1. Entry inhibitors:
a. Enfuvirtide (FuzeonT20)
b. Maraviroc (Selzentry –
FDA approved CCR5 co-
receptor antagonist for
treatment-experienced HIV adults with only CCR5-tropic
HIV-1 strains resistant to
multiple antiretroviral
agents. 2. Protease inhibitors:
darunavir and tipranavir 3. Integrase inhibitors:
raltegravir (Isentress)
approved by FDA for HIV
treatment-experienced
adult with HIV strains
resistant to multiple antiretroviral agents. There are three antiretroviral agents in development. 1. Entry inhibitors including
TNX-355 and vicriviroc 2.
Integrase inhibitors,
including elvitegravir, and
3. A novel agent belonging
to the maturation inhibitor class, bevirimat. The two classes of target for antiretroviral
therapy that will be discussed here are the entry
inhibitor maraviroc and the integrase inhibitor
raltegravir. The use of tropism assays including
Trofile and SensiTrop will be discussed to help
clinicians make decisions of when to use the CCXR5 inhibitor in treatment-experienced
patients. Mechanism of Entry Mechanisms of HIV entry involve attachment,
triggering and fusion. Entry of the virus into the CD4+ cell involves binding of the viral gp120 envelope protein to the CD4 receptor on the host
cell, followed by interactions with chemokine
receptors, either CCR5 or CXCR4, which leads to
fusion of the viral and cell membranes. (See “HIV
Inhibition” figure, below.) HIV INHIBITION GRAPHIC Graphic Source: Clinical Care Options
downloadable slideset: Understanding HIV
Entry and Targets for Therapy;October 2007.
Available at: www.clinicaloptions.com/tropism.
®Clinical Care Options 2007; reproduced with
permission. HIV tropism HIV tropism is the ability of a given
HIV strain to use CCR5 and/or CXCR4 as co- receptors for entering CD4+ cells.4 When protein on the virus binds to CCR5 or CXCR4,
conformational changes occur that enable it to
cause membrane fusion. Drugs that prevent
these steps are referred to as entry inhibitors.
The virus that enters the cell using the CCR5 co-
receptor is termed R5 virus. Viruses that use CXCR4 co-receptor are termed X4 viruses. Viruses
that can use either co-receptor are termed R5/X4 or dual tropic viruses.4 New HIV infections are almost always due to R5 viruses. The CCR5
antagonists have activity against R5 tropic virus
only, and cannot be used for patients who have
dual-mixed tropic (D/M) or X4 virus. In some
patients, D/M and/or X4 viruses emerge years
after infection. Most of the experience in clinical trials for assessing co-receptor tropism has been
with one commercially developed assay, the Trofile.5 1) HIV RNA suppression – Phase IIb/III studies of maraviroc in treatment experienced
patients and treatment-naïve patients with R5
virus have been presented. In MOTIVATE trials,
triple class-resistant patients were
randomized to maraviroc 150mg or 300mg
daily or BID or to placebo, both combined with an optimized background regimen (OBR).
At 24 weeks, twice the proportion of patients
on maraviroc plus OBR vs. placebo plus OBR
achieved the primary endpoint of HIV-1 RNA <400 copies/ml.6, 7 Use of maraviroc is not recommended in patients with D/M or X4
HIV-1, as efficacy was not demonstrated in a
Phase II study, nor is its safety and efficacy
established in treatment-naïve adult patients or pediatric patients.8 2) Tropism Shifting or Switching – In an HIV- positive patient, viral tropism is not fixed at
primary infection, but may evolve towards
CXCR4 use over time. In some patients only a
small amount of CXCR4 may be present,
possibly existing below the limits of detection
by current technologies. This drug associated shift or switch in the population tropism will
result in a change in the tropism call, e.g.,
from R5 to dual/mixed or X4 tropism. It has
not yet been determined whether such a
coreceptor antagonist associated switch/shift
has an impact on disease progression over long-term follow-up. 3) Unmasking caused by co-receptor
antagonist exposure – treatment with a co- receptor antagonist will suppress the majority
R5 population revealing the underlying CXCR4
virus. 4) Resistance – the virus may develop phenotypic resistance to the CCR5 coreceptor antagonist, and this area is being explored.9 Several studies have used this assay to define the
prevalence of co-receptor usage in various
patient populations. Data from 8 cohorts, 3 of
them treatment naïve-patients, and 5 of the
treatment-experienced patients revealed that
dual/mixed or X4 virus appears to be less prevalent among those with earlier stages of disease.6, 10-14 Even among treatment-naïve subjects, 12-19% of individuals had detectable D/ M or X4 virus.10,12 Therefore, it is necessary to assess each individual patient for viral tropism
before the use of a CCR5 antagonist cells to alter
the conformational state of the receptor.
Monogram’s co-receptor assay, Trofile, identifies
the tropism of a patient’s virus. The sensitivity to
detect minority variant populations is 100% when X4 virus is 10% and is 85% when X4 virus is
5% with successful amplification and reliable results with viral load >1000 copies/ml.8 Another challenge for the use of maraviroc will be
reimbursement for the cost of the tropism assay.
