New 96-Week ACTG Study Results Presented at CROI 2014; First Large Study Comparing ISENTRESS® (raltegravir) Regimen to Two Protease Inhibitor Regimens in Previously Untreated Adults with HIV-1


March 5, 2014 12:15 pm ET

Merck (NYSE:MRK), known as MSD outside the United States and Canada,
said today that in a new 96-week, open-label AIDS Clinical Trials Group
(ACTG) study designed to compare three different NNRTI-sparing HIV
regimens in treatment-naïve patients – one containing Merck’s
twice-daily ISENTRESS® (raltegravir) and two containing
different once-daily ritonavir-boosted protease inhibitors, atazanavir
and darunavir — all three regimens achieved high and equivalent levels
of efficacy, as measured by time to virologic failure (VF), the study’s
co-primary endpoint. On the other co-primary endpoint of failure due to
tolerability, the ISENTRESS and darunavir/r regimens were superior to
the atazanavir/r regimen. In addition, on the key secondary endpoint of
the combination of VF and tolerability failure (TF), the regimen with
ISENTRESS was superior to both of the protease inhibitor regimens. The
results of this ACTG study were presented in an oral session today at
the 21st Conference on Retroviruses and Opportunistic
Infections (CROI).

“These findings provide additional evidence of the efficacy and
tolerability of ISENTRESS in a diverse population of treatment-naïve
adults with HIV-1,” said Dr. Randi Leavitt, executive director,
Infectious Diseases, Merck Research Laboratories, and co-author of the
ACTG 5257 study. “We want to acknowledge the patients who participated
in this study, the ACTG and the trial investigators for this important
contribution to the therapeutic evaluation of medicines used to manage
the consequences of HIV infection.”

The 1,809-patient ACTG 5257 open-label study is the first large,
well-powered study to compare ISENTRESS (raltegravir) to protease
inhibitor-based treatment regimens in a treatment-naïve population.
Patients were randomized to receive atazanavir/r (300 mg/100mg once
daily), ISENTRESS (400 mg twice daily), or darunavir/r (800 mg once
daily). All patients in the study also received emtricitabine/tenofovir
disoproxil fumarate (200/300 mg once daily). The primary objective of
this study was to demonstrate equivalence of the regimens with regard to
virologic efficacy and tolerability over 96 weeks. The virologic
endpoint was time to VF, defined from study entry to confirmed viral
load above 1000 copies/mL (after week 16 and before week 24), or above
200 copies/mL (at or after week 24). Time to TF was defined from entry
to discontinuation of the atazanavir/r, ISENTRESS or darunavir/r
component of the regimen for toxicity. The key secondary composite
endpoint was time to first of VF or TF.

In this Phase 3 prospective, randomized study, 34 percent of patients
were non-Hispanic white, 42 percent were non-Hispanic black and 22
percent were Hispanic. Twenty-four percent were women. Mean entry viral
load was 4.6 log 10 copies/mL; 31 percent had viral load above 100,000
copies/mL. Mean baseline CD4 cell count was 308/mm3; CD4 was
below 200/mm3 for 30 percent.

Equivalence was declared if the two-sided 97.5 percent confidence
interval (CI) on the difference in 96-week cumulative probability of VF
in pairwise comparisons between each study regimen was entirely within
+/- 10 percent. Comparisons of TF and a composite of VF/TF were
similarly defined. In the event that equivalence was not shown,
superiority was declared if the 97.5 percent CI excluded zero.

ACTG 5257 Trial Results

At CROI, the ACTG reported that 92 percent of patients completed 96
weeks of the study. Equivalent rates of virologic control were attained
for all regimens. The percentage of patients maintaining ≤50 copies/mL
at week 96 was 94 percent, 88 percent and 89 percent for ISENTRESS,
atazanavir/r and darunavir/r, respectively, based on intent-to-treat
analysis. One percent, 16 percent and five percent discontinued
ISENTRESS, atazanavir/r and darunavir/r, respectively, for toxicity
largely due to clinical jaundice and hyperbilirubinemia with
atazanavir/r, and gastrointestinal symptoms with both atazanavir/r and
darunavir/r. Other discontinuations were similarly distributed across
all arms. The primary tolerability endpoint of discontinuation of the
randomized treatment was equivalent between ISENTRESS and darunavir/r,
while the incidence of discontinuation due to tolerability over 96 weeks
in the atazanavir/r group was 13 percent (97.5% CI: 9.4%, 16%) higher
than ISENTRESS and 9.2 percent (97.5% CI: 5.5%, 13%) higher than
darunavir/r. In pairwise comparisons of the cumulative incidence to
first of either VF or TF, ISENTRESS (raltegravir) was superior to both
atazanavir/r (largely due to elevated bilirubin) and darunavir/r (driven
by both virology and differences in gastrointestinal toxicity) when
considering tolerability and virologic efficacy together. In this
composite analysis, atazanavir/r was inferior to both ISENTRESS by 15
percent (97.5% CI: 10%, 20%) and darunavir/r by 7.6 percent (97.5% CI:
2.3%, 13%). Darunavir/r was inferior to ISENTRESS by 7.5 percent (97.5%
CI: 3.2%, 12%).


