National PBM Drug Monograph

Raltegravir (Isentress^TM^)

December 2007

VHA Pharmacy Benefits Management Service, the Medical Advisory Panel,
and the Public Health Strategic Healthcare Group

*The purpose of VACO PBM-SHG drug monographs is to provide a
comprehensive drug review for making formulary decisions.  These
documents will be updated when new data warrant additional formulary
discussion. Documents will be placed in the Archive section when the
information is deemed to be no longer current.*

# Executive Summary^1-5^: 

-   Raltegravir, an integrase strand transfer inhibitor, is the first
    agent in this new class of antiretrovirals to receive FDA approval
    in the US.

-   Raltegravir is indicated in combination with other antiretroviral
    agents for treatment of HIV-1 in treatment-experienced adult
    patients who have evidence of viral replication and HIV-1strains
    resistant to multiple antiretroviral agents.

-   Raltegravir has a novel mechanism of action. It blocks integration
    of the HIV DNA into host DNA. It has demonstrated in vitro activity
    against multi-drug resistant HIV-1 strains and does not show
    cross-resistance with other classes of antiretroviral agents.

-   The efficacy of raltegravir for the management of treatment
    experienced patients infected with HIV-1 has been demonstrated in
    two, randomized, double-blind, placebo-controlled superiority
    studies. In BENCHMRK 1 and BENCHMRK 2, treatment with raltegravir
    plus OBT produced statistically significant differences favoring
    raltegravir over placebo plus OBT for the primary endpoint
    (proportion of patients achieving VL \< 400 and VL \<50) and the
    secondary endpoint (change in CD4 count from baseline). Raltegravir
    demonstrated superiority compared with placebo and provided greater
    efficacy regardless of a patient's screening HIV-1 RNA level,
    baseline CD4 count strata, number of active protease inhibitor in
    OBT, and genotypic or phenotypic susceptibility score. The use of
    other active agents with raltegravir is associated with a greater
    likelihood of response.

# Raltegravir was generally well tolerated in clinical trials. The most common treatment related adverse events occurring in \>10% of patients treated with raltegravir were diarrhea, nausea, and headache and were similar in the placebo group. Other events which occurred with more frequency in the raltegravir treated patients included rash, elevated ALT/AST, and elevated CPK. Because of the risk of myopathy or rhabdomyolysis, caution should be used when prescribing raltegravir with other medications that can cause these conditions. A higher number of malignancies were initially observed in the raltegravir group, however, an updated analysis of malignancies shows that this imbalance was not sustained. 

# Raltegravir is primarily metabolized by glucoronidation mediated by the uridine diphosphate glucuronosyl transferase 1A1 isozyme (UGT1A1). Raltegravir is not an inhibitor, inducer, or substrate of the major CYP450 isoenzymes. 

-   The recommended dose of raltegravir is 400mg orally twice daily.
    Caution should be used when co-administering raltegravir with strong
    inducers of UGT1A1 (e.g., rifampin, phenytoin, phenobarbital) due to
    reduced plasma concentrations of raltegravir.

-   Place in therapy: Raltegravir has a role in treatment-experienced
    HIV-infected patient (defined as 3 class experience with at least
    one protease inhibitor failure) who have evidence of virologic
    failure on their current antiretroviral regimen.  Raltegravir should
    be utilized with a multi-drug regimen that includes, preferably, at
    least one additional active antiretroviral drug (if available). In
    addition, raltegravir may be utilized to replace an individual agent
    due to intolerance in a treatment-experienced patient.

**[Introduction]{.underline}**

The purposes of this monograph are to (1) evaluate the available
evidence of safety, efficacy, cost, and other pharmaceutical issues that
would be relevant to evaluating raltegravir for possible addition to the
VA National Formulary; (2) define its role in therapy; and (3) identify
parameters for its rational use in the VA.

# Pharmacology^1-3^

The integrase enzyme catalyzes the integration of viral DNA into host
DNA. Integration is essential for HIV-1 replication. The integration
reaction requires three steps: 1) assembly of a stable preintegration
complex at the termini of the viral DNA; 2) 3'-end endonucleolytic
processing to remove the terminal dinucleotide from each 3' end of viral
DNA; 3) strand transfer in which the viral DNA 3" ends are covalently
linked to the cellular DNA. Raltegravir has been shown to specifically
inhibit the strand transfer step in a biochemical reaction with an
IC~50~ value of 2 -- 7nM. Raltegravir maintains in vitro activity
against HIV strains resistant to other classes of antiretroviral agents.

**[Pharmacokinetics]{.underline}^1-3^**

Raltegravir exhibits dose proportional increases in dosing ranging
studies; however, high pharmacokinetic variability has been observed
with this agent. In BENCHMRK 1 and BENCHMRK 2, the coefficient of
variation for inter-subject variability was 212% and the CV for
intra-subject variability was 122%. This high variability may be related
to factors such as food (19% increase in AUC and 8.5-fold increase in
C12~hr~ when administered with high-fat meal), pH dependent solubility
(solubility increases with increasing pH), UGTIA1 polymorphism, UGT1A1
expression (hepatic UGT1A1 protein expression levels vary \>50-fold from
human liver samples), P-gp expression (high variability in intestinal
P-gp expression levels) or drug-drug interactions (raltegravir is a
substrate of UGT1A1 or P-gp).

