an OBT regimen
was maintained not only in patients with lower
CD4+ cell counts at baseline, but also in patients
with higher HIV-1 RNA levels and those receiv-
ing OBT regimens with genotypic or phenotypic
sensitivity scores of 0–2 (section 4). Although
more active OBT regimens (genotypic or pheno-
typic sensitivity scores >0) were associated with
higher absolute response rates than those with
a sensitivity score of 0, there appeared to be
little advantage in adding raltegravir to OBT
in patients with genotypic or phenotypic scores
of ‡3.[14]
A problem for all ART regimens is the develop-
ment of drug resistance, leading to viral rebound
and treatment failure. Moreover, continuing
ART in patients with drug failure is associated
with the selection of additional resistance muta-
tions.[54] This is particularly true for ART agents
with low genetic barriers to resistance, such as
the NNRTIs, lamivudine, emtricitabine and
enfuvirtide.[54] Expert opinion on the suscepti-
bility of raltegravir recipients to developing re-
sistance mutations is divided,[8,54,56] with some
authors suggesting that there is a low genetic
barrier to resistance[54] and some, using in vitro
serial passage models, suggesting that this barrier
is high.[8]
Resistance to raltegravir is usually associated
with two or more key mutations within the inte-
grase gene resulting in the amino acid substitu-
tions Q148H/K/R, N155H or Y143C/H/R.[54]
The mutations Q148H and N155H are known
specifically to decrease the susceptibility of
HIV-1 to raltegravir in vitro by 7- to 14-fold. In
the BENCHMRK trials, 105 of 462 raltegravir
recipients exhibited virological failure after
48 weeks of treatment; genotyping of 94 of these
showed that 64 had a mutation within the inte-
grase gene known to confer resistance and 30 had
genotypic changes of unknown significance.
However, of the 64 patients with virological fail-
ure and mutations known to confer resistance, 38
had a genotypic sensitivity score of 0, and 20 had
a genotypic score of 1.[14] Therefore, when ralte-
gravir is used within the recommended context of
combination with at least one other active ART
ª 2009 Adis Data Information BV. All rights reserved.
Croxtall & Keam
agent, patients’ susceptibility to resistance may be
less likely than previously thought.[54]
More importantly, prespecified subgroup
analyses of patients from the combined
BENCHMRK trials showed that those with
higher HIV-1 RNA levels and less active OBT
regimens at baseline were at the greatest risk of
integrase mutations arising.[14] In other words,
profiling patient characteristics at baseline not
only has a direct bearing on the potential inci-
dence of resistance to raltegravir, but also re-
inforces the desirability of individualized ART
regimens for HIV-1-infected patients in order to
optimize efficacy outcomes.[51]
Currently, raltegravir is not approved for use
in treatment-naive patients with HIV-1 infection.
However, preliminary evidence from a phase II
trial has suggested raltegravir may be as effica-
cious and better tolerated than efavirenz when
used in a combination regimen with tenofovir
plus lamivudine in treatment-naive patients.[41,42]
These observations are consistent with efficacy
outcomes and the tolerability profile for ralte-
gravir seen in treatment-experienced patients
(section 4).
Preliminary data suggest that raltegravir
shows inhibitory activity in human cells in culture
infected with a range of clinical isolates of HIV-2
(section 2.2). This viral strain is relatively in-
sensitive to inhibition by conventional ART
agents, and while inhibition by raltegravir is of
interest, this observation needs to be supported
with clinical data from patients with HIV-2 in-
fection before any meaningful conclusions may
be made.
Raltegravir was generally well tolerated in
combination with other ART agents, with an
adverse event profile similar to that seen with
placebo plus OBT (section 5). The majority of
adverse events were mild to moderate in severity
and treatment discontinuations were uncommon.
The most common systemic drug-related adverse
events reported were diarrhoea, headache, nau-
sea and fatigue. Furthermore, unlike other ART
agents, raltegravir did not appear to be asso-
ciated with clinically relevant hyperlipidaemia.
A numerically higher rate of new, recurrent or
progressive malignancies was observed in the
Drugs 2009; 69 (8)
Raltegravir: A Review
raltegravir plus OBT arms of the BENCHMRK
trials versus the placebo plus OBT arms. How-
ever, given the increased risk for malignancies
developing in this severely immunocompromised
patient population and other risk factors for
cancer, it is not known if the cancer diagnoses
were related to raltegravir treatment.
