Abstract
The emergence of antiretroviral drug resistance in patients infected
by the human immunodeficiency virus (HIV) has prompted efforts to
develop new antiretrovirals that differ from existing agents with
regard to mechanism of action and resistance profiles. We evaluated
the literature regarding a new class of antiretrovirals, the
integrase inhibitors. A MEDLINE search (January 1996 - May 2007) was
performed to identify relevant clinical trials and review articles;
abstracts from HIV conferences were also searched. Raltegravir
(MK-0518) and elvitegravir (GS-9137) are the two integrase
inhibitors in late-phase development. These agents prevent viral DNA
integration into the CD4+ cell chromosome. Both drugs showed potent
antiviral activity in large clinical trials that were performed in
treatment-experienced, multidrug-resistant patients. Promising
results have also been seen in an initial dose-ranging study with
raltegravir in treatment-naEFve patients. Preliminary data describe
integrase inhibitor resistance profiles, but more data are needed in
this area. Both agents were well tolerated in clinical trials, with
favorable pharmaco-kinetic profiles for once- or twice-daily dosing.
Raltegravir and elvitegravir differ in their metabolism, resulting
in distinct drug-interaction profiles for each agent. Based on
available data, this new class of antiretrovirals will soon be
widely used in antiretroviral-experienced patients infected with
HIV. In the future, this class of drugs may become a reasonable
treatment option for antiretroviral-naEFve patients, but more data
are needed in that patient population.
Introduction
Effective antiretroviral therapy for the treatment of human
immunodeficiency virus (HIV) has decreased opportunistic infections
and death.[1] Unfortunately, antiretroviral resistance continues to
develop and may limit available treatment options. New
antiretrovirals with novel mechanisms of actions and/or distinct HIV
resistance profiles are needed to continue to effectively treat the
HIV pandemic. Integrase inhibitors are a new class of
antiretrovirals with an novel mechanism of action that prevents
viral DNA integration into the CD4+ cell chromosome.[2] Two such
agents - raltegravir (MK-0518) and elvitegravir (GS-9137) - are in
late-phase clinical development. Clinical trials of these agents are
summarized in Table 1 .[3 - 8] Both have demon-strated potent
antiviral responses in patients with antiretroviral experience.[3 - 7]
Moreover, preliminarily data show that raltegravir generates
antiviral responses in treatment-naEFve patients.[8] We provide an
overview of these two agents with attention to their pharmacology,
pharmacokinetics, pharmacodynamics, and the clinical data that are
anticipated to lead to their approval by the United States Food and
Drug Administration (FDA).
Pharmacology
The enzyme HIV integrase is responsible for transferring the viral
DNA into the host cell's chromosome. This process begins when HIV
binds to the surface of the CD4+ T lymphocyte. After attachment, the
virus enters the cell by the fusion process. Next, single-stranded
viral RNA is converted to double-stranded viral DNA by reverse
transcriptase. The viral DNA can then be transferred into the cell
chromosome by HIV integrase. After the viral DNA is incorporated
into the chromosome, the cell begins to produce viral particles that
eventually undergo further processing and infect other immune
cells.[2,9,10]
Three essential steps for the actions of HIV integrase have been
identified: 3A2 processing, formation of the preintegrase complex,
and strand transfer. After reverse transcriptase creates the viral
DNA strand, integrase binds to it and cleaves the last two
nucleotides from the ends of the viral DNA strand. This is referred
to as 3A2 processing. A 3A2 hydroxyl group forms at each DNA strand
end. Once 3A2 processing occurs, the preintegration complex can
form. The preintegration complex consists of ring-shaped viral DNA
with associated viral and host proteins. The preintegration complex
structure enables the viral DNA to pass from the cell cytoplasm into
the cell nucleus through unknown mechanisms. It is thought that
viral reverse transcriptase, matrix, and nucleocapsis participate in
transferring the preintegration complex into the nucleus. In the
nucleus, integrase incorporates viral DNA strands into the host
chromosome through strand transfer. Gap repair-ligation occurs after
strand transfer to seal the viral DNA into the cell chromosome. If
strand transfer does not occur, the viral ring structures remain in
the cytoplasm of the nucleus. The clinical relevance of viral ring
structures that remain in the nucleus is not known.
A highly conserved region of HIV integrase called the catalytic core
is key to the binding of HIV integrase to host DNA. It is
hypothesized that divalent cations in this core enable integrase to
form covalent bonds with the phosphodiester backbone of DNA,
allowing viral DNA to incorporate itself into the host chromosome.