[]{.mark}

**Table 1. Pharma**cokinetics of Raltegravir

  ----------------- ------------------------------------------------------
  **Parameter**     **Raltegravir**

  C~12hr~           142nM

  Tmax~ss~          \~3 hours

  AUC~12hr~         14.3 µM∙hr

  T~1/2~ (terminal) \~9 hours

  Vd                NA

  Protein Binding   83% to human plasma proteins

  Bioavailability   NA

  Metabolism        Glucuronidation mainly by UGT1A1 with minor
                    contributions from UGT1A9 and UGT1A3

  Elimination       Feces (51%) and urine (32%)
  ----------------- ------------------------------------------------------

NA=not available

# 

# FDA Approved Indication^1^

Raltegravir is indicated in combination with other antiretroviral agents
for treatment of HIV-1 in treatment-experienced adult patients who have
evidence of viral replication and HIV-1strains resistant to multiple
antiretroviral agents.

# 

# Current VA National Formulary Alternatives

Other FDA-approved formulary options for treatment-experienced patients
include darunavir, enfuvirtide, maraviroc and tipranavir. Each of these
agents has a CFU.

# Dosage and Administration^1-3^

The recommended dose in adults is 400mg orally twice daily without
regard to food. Caution should be used when co-administering raltegravir
with strong inducers of UGT1A1 (e.g., rifampin) due to reduced plasma
concentrations of raltegravir.

# 

*Hepatic Impairment*: No dosage adjustment is necessary for patients
with mild to moderate hepatic impairment. The pharmacokinetics of
raltegravir has not been adequately evaluated in individuals with severe
hepatic impairment.

*Renal Impairment*: No dosage adjustment is necessary for patients with
renal impairment. The extent of raltegravir that is dialyzable is
unknown; therefore, dosing before a dialysis session should be avoided.

*Pediatric:* The pharmacokinetics, safety and effectiveness has not be
evaluated in patients \<16 years of age.

# Efficacy^2-5^

## The efficacy of raltegravir for the management of treatment experienced patients infected with HIV-1 has been demonstrated in two, randomized, double-blind, placebo-controlled superiority studies, Protocol 018 (BENCHMRK 1) and Protocol 019 (BENCHMRK 2). Sixteen and twenty-four week data from these trials were presented to the FDA, ultimately leading to FDA-approval. All patients completed 16 weeks and just over 60% completed 24 weeks of treatment. At the time of this writing, 24 week data is available for 100% of subjects, but have not yet been reviewed by the FDA. These trials are ongoing and have only been published in abstract form. 

In these studies, raltegravir 400mg BID was compared to placebo, both
with an optimized background regimen (OBT). The primary objective was to
confirm that raltegravir, in combination with an OBT, provided an
additional reduction in plasma HIV-1 RNA level compared to OBT alone as
measured by the proportion of patients achieving viral suppression
(defined as \< 400 HIV copies/mL, and \<50 HIV copies/mL) and the
magnitude of change in CD4 cell count from baseline to week 24. Included
patients had documented resistance to at least one agent from each of
the 3 antiretroviral classes, plasma HIV-RNA ≥1000 copies/mL while on at
least two months of stable ARV treatment, and resistance testing to
guide the investigators choice of OBT. The primary time point of Week 16
was chosen based on preliminary analyses which indicated the high
potency of raltegravir and superior efficacy results by 16 weeks which
were sustained through week 24. Randomization was stratified by degree
of resistance to protease inhibitors (1PI vs. \>1PI) and the use of
enfuvirtide in OBT.

Endpoints

-   The primary efficacy endpoints in BENCHMRK 1 and 2 was the
    proportion of patients with HIV RNA viral load \< 400 copies/mL and
    \<50 copies/mL.

-   Secondary endpoint included change from baseline in CD4 cell count.
    Time to loss of virologic response (TLOVR: time from randomization
    to rebound VL \> 400 copies/mL) was used to assess durability of
    antiretroviral effect. Safety and tolerability of raltegravir was
    assessed by clinical and laboratory adverse events.

