Although
there are 22 drugs already approved for the treatment of HIV infection, new drugs
with activity against drug-resistant strains of the virus are needed for treatment-experienced
HIV patients with virological failure. Novel antiretroviral agents belonging to
a new class of drugs known as entry
inhibitors may be useful for these patients.
The
initial step of HIV replication, entry into CD4 cells, consists of 3 sub-steps:
(1) HIV attachment to the CD4 receptor, (2) binding of the virus to a chemokine
co-receptor(CCR5 or CXCR4), and (3) viral-cell membrane fusion.
Enfuvirtide
(Fuzeon; T-20),
the first approved HIV-1 entry (fusion) inhibitor (from Roche), demonstrates anti-HIV
activityin treatment-experienced patients and was approved by the
U.S. Food and Drug Administration (FDA) in 2003. There are currently several experimental
HIV-1entry inhibitors in clinical trials, including CD4attachment
inhibitors and chemokinereceptor inhibitors.
In
the current double-blind, randomized, 24-week study (ACTG 5211), researchers evaluatedthe safety, tolerability, and virologicalactivity of vicriviroc
aspart of a ritonavir-containingregimen in 118 treatment-experienced
patients who were experiencing virological failure. The study was conducted at
33 medical centers in the U.S.
All
study participants had HIV RNAlevels ≥ 5000 copies/mL and had
virus that exclusively used the CCR5 co-receptor. Results of the vicriviroc study
appear in the July 1, 2007 issue of the Journal
of Infectious Diseases.
Study
subjects were 92%men and 8% womenand were 66% white, 20%
black,12% Hispanic, and 2% other race/ethnicity;4% had
a historyof injection drug use.A total of 39(33%)
subjects were enfuvirtide-experienced. The median HIVRNA level was
36,380copies/mL and themedian CD4 count was146
cells/mm3.
While
receiving a failing ritonavir-containing regimen, patients in the study received
vicriviroc once daily at5, 10, or 15mg, or else placebo,
for 14 days,after which the regimen was optimized. Theprimary
end-point wasthe change in plasmaHIV RNA levels atday 14; secondary end-points included safety,tolerability, andHIV RNA changes atweek 24. An
independentStudy Monitoring Committee (SMC)periodically
reviewed the study.
Results
·At its 3rd
review, the SMC recommended thatthe vicriviroc 5 mg dosebe discontinued because ofahigher rate of virologicalfailure.
·Atweek 24, the 10and 15 mg vicriviroc doseswere associated
with thegreatest mean decreases inHIV RNA and had the
greatestproportions of subjects withHIV RNA levels suppressedto < 400 or < 50copies/mL.
·Theestimated median times tovirological failure were 16weeks
(placebo), 32 weeks(5 mg), and > 48weeks (10 and 15mg).
·Compared
with the5 mg group, subjects inthe 10 and 15 mgdosing
groups experienced marginallylower rates of virologicalfailure.
·Insubjects randomized to receive vicriviroc,the greatest HIV RNAdecline occurred in subjectswho first used enfuvirtideat day 14 aspart of their optimizedbackground regimen;
this response was greaterthan that seen insubjects who
never usedenfuvirtide or insubjects with prior enfuvirtideuse.
·Compared
with placebo, therewas a marginally significantCD4 cell
count increasein the 5 mg group(P = 0.06) anda significant increase inthe 10 mg (P = 0.001)
and 15 mg (P= 0.002) groups; therewere no differences
betweenthe 3 vicriviroc doses.
·Grade 3/4adverse events were similaracross groups.
·A total
of 8 patients developed malignancies—6 on vicriviroc and 2 on placebo.
·As a result,
the SMC recommendedthat
patients be informedof this information, beunblinded,
and continue to befollowed; the study then became open-label.
Conclusion
and Discussion
In
conclusion, the study authors wrote, “In HIV-1–infected,treatment-experienced
patients, vicriviroc demonstratedpotent virologic suppression through24 weeks.”
“The
relationshipof vicriviroc to malignancyis uncertain,”
they added. “Further developmentof vicriviroc in treatment-experiencedpatients is warranted.”