Importantly, pharmacokinetic studies indicate
that raltegravir does not interact with the CYP
system (section 3.3). As a consequence, drug inter-
actions with other ART agents that are metabo-
lized by CYP isoenzymes are minimal (table II).
This is in contrast to elvitegravir, which is meta-
bolized by CYP3A4.[8] Like atazanavir, raltegravir
is metabolized via UGT-mediated glucuronida-
tion, and although exposure to raltegravir is
increased modestly when these agents are co-
administered, dosage adjustments are not re-
quired. Similarly, patients polymorphic for
UGT1A1 do not require dosage adjustments of
raltegravir.
Pharmacoeconomic analyses of raltegravir in
treatment-experienced patients with HIV-1 in-
fection are limited to a cost-effectiveness study
from the Swiss payer perspective published as an
abstract.[57] The incremental cost-effectiveness
ratio of raltegravir plus OBT versus OBT alone
was $US45 077 per quality-adjusted life year,
based on a raltegravir treatment period of 5 years
(2007 values).[57] Further pharmacoeconomic
analyses are warranted to clarify the cost effec-
tiveness of raltegravir-containing treatment regi-
mens relative to other agents used in combination
with OBT in these patients, and in other geo-
graphical regions
In conclusion, in clinical trials in treatment-
experienced patients with HIV-1 infection and
evidence of viral replication, the addition of oral
raltegravir to an OBT regimen improved viro-
logical and immunological responses at 16 and 48
weeks to a greater extent than placebo plus OBT.
Raltegravir therapy was generally well tolerated,
with a similar incidence of mild to moderate ad-
verse events in the treatment and placebo arms.
The introduction of integrase inhibitors extends
the options available for managing treatment-
experienced patients with multiple-drug-resistant
HIV-1 infection. Results to date suggest that the
ª 2009 Adis Data Information BV. All rights reserved.
1073
combination of raltegravir and OBT will be a
valuable treatment option for this difficult-to-
treat patient group.
Disclosure
The preparation of this review was not supported by any
external funding. During the peer review process, the manu-
facturer of the agent under review was offered an opportunity
to comment on this article. Changes resulting from comments
received were made on the basis of scientific and editorial
merit.
References
1. Joint United Nations Programme on HIV/AIDS. 2008 report
on the global AIDS epidemic [online]. Available from URL:
http://www.unaids.org/en/KnowledgeCentre/HIVData/
GlobalReport/2008/2008_Global_report.asp [Accessed 2008
Nov 26]
2. WHO, UNAIDS, UNICEF. Towards universal access:
scaling up priority HIV/AIDS interventions in the health
sector. Progress report 2008 [online]. Available from URL:
http://www.who.int/hiv/pub/towards_universal_access_
report_2008.pdf [Accessed 2008 Nov 26]
3. WHO. Global HIV prevalence has levelled off: improvements
in surveillance increase understanding of the epidemic,
resulting in substantial revisions to estimates [online]. Avail-
able from URL: http://www.who.int/mediacentre/news/
releases/2007/pr61/en/print.html [Accessed 2008 Nov 26]
4. Shet A, Berry L, Mohri H, et al. Tracking the prevalence of
transmitted antiretroviral drug-resistant HIV-1. J Aquir
Immune Defic Syndr 2006; 41 (4): 439-46
5. Dybul M, Fauci AS, Bartlett JG, et al. Guidelines for using
antiretroviral agents among HIV-infected adults and ado-
lescents: recommendations of the Panel on Clinical Prac-
tices for Treatment of HIV. MMWR Recomm Rep 2002
May 17; 51 (RR-7): 1-55
6. Richman D, Morton S, Wrin T, et al. The prevalence of
antiretroviral drug resistance in the United States. AIDS
2004; 18 (10): 1393-401
7. Pommier Y, Johnson AA, Marchand C. Integrase inhi-
bitors to treat HIV/AIDS. Nat Rev Drug Discov 2005; 4 (3):
236-48
8. Palmisano L. Role of integrase inhibitors in the treatment
of HIV disease: expert review of anti-infective therapy.