## 

## 

## 

## 

## 

## Summary of Efficacy Findings

##  Table 2. Efficacy Results at 16 weeks: BENCHMRK 1 and 2, Combined Analyses

  ------------------------- ------------------- -------------- -------------
                            **Raltegravir BID** **Placebo**    **p-value**

  N                         426                 209            

  VL \< 400 copies/mL       76.8%               41.8%          \<0.001

  VL \< 50 copies/mL        61.3%               34.6%          \<0.001

  Mean HIV-1 RNA change     -1.88               -0.92          \<0.001
  from baseline (log~10~                                       
  copies/mL )                                                  

  \>1 log~10~ drop in VL or 83.8%               46.0%          \<0.001
  VL \<400 copies/mL                                           

  Change in CD4 count from  +83.9               +35.6          \<0.001
  baseline (cells/mm3)                                         

  Virologic Failure:        2.8%                32.9%          
  non-responder                                                

  Virologic Failure:        12.3%               17.7%          
  rebound                                                      
  ------------------------- ------------------- -------------- -------------

In BENCHMRK 1 and BENCHMRK 2, treatment with raltegravir plus OBT
demonstrated superiority and consistently produced statistically
significant differences favoring raltegravir over placebo plus OBT for
the primary endpoints (Table 2). Week 24 efficacy data were consistent
with Week 16 data. Treatment failures beyond week 16 were uncommon based
on data out to 32 weeks. At Week 24 in the combined analyses, 11% and
44% of patients receiving raltegravir and placebo, respectively,
experienced virologic failure.

Furthermore, consistent efficacy was demonstrated in subgroup analyses
of baseline prognostic factors. Compared to placebo, raltegravir
provided greater efficacy regardless of a patient's screening HIV-1 RNA
level, baseline CD4 count strata, number of active protease inhibitor in
OBT, and genotypic or phenotypic susceptibility score (GSS or PSS, a
measure of potentially active agents present in OBT). Additional
analyses were conducted to evaluate the efficacy darunavir, enfuvirtide,
and tipranavir as part of OBT. Overall efficacy to raltegravir was
greatest when combined with 1 or 2 of these agents, and reached as high
as 98% when combined with both darunavir and enfuvirtide.

*Resistance^2,3^*

Viral rebound or non-response in BENCHMRK 1 and 2 occurred in 12.3% and
2.8% of raltegravir-treated subjects. Virologic failure appears to be
associated with 2 major pathways, Q148 and N155, which are independently
involved in the emergence of raltegravir resistance. These mutations
were observed to confer decreased susceptibility to raltegravir, but
also appear to decrease replication capacity in cell culture. The
majority of resistant viruses contained two or more mutations in the
integrase coding region.

Genotypic changes were identified in the HIV integrase gene in 39
individuals with available samples who experienced virologic failure
while receiving raltegravir in BENCHMRK 1 and 2. A median of 3
substitutions in HIV integrase were detected from these patients. The
seven amino acid changes observed in more than 3 patients who failed but
were not observed in patients with virologic response to raltegravir
include: Q148H/K/R, N155H, E92Q, G140A/S, Y143C/H/R, V151I, and S230N/R.
The N155H substitution was the most frequent (40.7%) and conferred
13.2-fold resistance to raltegravir. The Q148K substitution is a primary
contributor to resistance to raltegravir, conferring a 46-fold reduced
susceptibility in cell culture. The G140A/S substitutions play a
secondary role in raltegravir resistance, conferring a 3-fold reduced
susceptibility alone. Sequential addition of this substitutions
increased resistance to 521-fold.

Use of raltegravir in combination with other potent active agents can
minimize the likelihood of developing raltegravir resistance.

# Adverse Events (Safety Data)^1-3^

Adverse event reports from the raltegravir dose ranging study (Protocol
005), BENCHMRK 1 and 2 were pooled. Overall, raltegravir appeared to be
well tolerated with few patients discontinuing for adverse events.
Adverse events were common in study patients with \>85% of patients
enrolled in either treatment arm experiencing an event; most were mild
or moderate. Twelve patients in the raltegravir arm and 6 in the placebo
arm discontinued treatment due to adverse events.

The most common treatment related adverse events occurring in \>10% of
patients included diarrhea, headache, and nausea and were observed with
similar frequencies in both arms (Table 3). Mild to moderate rash (5.3%
vs 2.5%) and elevated CPK (3.7% vs. 1.1%) occurred with a higher
frequency in the raltegravir patients. There has been no consistent
pattern of rash and events related to rash have not led to the
discontinuation of raltegravir. Myopathy and rhabdomyolysis have been
reported and caution should be used when raltegravir is administered
with other medications known to cause these conditions.

A higher rate of laboratory-related hepatic events occurred in the
raltegravir arm but all other hepatic adverse events were balanced
between groups; one hepatic event occurred in the placebo group (patient
on tipranavir) and 4 in the raltegravir group. Raltegravir was generally
well tolerated in patients with hepatitis B and/or C with similar
clinical and laboratory events as seen in the general raltegravir
population, with the exception of marginally higher increases in AST or
ALT (26% and 27% versus 9% and 8%, respectively). Raltegravir does not
appear to be associated with lipodystrophy.

The rate of AIDS defining conditions (ADC) was 4.1% in the ratlegravir
arm and 6.3% in the placebo arm; more ADCs occurred earlier in the
raltegravir arm compared to the placebo arm (3% vs 2.5%).