Raltegravir and elvitegravir, like other integrase inhibitors,
prevent strand transfer by binding to divalent cations in the
catalytic core and preventing covalent bonds from forming between
integrase and host DNA. Hence, HIV integrase cannot incorporate the
viral DNA into the CD4+ cell chromosome, which results in the
prevention of strand transfer and viral replication.[2,9,10] Three
integrase inhibitor classes, diketoacids (DKAs), hydroxyquinolones,
and polyphenols, have been identified.[2] Raltegravir is a member of
the DKA class, whereas elvitegravir belongs to the hydroxyquinolone
class.
In order to be classified as an integrase inhibitor, a drug must
meet four criteria.[11] First, it must be active after HIV has
completed reverse transcription (~4 - 6 hrs after infection but not
later than 10 - 12 hrs after infection). Second, after HIV-infected
cells are exposed to the drug in vitro, the host chromosome must
undergo a decrease in viral DNA, causing the cell nucleus to
accumulate viral circular DNA that has failed to incorporate into
the chromosome. Third, integrase mutations must be found in
drug-resistant viruses. Fourth, in the presence of integrase
mutations, the drug must become inactive in biochemical assays.
Resistance
Due to the short history of this drug class, data regarding
resistance mutations associated with virologic failure are limited.
Resistance-testing results are available for 41 patients who
experienced failure in the raltegravir groups in the BENCHMRK-1 and
-2 studies.[4,5] Nine of these patients had no integrase mutations,
whereas 32 patients had one or more integrase mutations. Raltegravir
failure was generally associated with one of two main amino acid
mutations: N155H or Q148K/R/H. Secondary mutations were observed
with both primary mutations. The primary N155H mutation was
associated with E92Q, V151I, T97A, G163R, and L74M, and the primary
Q148K/R/H mutation was associated with G140S/A and E138K. Other
resistance mutations may also exist, including Y143R/C plus L74A/I,
E92Q, T97A, I203M, and S230R. Longitudinal analyses of these
mutations and their associations are ongoing.
Even less information about elvitegravir resistance is available. In
vitro data show that the T66I mutation in the catalytic core and the
R263K mutation located in the C-terminal domain affect elvitegravir
antiviral susceptibility.[19] Viral strains harboring the T66I,
R263K, or T66I plus R263 mutations have 15.1-, 5.2- and 98-fold
reductions in drug susceptibility. Secondary mutations that may
affect elvitegravir antiviral activity include S153Y and F121Y.
Raltegravir remains active in the presence of these mutations.
However, the E92Q mutation gives rise to cross-resistance that
decreases the antiviral activity of elvitegravir and raltegravir by
36- and 7-fold, respectively. Thus, certain mutations appear to have
minimal to no cross-resistance, while other mutations can
significantly decrease susceptibility to both agents. These
mutations did not alter the susceptibility of antiretroviral drugs
from other antiretroviral classes. More data are needed to gain a
better understanding of the significance of HIV mutations that
affect viral susceptibility to integrase inhibitors.
Conclusion
Elvitegravir and raltegravir are members of a new class of
antiretrovirals called integrase inhibitors. Based on the available
data, these agents possess potent antiretroviral activity and offer
clinical benefits in patients with limited antiretroviral treatment
options. Both agents are available in oral formulations and appear
to have favorable safety profiles. Both also have a low pill burden
and favorable dosing frequency.
Elvitegravir is entering phase III clinical trials in
antiretroviral-experienced patients, whereas raltegravir is
completing phase III trials and is available at select centers
through an expanded-access program in patients with three-class drug
resistance. Based on the available data in treatment-experienced
patients, this class of drugs will likely gain FDA approval in the
near future and will be widely used in treatment-experienced
HIV-infected patients with multidrug-resistant virus.
To our knowledge, data in treatment-naEFve patients are only
available with raltegravir; these are preliminary but show promising
results. However, many highly efficacious antiretroviral regimens
are available for this patient population. Significantly more
clinical data are needed before this drug class becomes an
antiretroviral treatment option for patients with HIV infection who
are naEFve to therapy. Moreover, important advantages over the
currently available regimens would have to be shown, such as a low
pill burden and excellent tolerability.
Relentless research in the field of HIV pharmacotherapy has led to
continual develop-ment of new antiretrovirals, constantly reshaping
HIV clinical practice and improving morbidity and mortality.
Integrase inhibitors are the most recent advance in this area and
offer a new, effective treatment option for this patient population.
INTEGRASE INHIBITORS
Drugs List :
| Brand
Name |
Generic
Name |
Manufacturer Name |
|
Isentress |
raltegravir |
Merck & Co., Inc. |
|