Exp Rev Anti-Infect Ther 2007; 5 (1): 67-75
9. Croxtall JD, Lyseng-Williamson KA, Perry CM. Ralte-
gravir. Drugs 2008; 68 (1): 131-8
10. Summa V, Petrocchi A, Bonelli F, et al. Discovery of ralte-
gravir, a potent, selective orally bioavailable HIV-integrase
inhibitor for the treatment of HIV-AIDS infection. J Med
Chem 2008; 51 (18): 5843-55
11. Marinello J, Marchand C, Mott BT, et al. Comparison of
raltegravir and elvitegravir on HIV-1 integrase catalytic
reactions and on a series of drug-resistant integrase
mutants. Biochemistry (Mosc) 2008; 47 (36): 9345-54
12. Danovich R, Ke Y, Wan H, et al. Raltegravir has similar
in vitro antiviral potency, clinical efficacy, and resistance
Drugs 2009; 69 (8)
1074
patterns in B subtype and non-B subtype HIV-1 [abstract no.
TUAA0302]. 17th International AIDS Conference; 2008 Aug
3-8; Mexico City
13. Roquebert B, Damond F, Collin G, et al. HIV-2 integrase gene
polymorphism and phenotypic susceptibility of HIV-2 clin-
ical isolates to the integrase inhibitors raltegravir and elvite-
gravir in vitro. J Antimicrob Chemother 2008; 62 (5): 914-20
14. Cooper DA, Steigbigel RT, Gatell JM, et al. Subgroup and
resistance analyses of raltegravir for resistant HIV-1 in-
fection. N Engl J Med 2008; 359 (4): 355-65
15. Charpentier C, Karmochkine M, Laureillard D, et al. Drug
resistance profiles for the HIV integrase gene in patients fail-
ing raltegravir salvage therapy. HIV Med 2008; 9 (9): 765-70
16. Malet I, Delelis O, Valantin MA, et al. Mutations associated
with failure of raltegravir treatment affect integrase sensi-
tivity to the inhibitor in vitro. Antimicrob Agents Chemo-
ther 2008; 52 (4): 1351-8
17. Van Baelen K, Van Eygen V, Rondelez E, et al. Clade-
specific HIV-1 integrase polymorphisms do not reduce
raltegravir and elvitegravir phenotypic susceptibility.
AIDS 2008; 22 (14): 1877-80
18. Isentress (raltegravir): US prescribing information.
Whitehouse Station (NJ): Merck and Co., Inc., 2009
19. European Medicines Agency. Raltegravir: summary of pro-
duct characteristics [online]. Available from URL: http://
www.emea.europa.eu/humandocs/PDFs/EPAR/isentress/
H-860-PI-en.pdf [Accessed 2009 May 20]
20. Rowley M. The discovery of raltegravir, an integrase in-
hibitor for the treatment of HIV infection. Prog Med Chem
2008; 46: 1-28
21. Evering TH, Markowitz M. Raltegravir (MK-0518): an in-
tegrase inhibitor for the treatment of HIV-1. Drugs Today
2007; 43 (12): 865-77
22. Hazuda DJ, Felock P, Witmer M, et al. Inhibitors of strand
transfer that prevent integration and inhibit HIV-1 re-
plication in cells. Science 2000; 287 (5453): 646-50
23. Roquebert B, Blum L, Collin G, et al. Selection of the Q148R
integrase inhibitor resistance mutation in a failing raltegravir
containing regimen [letter]. AIDS 2008; 22 (15): 2045-6
24. Hazuda DJ, Miller MD, Nguyen BY. Resistance to the HIV-
integrase inhibitor raltegravir: analysis of protocol 005, a
phase II study in patients with triple-class resistant HIV-1
infection [abstract no. 8]. Antiviral Therapy 2007 June
12-16; 12 (5): S10
25. Garrett N, Xu L, Smit E, et al. Raltegravir treatment re-
sponse in an HIV-2 infected patient: a case report [letter].
AIDS 2008 May 31; 22 (9): 1091-2
26. Steigbigel RT, Cooper DA, Kumar PN, et al. Raltegravir
with optimized background therapy for resistant HIV-1
infection. N Engl J Med 2008; 359 (4): 339-54
27. Iwamoto M, Kost JT, Mistry GC, et al. Raltegravir tho-
rough QT/QTc study: a single supratherapeutic dose of
raltegravir does not prolong the QTcF interval. J Clin
Pharmacol 2008; 48 (6): 726-33
28. Wenning LA, Petry A, Kost JT, et al. Pharmacokinetics of
raltegravir in individuals with UGT1A1polymorphisms.