In
this study, treatment-experienced subjects who added vicriviroc to a ritonavir-containing
antiretroviral regimen experienced significantly greater declines in plasma HIV-1
RNA levels over 14 days than those who added placebo.
After
optimization of the ritonavir-containing regimen, patients randomized to receive
10 or 15 mg daily doses of vicriviroc had significantly better virological and
immunological responses than those receiving placebo over 24 weeks.
“These
data establish the antiretroviral activity of a vicriviroc-containing regimen
in treatment-experienced individuals and
are the first to demonstrate prolonged effects of a CCR5 inhibitor-based regimen
in HIV-1-infected subjects,” according to the study authors [emphasis added—Ed].
Use
of the HIV fusion inhibitor enfuvirtide as a new drug in the optimized background
regimen was associated with better HIV RNA suppression in both the vicriviroc
and placebo groups. Synergy between enfuvirtide and vicriviroc (as well as other
CCR5 inhibitors) has been demonstrated in vitro [3].
In
this study, 12 subjects (10%) with CCR5-tropic virus at screening had dual/mixed-tropic
(D/M) virus at study entry; however, no reduction in CD4 cell counts occurred
in the 10 subjects with D/M virus who received vicriviroc.
The
6 malignancies inthe vicriviroc groups wereof diverse
cell types(2 Hodgkin disease, 2non-Hodgkin lymphomas,
1 gastricadenocarcinoma, and 1 HPV-relatedsquamous cell
carcinoma), and2 of these occurredin patients with priortreated Hodgkin disease. The2 malignancies in theplacebo
group were bothsquamous cell carcinomas, oneof which was
HPV-related.
“Despite
effective antiretroviraltherapy, malignancies continue tooccur
commonly in patientswith advanced HIV disease,”the authors noted. “Also, it iswell established that patientswith treated Hodgkin diseaseare at risk fordeveloping
a second malignancy,” they wrote. For these reasons, the independentSMC
concluded that acausal relationship with vicriviroccould
not be established.
“Nevertheless,”
the authors emphasize, “given the biologicplausibility that a CCR5antagonist potentially could adverselyimpact tumor surveillance,
longerterm follow-up of patientsexposed to CCR5 inhibitorsis needed to determinethe relationship, if any,to
the development ofmalignancies.”
Editorial
on CCR5Inhibitors: “PromisingyetChallenging”
An
editorial by Bonaventura Clotet, MD, on the CCR5 inhibitors accompanied
the report on the vicriviroc study. Dr. Clotet is associated with the AIDS Care
Unit at the Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Spain.
Following is a summary of his remarks:
·Cohort studies
show that 81%-88% of HIV-1 variants in treatment-naive patients are CCR5-tropic
and that almost all the remaining variants are dual/mixed-tropic (i.e., are able
to utilize both CCR5 and CXCR4 co-receptors). In treatment-experienced patients,
49%-78% of HIV variants are purely CCR5 tropic, 22%-48% are D/M tropic, and 2%-5%
exclusively utilize CXCR4.
·HIV infection
in persons homozygous for CCR532 (~1% of white Northern Europeans)
is extremely rare, and, when it occurs, it is caused by viral strains that utilize
CXCR4 for viral entry.
·HIV-infected
individuals who are heterozygous for CCR532 have slower rates of
disease progression [4]. Early reports
suggested that this deletion had no apparent effect on the functioning of the
immune system. These findings prompted pharmaceutical companies to develop a CCR5 antagonist for clinical
use.
·On the other
hand, lower rates of the immune reconstitution syndrome have been suggested for
HIV-infected patients treated with a regimen including a CCR5 antagonist [5].
Could use of a CCR5 antagonist, in addition, increase the risk of opportunistic
infections and malignancies in HIV patients?
·The recently
presented results of the MOTIVATE
1 and 2 trials of maraviroc (Celsentri) suggest otherwise.
These studies, conducted with maraviroc in a treatment-experienced population
harboring only CCR5-tropic virus, showed significantly superior virological control
and increases in CD4 cell count compared with placebo plus optimized background therapy.