The FDA has approved Pathway Diagnostics for
the process of SensiTrop HIV Co-receptor Tropism
Assay, a secondgeneration molecular based
diagnostic HIV tropism assay, with a projected turn around time as fast as 2-4 days compared to
the cell based assay development time of two
weeks or more. Pathway describes this assay as
highly sensitive in detecting CXCR4-tropic HIV in
patient samples that contain as little as 1% CXCR4.10
Entry Inhibitors Maraviroc is an antiviral CCR5 co-receptor
antagonist indicated for treatment-
experienced adults infected with only CCR5-
tropic HIV-1 who have evidence of viral
replication and HIV-1 strains resistant to
multiple antiretroviral agents. Use of this drug is not recommended in patients with dual/
mixed or CXCR4 tropic HIV-1 as efficacy was not
demonstrated in a Phase 2 study of this patient
group and safety and efficacy have not been
established in treatmentnaïve adult or
pediatric patients. The recommended dose differs based on concomitant medications
used. Dosing may be 150mg BID, 300mg BID or
600mg BID. Maraviroc comes with a black box
warning of hepatoxicity with allergic features.
In such cases, discontinuation of the
medication should be considered with signs and symptoms of hepatitis, or with increased
liver transaminases combined with a rash. The drug should be used with caution in
patients with increased cardiovascular risk,as
myocardial ischemia and/or infarction were
observed in patients. Immune reconstitution
syndrome has been reported in patients
treated with a combination antiretroviral therapy as well as increased risk of developing
upper respiratory infections and herpes virus
infections.There was no potential risk of
malignancy due to maraviroc, but long-term
follow-up is needed to assess this risk. The
most common adverse events with twice daily therapy included cough, pyrexia, upper
respiratory tract infections, rash,
musculoskeletal symptoms, abdominal pains,
and dizziness. Some of the less common side
effects included Clostridium difficile colitis.
Maraviroc is a substrate for cytochrome P4503A4 and so several antiretroviral agents
have been shown to have relevant drug-drug interactions with it as shown below.15 Maraviroc Dosage Adjustments with Co- Administered CYP3A Inhibitors or Inducers Reduce dose when given with
strong CYP3A inhibitors (with or
without CYP3A inducers)
including PI (except tipranavir/
ritonavir), delavirdine,
ketoconazole, itraconazole, clarithromycin, telithromycin 150 mg twice daily Use standard dose when given
with NRTI, tipranavir/ritonavir,
nevirapine, enfuvirtide and other
drugs that are not strong CYP3A
inhibitors or CYP3A inducers 300 mg twice daily Increase dose when given with
CYP3A inducers (without a strong
CYP3A inhibitor) including
efavirenz, rifampin,
carbamazepine, phenobarbital,
phenytoin 600 mg twice daily Administration of maraviroc with St. John’s
Wort is not recommended as it will decrease
maraviroc concentrations and lead to loss of
virologic response and possible resistance.
Maraviroc should be used with caution in
patients with renal impairment and in patients with pre-existing liver dysfunction, or who are
co-infected with hepatitis B or C. It can be
taken with or without food. Integrase Inhibitors Integrase enzyme is required for HIV-1
replication. It catalyzes the irreversible process
of integrating the viral DNA into the host cell’s
DNA, called integration. The viral integrase
enzyme is a target for antiviral therapy by
integrase inhibitors. Raltegravir (formerly MK-0518) was recently approved by the FDA for
the treatment of HIV-1 infection in treatment-
experienced adult patients who have HIV-1
strains that are resistant to multiple
antiretroviral agents. The safety and efficacy of
raltegravir have not been established in treatmentnaïve adult patients or pediatric
patients. The dosage is 400mg twice daily with or without food.16 Caution should be used during the initial phase
of treatment, when patients may develop
immune reconstitution syndrome. The most
common side effects reported are diarrhea,
nausea, headache, and pyrexia. Cancers like
Kaposi’s sarcoma, lymphoma, squamous cell carcinoma, hepatocellur carcinoma, and anal
cancer were reported in treatment experienced
subjects, but it is unknown if these cancers
were related to raltegravir use. The rates of AST
and ALT abnormalities were higher in the
subjects co-infected with hepatitis B and/or hepatitis C. It is metabolized by UGT1A1
glucuronidation pathway, and hence, caution
should be used with rifampin or other strong
inducers of UGT1A1. Less strong inducers like
efavirenz, nevirapine, rifabutin, and St. John’s Wort may be used with raltegravir.15 The mutations that resulted in raltegravir
resistance included an amino acid substitution
at either Q148 (changed to H, K, or R) or N155
(changed to H) plus one or more substitutions
(L74M/R, E92Q,T97A, e138A/K, G140A/S, V151I,
G163R, H183P, Y226D/F/H, S230R and D232N). Another pathway to raltegravir resistance was
seen with amino acid substitution at Y143C/H/ R.15 BENCHMRK 1 and 2 studies confirmed the
potency of raltegravir in treatment- experienced patients.16,17 Patients were randomized to raltegravir 400mg twice daily,
or to placebo plus an OBR. At 16 weeks, 77% of
patients in the raltegravir arms had HIV-1 RNA
<400 copies/ml compared to 41-43% of placebo patients. CD4+ cell count response was also significantly higher in the raltegravir arms
(83-86 cells/mm3) than in control as (31-40
cells/mm3). Data from BENCHMRK studies
indicate that this drug will be beneficial in
treatment-experienced patients when
combined with at least one other active agent. Raltegravir does not require ritonavir boosting.
Twice daily dosing will be a drawback, but the
drug’s tolerability and lack of toxicity in studies
will expand the options for sequential
antiretroviral regimens. CONCLUSION As with any antiretroviral agent, the patient
should be informed that neither maraviroc nor
raltegravir is a cure for HIV infection, and that
he or she can still develop opportunistic
infections. These treatments do not lower the
risk of passing HIV to other people through sexual contact or sharing needles, so they
should continue to practice safer sex, and use
barrier methods to lower the chance of sexual
contact with any body fluids. Patients should
remain under the care of a physician when
using these drugs, and if they forget to take a dose, they should take the next dose of
medication as soon as possible and then take their next scheduled dose at its regular time.