Clin Pharmacol Ther. Epub 2009 Mar 11
29. Wenning L, Anderson M, Petry A, et al. Raltegravir (RAL)
dose proportionality and effect of food [abstract no.
H-1046]. 47th Interscience Conference on Antimicrobial
Agents and Chemotherapy; 2007 Sep 17-20; Chicago (IL)
ª 2009 Adis Data Information BV. All rights reserved.
Croxtall & Keam
30. Iwamoto M, Wenning LA, Petry AS, et al. Safety, toler-
ability, and pharmacokinetics of raltegravir after single and
multiple doses in healthy subjects. Clin Pharmacol Ther
2008; 83 (2): 293-9
31. Kassahun K, McIntosh I, Cui D, et al. Metabolism and
disposition in humans of raltegravir (MK-0518), an anti-
AIDS drug targeting the HIV-1 integrase enzyme. Drug
Metab Dispos 2007; 35 (9): 1657-63
32. Iwamoto M, Wenning LA, Mistry GC, et al. Atazanavir
modestly increases plasma levels of raltegravir in healthy
subjects. Clin Infect Dis 2008; 47 (1): 137-40
33. Iwamoto M, Wenning LA, Petry AS, et al. Minimal effects of
ritonavir and efavirenz on the pharmacokinetics of ralte-
gravir. Antimicrob Agents Chemother 2008; 52 (12): 4338-43
34. Iwamoto M, Kassahun K, Troyer MD, et al. Lack of a
pharmacokinetic effect of raltegravir on midazolam:
in vitro/in vivo correlation. J Clin Pharmacol 2008; 48 (2):
209-14
35. Iwamoto M, Wenning, LA, Nguyen BY et al. Effects of
omeprazole on plasma levels of raltegravir. Clin Infect Dis.
Epub 2009 Jan 1
36. Markowitz M, Morales-Ramirez JO, Nguyen BY, et al. Anti-
retroviral activity, pharmacokinetics, and tolerability of
MK-0518, a novel inhibitor of HIV-1 integrase, dosed as
monotherapy for 10 days in treatment-naive HIV-1-infected
individuals. J Acquir Immune Defic Syndr 2006; 43 (5):
509-15
37. Iwamoto M, Hanley WD, Petry AS. Lack of a clinically
important effect of moderate hepatic insufficiency and
severe renal insufficiency on raltegravir pharmacokinetics.
Antimicrob Agents Chemother 2009 May; 53 (5): 1747-52
38. Wenning L, Hanley W, Brainard D, et al. Effect of rifampin,
a potent inducer of drug metabolizing enzymes, on the
pharmacokinetics of raltegravir. Antimicrob Agents Che-
mother. Epub 2009 May 11
39. Hanley W, Wenning L, Moreau A, et al. Effect of tiprana-
vir + ritonavir on pharmacokinetics of raltegravir. Anti-
microb Agents Chemother. Epub 2009 Apr 27
40. McKeage K, Perry C, Keam S. Darunavir: a review of its use
in the management of HIV infection in adults. Drugs 2009;
69 (4): 477-503
41. Markowitz M, Nguyen B-Y, Gotuzzo E, et al. Rapid and
durable antiretroviral effect of the HIV-1 integrase
inhibitor raltegravir as part combination therapy in
treatment-naive patients with HIV-1 infection. J Acquir
Immune Defic Syndr 2007; 46 (2): 125-33
42. Markowitz M, Nguyen BY, Gotuzzo E, et al. Sustained
antiretroviral efficacy of raltegravir as part of combination
ART in treatment-naive HIV-1 infected patients: 96-week
data [abstract no. TUAB0102]. 17th International AIDS
Conference; 2008 Aug 3-8; Mexico City
43. Steigbigel R, Cooper D, Eron J, et al. 96-week results from
BENCHMRK 1 and 2, phase III studies of raltegravir in
patients failing ART with triple-class-resistant HIV [ab-
stract no. K-105]. 16th Conference on Retroviruses and
Opportunistic Infections; 2009 Feb 9-11; Montreal (QC)
44. Grinsztejn B, Nguyen BY, Katlama C, et al. Safety and
efficacy of the HIV-1 integrase inhibitor raltegravir
(MK-0518) in treatment-experienced patients with multi-
drug-resistant virus: a phase II randomised controlled trial.