An initial imbalance in malignancy rate was observed in the raltegravir
arm (2.2%) vs the placebo arm (0%). However, a recent update on
malignancy in these protocols shows that this imbalance was not
sustained and occurs at similar rates: 2.5% in raltegravir treated
patients and 1.5% in placebo treated patients (relative risk of 1.209,
95% CI 0.44, 4.14). Many of the cancers in the raltegravir arm were
either recurrent, or occurred within 3 months of enrollment. The FDA
interpreted the imbalance to a paucity of malignancies in the placebo
group rather than an increased rate in the raltegravir group. The
malignancies identified are not unexpected in treatment experienced HIV
infected patients and there was no apparent pattern or type of
malignancy observed. Evaluation and follow-up for malignancy will be
ongoing.

**Table 3. Adverse Events Reported in \>2% of Subjects**, Combined
Analyses

  ------------------------- ------------------------- -------------------
                            **Raltegravir BID         **Placebo (n=282)**
                            (n=507)**                 

  Subjects with one or more 81.1%                     84.4%
  AEs                                                 

  Total SAEs                10.7%                     12.8%

  AEs resulting in          2.0%                      1.4%
  discontinuation                                     

  Treatment -- related AEs  0.8%                      0.7%
  (investigator determined)                           

  diarrhea                  16.6%                     19.5%

  headache                  9.7%                      11.7%

  nausea                    9.9%                      14.2%

  fatigue                   7.9%                      4.6%

  nasopharyngitis           6.1%                      3.9%

  rash                      5.3%                      2.5%

  abdominal pain            5.1%                      3.9%

  cough                     4.7%                      2.8%

  myalgia                   4.5%                      2.5%

  Herpes Zoster             4.1%                      0.7%

  dizziness                 3.9%                      2.1%

  Increased AST             9.0%                      7.8%

  Increased ALT             4.7%                      1.8%

  Increased CPK             3.7%                      1.1%
  ------------------------- ------------------------- -------------------

**Deaths^2,3^**

No clinically significant imbalance in the number of deaths was
observed. A total of 16 deaths occurred during treatment; 13 in the
raltegravir arm and 3 in the placebo arm. The majority of deaths were
related to infection (n=10) or malignancy (n=4). No deaths were
considered, by the investigator, as possibly related to raltegravir.
Mortality rates per 100-patient years were 2.3% for raltegravir and 2.0%
for placebo and do not appear to be in excess of expected mortality
rates in this population and is similar to rates observed in other
clinical trials.

**[Contraindications/precautions^1^]{.underline}**

## Contraindications

None

**Warnings and Precautions**

-   Monitor for immune reconstitution syndrome.

-   Caution should be used when co-administering raltegravir with strong
    inducers of UGT1A1 (e.g., rifampin) due to reduced plasma
    concentrations of raltegravir.

**Pregnancy/Nursing Mothers**

-   Pregnancy category C.

-   Nursing mothers: Because of the potential for both HIV transmission
    and serious adverse reactions in nursing infants, mothers should be
    instructed not to breast-feed if they are receiving raltegravir.

# Look-alike / Sound-alike (LA / SA) Error Risk Potential

The VA PBM and Center for Medication Safety is conducting a pilot
program which queries a multi-attribute drug product search engine for
similar sounding and appearing drug names based on orthographic and
phonologic similarities, as well as similarities in dosage form,
strength and route of administration. Based on similarity scores as well
as clinical judgment, the following drug names [may]{.underline} be
potential sources of drug name confusion:

[LA/SA for Isentress^TM^]{.underline}

Isotretinoin 10mg capsule, trental 400mg tablet, B-stress tablet,
sectral 400mg capsule, stress 600 with zinc tablet, isuprel 0.2mg
injectable (high alert according to ISMP), I-sense tablet, Ibu-tab 400mg
tablet, Iressa 250mg tablet, isochron 40mg tablet, isoniazid 150mg
capsule, isoptin 40mg tablet, stresstabs tablet

[LA/SA for Raltegravir]{.underline}

Entecavir 0.5mg tablet, abacavir 600mg tablet, retrovir 300mg tablet,
ritonavir 50mg tablet, acyclovir 400mg tablet, adefovir dipivoxil 10mg
tablet, atazanavir sulfate 100mg capsule, darunavir 300mg tablet,
lopinavir 200mg tablet, nelfinavir 625mg tablet, saquinavir 500mg
tablet, raloxifene 60mg tablet, relamine 400mg tablet, sevelamer 400mg
tablet, tiprananvir 250mg capsule

# 

# Drug-Drug Interactions^1-3^

Raltegravir is not expected to impact the pharmacokinetics of
co-administered agents. It is not an inhibitor of the major CYP450
isoenzymes, UGTs (UGT1A1, UGT2B7), or p-glycoprotein (p-gp). It is not
an inducer or substrate of CYP3A4.