·The current
study by Gulick and colleagues had a larger number of malignancies in treatment-experienced
subjects receiving an optimized antiretroviral regimen plus vicriviroc than in
those treated with an optimized regimen plus placebo (6 vs 2).
·However,
according to Dr. Clotet, “The potency of vicriviroc, the clinical need for orallybioavailable entry inhibitors, thelack of significant differencesin cancer risk betweenthe 2 treatment arms,the absence
of aclear causal relationship betweenvicriviroc exposure
and developmentof cancer, and thefact that other CCR5antagonists have not beenassociated with increased riskfor malignancies so farwarrant continuing the studyof
this compound andothers of its class.”
·“Any new
studies of CCR5 antagonistsshould incorporate strict tumorsurveillance
and long-term follow-upto address properly thepotential
for immune deregulation,opportunistic infections, and malignancies,”
he wrote.
·Early clinical
trials involving CCR5 antagonists also raised concerns about the their potential
for liver toxicity. The development of aplaviroc by GlaxoSmithKline was terminated
because a number of patients developed severe hepatotoxicity.
·“Our impression
is that hepatotoxicity does not seem thus far to be a major complication of CCR5 antagonists (other than for aplaviroc),”
wrote Dr. Clotet. “Nonetheless, there is an important need for clinical trials
addressing the hazard for liver toxicity of CCR5 antagonists in patients with
hepatitis C virus (HCV) or HBV coinfection,” he noted.
·The outcome
in individuals with advanced HIV disease harboring D/M-tropic or CXCR4-tropic
viruses who are treated with a CCR5 antagonist needs to be addressed, since incomplete
virological suppression might facilitate the emergence of CXCR4-tropic viruses,
which in turn might accelerate disease progression in these patients. However,
reports suggest that co-receptor switching is a rare cause of viral escape in
patients treated with CCR5 antagonists.
·There is
an urgent need for active compounds
to treat individuals with advanced HIV disease who have multidrug-resistant virus;
this should drive continued study of the role of CCR5 antagonists in salvage therapy.
·It is also
important to evaluate the role of CCR5 inhibitors in the prevention of HIV infection,
according to Dr. Clotet.
·Finally,
current data support continuation of the development of CCR5 antagonists in different
settings related to HIV infection. “If safety issues do not emerge, these compounds
could be useful from very early stages of HIV infection (even as first-line therapy)
to salvage strategies in patients with CCR5-tropic viruses,” Dr. Clotet concluded.
R M Gulick, Z Su,C Flexner,
and others (fortheAIDSClinicalTrialsGroup5211Team).
Phase2StudyoftheSafetyandEfficacyofVicriviroc,aCCR5Inhibitor,inHIV-1–Infected,Treatment-ExperiencedPatients:AIDSClinicalTrialsGroup5211. Journal
of Infectious Diseases 196(2): 304-312. July 15, 2007.
B Clotet. CCR5Inhibitors:PromisingyetChallenging (Editorial). The Journal of Infectious Diseases
196(2):178-180. July 15, 2007.
References
1.
D Schürmann, C Pechardscheck, R Rouzier, and others. SCH 417690: Antiviral Activity
of a Potent New CCR5 Receptor Antagonist. 3rd
International AIDS Society Conference on HIV Pathogenesis and Treatment.Rio de
Janeiro. July 24-27,
2005. Abstract TuOa0205.
2. D Schürmann, G Fatkenheuer, J Reynes,
and others. Antiviral activity, pharmacokinetics and safety of vicriviroc, an
oral CCR5 antagonist, during 14-day monotherapy in HIV-infected adults. AIDS
21(10): 1293-1299. June 2007.
3.
C L Tremblay, F Giguel, C Kollmann, and others. Anti-human Immunodeficiency Virus
Interactions of SCH-C (SCH 351125), a CCR5 Antagonist, with other antiretroviral
agents in vitro. Antimicrobial Agents and Chemotherapy 46(5):
1336-1339. May 2002.
4.
G Bratt, A C Leandersson, J Albert, and others. MT-2 tropism and CCR5 genotype
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