Effects of Maraviroc (MVC) on HIV-related Kaposi's Sarcoma (KS)

Although the advent of antiretroviral therapy (ART) may have greatly decreased the incidence
of Kaposi's Sarcoma (KS) in resource rich settings, KS continues to be the most prevalent
AIDS-defining malignancy in the world and carries with it significant morbidity and
mortality[1]. Indeed, in a recent epidemiological study examining cancers in Kampala, Uganda,
KS was found to be second only to prostate cancer in terms of incidence rates[2].

There is growing evidence that CCR5 may be involved in the pathogenesis of KS. Kaposi's
Sarcoma-associated Herpes Virus (KSHV), an agent found as necessary for KS pathogenesis [10,
11], encodes viral macrophage inflammatory proteins or vMIP [7-9]. vMIP-I and vMIP-II have
been found to be ligands for chemokine receptors, and in particular the CCR5 receptor [5, 6],
suggesting a potential role in the inflammatory process needed for KS pathogenesis. Further,
vMIP-I induces Ca(2+) mobilization in monocytes expressing CCR5, suggesting an agonistic
relationship between vMIP-I and the CCR5 receptor [4]. In addition, vMIP has been found to be
proangiogenic when expressed in endothelial cells, a key feature of KS tumor survival [12].
As well, CCR5 has been found to be significantly increased in T cells populations of KS
patients (from a preliminary study), and in 2 double-blind, placebo-controlled phase 3
studies in which a total of 1049 patients received the randomly assigned drug MVC, there was
a trend revealing a lower incidence of KS in MVC arms vs placebo (0.36% vs 1.43%) [3]. This
agonistic binding relationship between protein vMIP and CCR5, the proangiogenic activity
associated with vMIP, the increased expression of CCR5 in KS, and trend towards lower
incidence of KS when patients are taking MVC, suggest CCR5 may play an important role in KS
pathogenesis. This involvement of CCR5 in KS pathogenesis implies that MVC may function as a
potential therapeutic for KS. To date, there have been no studies examining the effect of MVC
on KS.

There is a need for therapeutic development for KS. Standard of care for KS involves
initiation or optimization of antiretroviral therapy. A significant proportion of KS cases do
not respond to ART alone, with non-response rates ranging from 25-55%, with response times
averaging 9 or more months depending on which patient series is identified [13, 14]. In
severe or in cases of KS unresponsive to ART, standard of care involves systemic chemotherapy
with liposomal doxorubicin [15], which is not without adverse reactions. Adverse reactions to
liposomal doxorubicin include cardiac toxicity, nausea, vomiting, diarrhea, abdominal pain,
fatigue, and patients may require pre-regime tests of varying costs, along with resources and
time needed for intravenous infusion [16]. Nonresponse rates for liposomal doxorubicin hover
around 20% [15, 17]. Focal cases may be more amenable to radiation therapy or intralesional
velban [18, 19]. However, radiation and intralesional therapies are limited to focal sites,
require monitored visits and specialized care, can be given only in limited amounts, and
carry various adverse effects [18, 19]. With these nonresponse rates, potential adverse
reactions, and resources and time needed for therapeutic delivery, there are clear benefits
proferred by an effective oral therapy requiring minimal monitoring, as is the case with MVC.

Maraviroc (MVC) is a member of a new class of antiretroviral compounds known as small
molecule CCR5 antagonists that block R5 HIV entry into CD4 cells. Maraviroc has demonstrated
selective and reversible binding to CCR5, as well as potent antiviral activity in vitro
against a wide range of laboratory adapted strains of R5 HIV from Clades A, B, C, D, E, F, G,
J and O. Maraviroc also retains in vitro antiviral activity against clinical isolates
resistant to the existing drug classes, but has no activity against viruses that enter CD4+
cells using CXCR4. In vitro studies with approved antiretroviral medications indicate that
there is no evidence of antagonism with any members of the other four classes of
antiretroviral medications; nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs),
non- nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs) or
fusion inhibitors.

Although there is growing evidence that CCR5, a potential therapeutic target, is involved in
KS pathogenesis [3-9], to date there are no studies examining the effects of a CCR5 inhibitor
such as Maraviroc (MVC) on KS. As such, the aim of this study is to examine the effect of
Maraviroc, a CCR5 inhibitor, on KS.

Inclusion Criteria:

- HIV-1 infected, as documented by any licensed ELISA test kit and confirmed by Western
blot at any time prior to study entry. HIV-1 culture, HIV-1 antigen, plasma HIV-1 RNA,
or a second antibody test by a method other than ELISA is acceptable as an alternative
confirmatory test.

- Active biopsy confirmed KS

- Screening plasma HIV RNA < 75 copies/mL

- Patients have unremitting KS. Unremitting is defined as having active biopsy confirmed
KS in spite of having had sustained HIV RNA < 75 copies/mL for 24 prior months.
Isolated values that are detectable but < 500 copies will be allowed as long as the
plasma HIV RNA levels before and after this time point are undetectable.

- >90% adherence to therapy within the preceding 30 days, as determined by self-report.

- Both male and female subjects are eligible. Females of childbearing potential must
have a negative serum pregnancy test at screening and agree to use a double-barrier
method of contraception throughout the study period.

- Ability and willingness of subject or legal guardian/representative to provide
informed consent

Exclusion Criteria:

- Patients who are intending to modify antiretroviral therapy in the next 24 weeks for
any reason.

- Serious illness requiring hospitalization or parental antibiotics within preceding 3
months.

- Concurrent treatment with immunomodulatory drugs or therapies, or exposure to any
immunomodulatory drug or therapy in past 16 weeks.

- Prior exposure to CCR5 inhibitors

- Screening absolute neutrophil count <1,000 cells/mm3, platelet count <50,000
cells/mm3, hemoglobin < 8mg/dL, estimated creatinine clearance <40 mL/minute.

- Elevated transaminases greater than 2.5 times the upper limit of normal.

- Evidence of cirrhosis

- Pregnant or breastfeeding women

- Use of both Tenofovir and Didanosine in current antiretroviral therapy regimen.

- Local therapy for any KS index lesion in preceding 60 days, unless lesion has clearly
progressed with enlargement since the local therapy