Raltegravir has shown to be a substrate of UGT1A1 and p-glycoprotein
(p-gp) in vitro. Pharmacokinetic studies were conducted to evaluate the
co-administration of inducers (e.g., rifampin) or inhibitors (e.g.,
atazanavir) of UGT1A1 on raltegravir (Table 4). Due to the reduced
plasma concentrations of raltegravir when co-administered with rifampin,
the PI recommends using caution with this combination; data presented to
the FDA suggests the consideration of doubling the raltegravir dose when
co-administered with rifampin. Similarly, caution should be exercised
with the co-administration of phenytoin or phenobarbital and
raltegravir, with consideration given to doubling the raltegravir dose.
Co-administration of atazanavir (with or without ritonavir) increased
plasma concentrations of raltegravir (30-70% increase in AUC) but were
not considered clinically meaningful. Other assessments of drug -- drug
interactions with raltegravir included tenofovir, lamivudine, ritonavir,
efavirenz, tipranavir, and etravirine, none of which had significant
effects on raltegravir pharmacokinetics which would require dose
adjustments. Based upon data from studies of stronger inducers such as
rifampin or efavirenz with raltegravir, no dosage modification is
recommended with the co-administration of weaker inducers such as
nevirapine, rifabutin, or St. John's Wort. The impact of UGT1A1
polymorphism on raltegravir pharmacokinetics has not been sufficiently
evaluated.

> []{.mark}

**Table 4. Effect of the Co-administration of Agents on the
Pharmacokinetics of Raltegravir**

+-------+--------+-----------+-----------+-----------+---------------+
|       | Impact | C~max~    | AUC       | C~min~    | Re            |
|       | on     |           |           |           | commendations |
|       | UGT1A1 | Ratio^a^  | Ratio^a^  | Ratio^a^  | for           |
|       |        | (90% CI)  | (90% CI)  | (90% CI)  | raltegravir   |
|       |        |           |           |           | dosage        |
+-------+--------+-----------+-----------+-----------+---------------+
| Ataza | Inh    | 1.53      | 1.72      | 1.95      | No dosage     |
| navir | ibitor | (1.11,    | (1        | (1.30,    | modification  |
|       |        | 2.12)     | .47,2.02) | 2.92)     |               |
+-------+--------+-----------+-----------+-----------+---------------+
| Ataza | A:Inh  | 1.24      | 1.41      | 1.77      | No dosage     |
| navir | ibitor | (0.87,    | (1        | (1        | modification  |
| /rito |        | 1.77)     | .12,1.78) | .39,2.25) |               |
| navir | R:I    |           |           |           |               |
|       | nducer |           |           |           |               |
+-------+--------+-----------+-----------+-----------+---------------+
| Efav  | I      | 0.64      | 0.64      | 0.79      | No dosage     |
| irenz | nducer | (0.41,    | (0.52,    | (0.49,    | modification  |
|       |        | 0.98)     | 0.80)     | 1.28)     |               |
+-------+--------+-----------+-----------+-----------+---------------+
| Rif   | Potent | 0.62      | 0.60      | 0.39      | Caution       |
| ampin | I      | (0.37,    | (0.39,    | (0.30,    | should be     |
|       | nducer | 1.04)     | 0.91)     | 0.51)     | used with     |
|       |        |           |           |           | co-a          |
|       |        |           |           |           | dministration |
|       |        |           |           |           | of rifampin   |
|       |        |           |           |           | and           |
|       |        |           |           |           | raltegravir   |
+-------+--------+-----------+-----------+-----------+---------------+
| Teno  | None   | 1.64      | 1.49      | 1.03      | No dosage     |
| fovir |        | (1.16,    | (1.15,    | (0.73,    | modification  |
|       |        | 2.32)     | 1.94)     | 1.45)     |               |
+-------+--------+-----------+-----------+-----------+---------------+
| Tipra | T:None | 0.82      | 0.76      | 0.45      | No dosage     |
| navir |        | (0.46,    | (0.49,    | (0.31,    | modification  |
| /rito | R:I    | 1.46)     | 1.19)     | 0.66)     |               |
| navir | nducer |           |           |           |               |
+-------+--------+-----------+-----------+-----------+---------------+

^a^ Ratio of raltegravir pharmacokinetics parameters with/without
co-administered drug; no effect = 1.00

**[Acquisition Costs]{.underline}**

The cost of raltegravir (one bottle of 60 tablets of 400mg) is \$603.29
(Big 4).

Table 5. Cost of Antiretroviral Agents for Treatment-Experienced
Patients

+------------------+--------------------+--------------+-------------+
| **Drug &         | **Dosage Regimen** | **Cost Dose  | **Cost/Y    |
| Strength**       |                    | (\$)**       | ear/patient |
|                  |                    |              | (\$)**      |
+------------------+--------------------+--------------+-------------+
| Raltegravir      | 400mg orally twice | \$10.05 (Big | \$7239.48   |
| 400mg            | daily              | 4)           |             |
+------------------+--------------------+--------------+-------------+
| Maraviroc 150mg, | 150mg orally twice | \$10.83 (Big | \$7905.90   |
| 300mg            | daily              | 4)           |             |
|                  |                    |              | \$7905.90   |
|                  | 300mg orally twice | \$10.83 (Big |             |
|                  | daily              | 4)           | \$15,811.80 |
|                  |                    |              |             |
|                  | 600mg orally twice | \$21.66 (Big |             |
|                  | daily              | 4)           |             |
+------------------+--------------------+--------------+-------------+
| Enfuvirtide      | 90mg               | \$21.00 (Big | \$15,330.00 |
| 90mg/mL          | subcutaneously     | 4)           |             |
|                  | twice daily        |              |             |
+------------------+--------------------+--------------+-------------+
| Darunavir 300mg  | 600mg darunavir +  | \$9.04 (FSS) | \$7,774.50  |
|                  | 100mg ritonavir    |              |             |
|                  | orally twice daily | \+           |             |
|                  |                    |              |             |
|                  |                    | \$1.16 (FSS) |             |
+------------------+--------------------+--------------+-------------+
| Tipranavir 250mg | 500mg tipranavir + | \$10.59      | \$9,424.30  |
|                  | 200 ritonavir      | (FSS)        |             |
|                  | orally twice daily |              |             |
|                  |                    | \+           |             |
|                  |                    |              |             |
|                  |                    | \$2.32 (FSS) |             |
+------------------+--------------------+--------------+-------------+