ISENTRESS is Merck’s integrase inhibitor indicated in combination with
other antiretroviral (ARV) agents for the treatment of HIV-1 infection
in adults. This indication is based on analyses of plasma HIV-1 RNA
levels in three double-blind controlled studies of ISENTRESS. Two of
these studies were conducted in clinically advanced, three-class ARV
[non-nucleoside reverse transcriptase inhibitor (NNRTI), nucleoside
reverse transcriptase inhibitor (NRTI), protease inhibitor (PI)]
treatment-experienced adult patients through 96 weeks, and one was
conducted in treatment-naïve adults through 240 weeks. The use of other
active agents with ISENTRESS is associated with a greater likelihood of
treatment response.

Important Safety Information

ISENTRESS does not cure HIV-1 infection or AIDS.

Severe, potentially life-threatening and fatal skin reactions have been
reported. This includes cases of Stevens-Johnson syndrome,
hypersensitivity reaction and toxic epidermal necrolysis. Immediately
discontinue treatment with ISENTRESS and other suspect agents if severe
hypersensitivity, severe rash, or rash with systemic symptoms or liver
aminotransferase elevations develop and monitor clinical status,
including liver aminotransferases closely.

Immune reconstitution syndrome can occur, including the occurrence of
autoimmune disorders with variable time to onset, which may necessitate
further evaluation and treatment.

Co-administration of ISENTRESS with drugs that are strong inducers of
uridine diphosphate glucuronosyltransferase (UGT1A1) may result in
reduced plasma concentrations of raltegravir. Co-administration of
ISENTRESS and other drugs may alter the plasma concentration of
raltegravir. The potential for drug-drug interactions (DDIs) must be
considered prior to and during therapy. Co-administration or staggered
administration (by 2 hours) of aluminum and/or magnesium
hydroxide-containing antacids and ISENTRESS is not recommended.
Rifampin, a strong inducer of UGT1A1, reduces plasma concentrations of
ISENTRESS. Therefore, the dose of ISENTRESS (raltegravir) for adults
should be increased to 800 mg twice daily during coadministration with
rifampin. There are no data to guide co-administration of ISENTRESS with
rifampin in patients below 18 years of age.

The most commonly reported (≥2%) drug-related clinical adverse reactions
of moderate to severe intensity in treatment-naïve adult patients
receiving ISENTRESS compared with efavirenz were insomnia (4% vs 4%),
headache (4% vs 5%), nausea (3% vs 4%), fatigue (2% vs 3%) and dizziness
(2% vs 6%), respectively. In treatment-experienced adult patients
receiving ISENTRESS, the most commonly reported (≥2% in either treatment
group) drug-related clinical adverse reactions of moderate to severe
intensity and at a higher incidence compared with placebo was headache
(2% vs 1%). Intensities were defined as follows: Moderate (discomfort
enough to cause interference with usual activity); or Severe
(incapacitating with inability to work or do usual activity).

Grade 2 to 4 creatine kinase laboratory abnormalities were observed in
patients treated with ISENTRESS. Myopathy and rhabdomyolysis have been
reported. Use with caution in patients at increased risk of myopathy or
rhabdomyolysis, such as patients receiving concomitant medications known
to cause these conditions and patients with a history of rhabdomyolysis,
myopathy or increased serum creatine kinase.

Rash occurred more commonly in treatment-experienced subjects receiving
regimens containing ISENTRESS (raltegravir) plus darunavir/ritonavir,
compared to subjects receiving ISENTRESS without darunavir/ritonavir or
darunavir/ritonavir without ISENTRESS. However, rash that was considered
drug-related occurred at similar rates for all three groups. These
rashes were mild to moderate in severity and did not limit therapy;
there were no discontinuations due to rash.

ISENTRESS should be used during pregnancy only if the potential benefit
justifies the potential risk to the fetus. To monitor maternal-fetal
outcomes of pregnant patients exposed to ISENTRESS, an Antiretroviral
Pregnancy Registry has been established. Physicians are encouraged to
register patients by calling 1-800-258-4263.

About Merck

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Forward-Looking Statement

This news release includes “forward-looking statements” within the
meaning of the safe harbor provisions of the United States Private
Securities Litigation Reform Act of 1995. These statements are based
upon the current beliefs and expectations of Merck’s management and are
subject to significant risks and uncertainties. If underlying
assumptions prove inaccurate or risks or uncertainties materialize,
actual results may differ materially from those set forth in the
forward-looking statements.

Risks and uncertainties include but are not limited to, general industry
conditions and competition; general economic factors, including interest
rate and currency exchange rate fluctuations; the impact of
pharmaceutical industry regulation and health care legislation in the
United States and internationally; global trends toward health care cost
containment; technological advances, new products and patents attained
by competitors; challenges inherent in new product development,
including obtaining regulatory approval; Merck’s ability to accurately
predict future market conditions; manufacturing difficulties or delays;
financial instability of international economies and sovereign risk;
dependence on the effectiveness of Merck’s patents and other protections
for innovative products; and the exposure to litigation, including
patent litigation, and/or regulatory actions.

Merck undertakes no obligation to publicly update any forward-looking
statement, whether as a result of new information, future events or
otherwise. Additional factors that could cause results to differ
materially from those described in the forward-looking statements can be
found in Merck’s 2013 Annual Report on Form 10-K and the company’s other
filings with the Securities and Exchange Commission (SEC) available at
the SEC’s Internet site (

Please see Prescribing Information for ISENTRESS (raltegravir) at
and Patient Information for ISENTRESS at

ISENTRESS® is a registered trademark of
Merck & Co., Inc., Whitehouse Station, N.J., USA.

Caroline Lappetito, 267-305-7639
Sarra Herzog, 201-669-6570
Carol Ferguson, 908-423-4465
Justin Holko, 908-423-5088

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