Lancet 2007; 369 (9569): 1261-9
45. Yazdanpanah Y, Fagard C, Descamps D, et al. High rate of
virologic success with raltegravir plus etravirine and
Drugs 2009; 69 (8)
Raltegravir: A Review
darunavir/ritonavir in treatment-experienced patients with
multidrug-resistant virus: results of the ANRS 139 TRIO
trial [abstract no. THAB0406]. 17th International AIDS
Conference; 2008 Aug 3-8; Mexico City
46. Harris M, Larsen G, Montaner JS. Outcomes of multidrug-
resistant patients switched from enfuvirtide to raltegravir
within a virologically suppressive regimen. AIDS 2008 Jun
19; 22 (10): 1224-6
47. De Castro N, Braun J, Charreau I, et al. Switch from en-
fuvirtide (E) to raltegravir (R) in highly treatment-experi-
enced HIV-1 infected patients: a randomized open-label
non-inferiority trial (Easier - ANRS 138) [abstract no. 572].
16th Conference on Retroviuses and Opportunistic Infec-
tions; 2009 Feb 8-11; Montreal (QC)
48. Cooper D, Steigbigel R, Lennox J, et al. Review of cancer
incidence in raltegravir (RAL) clinical trials [abstract no.
R-106]. 16th Conference on Retroviruses and Opportu-
nistic Infections; 2009 Feb 8-11; Montreal (QC)
49. DHHS panel on antiretroviral guidelines for adults and ado-
lescents: a working group of the Office of AIDS Research
Advisory Council (OARAC). Guidelines for the use of anti-
retroviral agents in HIV-1-infected adults and adolescents
[online]. Available from URL: http://aidsinfo.nih.gov/con
tentfiles/AdultandAdolescentGL.pdf [Accessed 2008 Nov 26]
50. Hammer SM, Eron Jr JJ, Reiss P, et al. Antiretroviral
treatment of adult HIV infection: 2008 recommendations
of the International AIDS Society-USA panel. JAMA
2008; 300 (5): 555-70
51. Gazzard BG. British HIV Association guidelines for the
treatment of HIV-1-infected adults with antiretroviral
therapy 2008. HIV Med 2008; 9 (8): 563-608
ª 2009 Adis Data Information BV. All rights reserved.
1075
52. European AIDS Clinical Society (EACS). Guidelines for the
clinical management and treatment of HIV infected adults
in Europe [online]. Available from URL: http://www.
europeanaidsclinicalsociety.org/guidelinespdf/1_Treatment_
of_HIV_Infected_Adults.pdf [Accessed 2009 Mar 26]
53. Palella FJ, Delaney K, Moorman A, et al. Declining mor-
bidity and mortality among patients with advanced human
immunodeficiency virus infection. N Engl J Med 1998; 338
(13): 853-60
54. Hirsch MS, Gunthard HF, Schapiro JM, et al. Anti-
retroviral drug resistance testing in adult HIV-1 infection:
2008 recommendations of an International AIDS Society-
USA panel. Clin Infect Dis 2008; 47 (2): 266-85
55. Daar E. Emerging resistance profiles of newly approved
antiretroviral drugs. Top HIV Med 2008; 16 (4): 110-6
56. Hughes A, Barber T, Nelson M. New treatment options for
HIV salvage patients: an overview of second generation
PIs, NNRTIs, integrase inhibitors and CCR5 antagonists.
J Infect 2008; 57 (1): 1-10
57. Elbasha E, Szucs T, Chaudhary M, et al. Cost-effectiveness
analysis of raltegravir in treatment-experienced HIV-1
infected patients in Switzerland [abstract no. TUPDD203].
17th International AIDS Conference; 2008 Aug 3-8;
Mexico City
Correspondence: Jamie D. Croxtall, Wolters Kluwer
Health | Adis, 41 Centorian Drive, Private Bag 65901,
Mairangi Bay, North Shore 0754, Auckland, New Zealand.
E-mail: demail@adis.co.nz
Drugs 2009; 69 (8)