# 

# Conclusions^1-5^

Raltegravir, an integrase inhibitor, is the first agent in this new
class of antiretrovirals to receive FDA approval in the US. The FDA has
approved raltegravir for treatment-experienced adults infected with
HIV-1, who have evidence of viral replication and HIV-1 strains
resistant to multiple antiretroviral agents. Raltegravir has
demonstrated in vitro activity against multi-drug resistant strains of
HIV-1; however, clinical resistance to raltegravir has been detected. In
BENCHMRK 1 and BENCHMRK 2, treatment with raltegravir plus OBT produced
statistically significant differences favoring raltegravir over placebo
plus OBT for the primary endpoints (proportion of patients achieving VL
\< 400 and VL \<50) and the secondary endpoint (change in CD4 count from
baseline). Raltegravir demonstrated superiority compared with placebo
and provided greater efficacy regardless of a patient's screening HIV-1
RNA level, baseline CD4 count strata, number of active protease
inhibitor in OBT, and genotypic or phenotypic susceptibility score.
Raltegravir was generally well tolerated in clinical trials. The most
common treatment related adverse events were diarrhea, nausea, and
headache and were similar in the placebo group. Other events which
occurred with more frequency in the raltegravir treated patients
included rash, elevated CPK, and elevated ALT/AST. A higher number of
malignancies were initially observed in the raltegravir group, however,
an updated analysis of malignancies shows that this imbalance was not
sustained. Raltegravir is primarily metabolized by glucoronidation
mediated by the UGT1A1 isoenzyme. Caution should be used when
co-administering raltegravir with strong inducers of UGT1A1 (e.g.,
rifampin, phenytoin, phenobarbital) due to reduced plasma concentrations
of raltegravir. Raltegravir is not an inhibitor, inducer, or substrate
of the major CYP450 isoenzymes.

# Recommendations

Raltegravir has a role in treatment-experienced HIV-infected patient
(defined as 3 class experience with at least one protease inhibitor
failure) who have evidence of virologic failure on their current
antiretroviral regimen.  Raltegravir should be utilized with a
multi-drug regimen that includes, preferably, at least one additional
active antiretroviral drug (if available). In addition, raltegravir may
be utilized to replace an individual agent due to intolerance in a
treatment-experienced patient.

# References:

1.  Isentress(Raltegravir) package insert, Merck Inc. October 2007.

2.  FDA product review transcripts. August 8, 2007.

3.  FDA product review Briefing Document. Isentress (raltegravir) 400mg
    for treatment of HIV. September 5, 2007. Merck.

4.  Cooper D, Gatell J, Rockstroh J, Katlama C, Yeni P, Lazzarin A, et
    al. Results of BENCHMRK-1 a phase 3 study evaluating the efficacy
    and safety of MK-0518 a novel HIV-1 integrase inhibitor in patients
    with triple-class resistant virus. Poster presented at the 14^rd^
    Conference on Retroviruses and Opportunistic Infections; 2007
    February 25-28; Los Angeles, CA, USA.

5.  Steigbigel R, Kumar P, Eron J, Schechter M, Markowitz M, Loutfy M,
    et al. Results of BENCHMRK-2 a phase 3 study evaluating the efficacy
    and safety of MK-0518 a novel HIV-1 integrase inhibitor in patients
    with triple-class resistant virus. Poster presented at the 14^rd^
    Conference on Retroviruses and Opportunistic Infections; 2007
    February 25-28; Los Angeles, CA, USA.

[Prepared by Pam Belperio,PharmD and Melinda Neuhauser,
PharmD\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_]{.underline}

+------------+---------------------------------------------------------+
| ######     | BENCHMRK 1 (Protocol 018)                               |
| # Citation |                                                         |
|            | Cooper D, Gatell J, Rockstroh J, Katlama C, Yeni P,     |
|            | Lazzarin A, et al. Results of BENCHMRK-1 a phase 3      |
|            | study evaluating the efficacy and safety of MK-0518 a   |
|            | novel HIV-1 integrase inhibitor in patients with        |
|            | triple-class resistant virus. Poster presented at the   |
|            | 14^rd^ Conference on Retroviruses and Opportunistic     |
|            | Infections; 2007 February 25-28; Los Angeles, CA, USA.  |
+------------+---------------------------------------------------------+
| ####### S  | ## To evaluate the safety a                             |
| tudy Goals | nd efficacy of raltegravir in triple-class antiretrovir |
|            | al treatment-experienced patients with HIV-1 infection. |
+------------+---------------------------------------------------------+
| #####      | ####### Study Design                                    |
| ## Methods |                                                         |
|            | The BENCHMRK-1 study is an ongoing triple-blind         |
|            | randomized, placebo-controlled, multicenter study which |
|            | enrolled patients failing antiretrovirals with 3 class  |
|            | resistance from Europe, Asia and Pacific, and Peru.     |
|            | Included subjects were randomized 1:2 to receive        |
|            | placebo or raltegravir 400mg bid, plus an optimized     |
|            | background therapy (OBT). The optimized background      |
|            | therapy was selected based on patients' prior treatment |
|            | history and results from HIV resistance testing. These  |
|            | are results of the 16 week interim analysis. Efficacy   |
|            | endpoints included the proportion of patients achieving |
|            | viral suppression (defined as \< 400 HIV copies/mL, and |
|            | \<50 HIV copies/mL) and magnitude of change in CD4 cell |
|            | count from baseline to week 16.                         |
|            |                                                         |
|            | ####### Data Analysis                                   |
|            |                                                         |
|            | The Full Analysis Set (FAS) population consisted of all |
|            | randomized patients who received at least 1 study drug  |
|            | dose, both as randomized and as treated, both of which  |
|            | were used to analyze the primary endpoint. The FAS-as   |
|            | treated population was used for the analysis of all     |
|            | secondary endpoints. Analysis of percent responders was |
|            | performed using the time to loss of virologic response  |
|            | (TLOVR) algorithm. Change in HIV-1 RNA from baseline    |
|            | was performed using a noncompleter equal failure (NC =  |
|            | F) analysis and immunologic response was measured using |
|            | a last observation carried forward (LOCF) analysis.     |
+------------+---------------------------------------------------------+
| ######     | ####### Inclusion criteria                              |
| # Criteria |                                                         |
|            | Male and female subjects were included in the study if  |
|            | they were 18 years of age or older, had a plasma HIV-1  |
|            | RNA \> 1,000 copies/mL on stable antiretrovirals for at |
|            | least two months and had evidence of genotypic or       |
|            | phenotypic resistance to one or more drugs in each of   |
|            | the three ARV classes. Patients with Hepatitis B or C   |
|            | were allowed to enter the study, although the numbers   |
|            | were small (22%).                                       |
|            |                                                         |
|            | ####### Exclusion criteria                              |
+------------+---------------------------------------------------------+
| #####      | ####### A total of 350 trea                             |
| ## Results | tment experienced patients were included in the study.  |
|            |                                                         |
|            | ####### Baseli                                          |
|            | ne characteristics were similar across treatment arms.  |
|            |                                                         |
|            | #######                                                 |
|            |                                                         |
|            | ####### [Baseline Characteristics]{.underline}:         |
|            |                                                         |
|            | *Median CD4 count and mean HIV-1 RNA:*                  |
|            |                                                         |
|            | -   Placebo: 153 cells/mm3, and 4.5 log~10~             |
|            |                                                         |
|            | -   Raltegravir BID: 156 cells/mm3, and 4.6 log~10~     |
|            |                                                         |
|            | #######                                                 |
|            |                                                         |
|            | ####### [Primary Endpoints]{.underline}:                |
|            |                                                         |
|            | *Proportion of patients with viral load \< 400          |
|            | copies/mL:*                                             |
|            |                                                         |
|            | -   Placebo + OBT (n=118): 41%                          |
|            |                                                         |
|            | -   Raltegravir BID + OBT (n=232): 77% (p\<0.001)       |
|            |                                                         |
|            | *Proportion of patients with viral load \< 50           |
|            | copies/mL:*                                             |
|            |                                                         |
|            | -   Placebo + OBT (n=118): 33%                          |
|            |                                                         |
|            | -   Raltegravir BID + OBT (n=232): 61% (p\<0.001)       |
|            |                                                         |
|            | *Mean CD4 increase from baseline (cells/mm^3^):*        |
|            |                                                         |
|            | -   Placebo + OBT (n=118): +31                          |
|            |                                                         |
|            | -   Raltegravir BID + OBT (n=232): +83 (p\<0.001)       |
+------------+---------------------------------------------------------+
| ####### C  | The authors concluded that in this                      |
| onclusions | treatment-experienced population, raltegravir + OBT     |
|            | provided significantly superior virologic control and   |
|            | increases in CD4 cell counts compared with placebo +    |
|            | OBT.                                                    |
+------------+---------------------------------------------------------+

+------------+---------------------------------------------------------+
| ######     | BENCHMRK-2 (Protocol 019)                               |
| # Citation |                                                         |
|            | Steigbigel R, Kumar P, Eron J, Schechter M, Markowitz   |
|            | M, Loutfy M, et al. Results of BENCHMRK-2 a phase 3     |
|            | study evaluating the efficacy and safety of MK-0518 a   |
|            | novel HIV-1 integrase inhibitor in patients with        |
|            | triple-class resistant virus. Poster presented at the   |
|            | 14^rd^ Conference on Retroviruses and Opportunistic     |
|            | Infections; 2007 February 25-28; Los Angeles, CA, USA.  |
+------------+---------------------------------------------------------+
| ####### S  | ## To evaluate the safety a                             |
| tudy Goals | nd efficacy of raltegravir in triple-class antiretrovir |
|            | al treatment-experienced patients with HIV-1 infection. |
+------------+---------------------------------------------------------+
| #####      | ####### Study Design                                    |
| ## Methods |                                                         |
|            | The BENCHMRK-2 study is an ongoing triple-blind         |
|            | randomized, placebo-controlled, multicenter study which |
|            | enrolled patients failing antiretrovirals with 3 class  |
|            | resistance from North, Central, and South America.      |
|            | Included subjects were randomized 1:2 to receive        |
|            | placebo or raltegravir 400mg bid, plus an optimized     |
|            | background therapy (OBT). These are results of the 16   |
|            | week interim analysis. Efficacy endpoints included the  |
|            | proportion of patients achieving viral suppression      |
|            | (defined as \< 400 HIV copies/mL, and \<50 HIV          |
|            | copies/mL) and magnitude of change in CD4 cell count    |
|            | from baseline to week 16.                               |
|            |                                                         |
|            | ####### Data Analysis                                   |
|            |                                                         |
|            | The Full Analysis Set (FAS) population consisted of all |
|            | randomized patients who received at least 1 study drug  |
|            | dose, both as randomized and as treated, both of which  |
|            | were used to analyze the primary endpoint. The FAS-as   |
|            | treated population was used for the analysis of all     |
|            | secondary endpoints. Analysis of percent responders was |
|            | performed using the time to loss of virologic response  |
|            | (TLOVR) algorithm. Change in HIV-1 RNA from baseline    |
|            | was performed using a noncompleter equal failure (NC =  |
|            | F) analysis and immunologic response was measured using |
|            | a last observation carried forward (LOCF) analysis.     |
+------------+---------------------------------------------------------+
| ######     | ####### Inclusion criteria                              |
| # Criteria |                                                         |
|            | Male and female subjects were included in the study if  |
|            | they were 18 years of age or older, had a plasma HIV-1  |
|            | RNA \> 1,000 copies/mL on stable antiretrovirals for at |
|            | least two months and had evidence of genotypic or       |
|            | phenotypic resistance to one or more drugs in each of   |
|            | the three ARV classes. Patients with Hepatitis B or C   |
|            | were allowed to enter the study, although the numbers   |
|            | were small (10%).                                       |
|            |                                                         |
|            | ####### Exclusion criteria                              |
+------------+---------------------------------------------------------+
| #####      | ####### A total of 349 trea                             |
| ## Results | tment experienced patients were included in the study.  |
|            |                                                         |
|            | ####### Baseli                                          |
|            | ne characteristics were similar across treatment arms.  |
|            |                                                         |
|            | #######                                                 |
|            |                                                         |
|            | ####### [Baseline Characteristics]{.underline}:         |
|            |                                                         |
|            | *Median CD4 count and mean HIV-1 RNA:*                  |
|            |                                                         |
|            | -   Placebo: 163 cells/mm3, and 4.7 log~10~             |
|            |                                                         |
|            | -   Raltegravir BID: 146 cells/mm3, and 4.7 log~10~     |
|            |                                                         |
|            | #######                                                 |
|            |                                                         |
|            | ####### [Primary Endpoints]{.underline}:                |
|            |                                                         |
|            | *Proportion of patients with viral load \< 400          |
|            | copies/mL:*                                             |
|            |                                                         |
|            | -   Placebo + OBT (n=119): 43%                          |
|            |                                                         |
|            | -   Raltegravir BID + OBT (n=230): 77% (p\<0.001)       |
|            |                                                         |
|            | *Proportion of patients with viral load \< 50           |
|            | copies/mL:*                                             |
|            |                                                         |
|            | -   Placebo + OBT (n=119): 36%                          |
|            |                                                         |
|            | -   Raltegravir BID + OBT (n=230): 62% (p\<0.001)       |
|            |                                                         |
|            | *Mean CD4 increase from baseline (cells/mm^3^):*        |
|            |                                                         |
|            | -   Placebo + OBT (n=119): +40                          |
|            |                                                         |
|            | -   Raltegravir BID + OBT (n=230): +86 (p\<0.001)       |
+------------+---------------------------------------------------------+
| ####### C  | The authors concluded that in this                      |
| onclusions | treatment-experienced population, raltegravir + OBT     |
|            | provided significantly superior virologic control and   |
|            | increases in CD4 cell counts compared with placebo +    |
|            | OBT.                                                    |
+------------+---------------------------------------------------------+