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5 Newer Classes: Entry Inhibitors and Integrase Inhibitors
4.5 Newer Classes: Entry Inhibitors and Integrase Inhibitors
HIV Entry Mechanism
R5 or X4
HIV 3b. coil-coil
Figure 4.6 Mechanism of action of the HIV entry inhibitors.
tropism assay optimized their background regimens on the basis of treatment history
and drug-resistance testing, and then were randomized to receive either maraviroc
(at one of two doses) or matching placebo . In total, 46% of the maraviroc twicedaily recipients compared to 17% of placebo recipients had HIV RNA <50 copies
mlÀ1 at week 48 (p < 0.001). Since maraviroc was the ﬁrst antiretroviral drug to target
a host immune cell receptor, concerns about immune effects or unusual toxicities
have been raised. In patients congenitally lacking the CCR5 receptor, there are
demonstrable immune effects, e.g. increased morbidity and mortality following West
Nile Virus infection . However, no excess hepatic toxicity, unusual infections or
malignancies were associated with maraviroc use in the MOTIVATE studies, in
contrast to other investigational CCR5 antagonists [59, 60]. Of note, the Food and
Drug Administration (FDA) required that all study subjects who received a CCR5
antagonist in a clinical trial be followed for clinical events for ﬁve years. The use of
CCR5 antagonists in developing countries represents a major challenge due to a need
for the viral tropism assay. The concomitant treatment of TB and HIV with a
maraviroc-containing regimen is also complicated by a signiﬁcant drug–drug
interaction, whereby rifampin cause a >60% decrease in maraviroc concentrations
that would necessitate the maraviroc dose to be adjusted. At present, no data are
available regarding any interactions of maraviroc with rifabutin .
The most recently approved member of a new class of drugs was the strand transfer
integrase inhibitor, raltegravir. The HIV integrase enzyme catalyzes three steps of
j 4 HIV/AIDS Drugs
Viral DNA Synthesis
Assembly on Viral DNA in a
Figure 4.7 Mechanism of action of the HIV integrase inhibitors.
integration: (1) formation of the double-stranded viral DNA complex; (2) the 30 processing of the DNA; and (3) transport and insertion of the viral DNA into the host
cell DNA in a process called strand transfer  (Figure 4.7). Raltegravir was
approved in 2007 on the basis of demonstrating signiﬁcant virologic activity in the
benchmark studies of 699 treatment-experienced patients in the BENCHMRK
studies, whereby 62% of raltegravir versus 33% of placebo recipients had HIV RNA
<50 copies mlÀ1 at 48 weeks (p < 0.001) . However, the majority of patients who
experienced virologic failure also developed drug resistance to raltegravir .
Raltegravir also was compared to efavirenz, both in combination with NRTIs, in a
Phase II study of treatment-na€ıve patients and demonstrated comparable virologic
suppression rates with 85–95% of patients having HIV RNA <50 copies mlÀ1
through 48 weeks [64, 65]. Raltegravir demonstrated a side-effect proﬁle similar to
that of placebo in all of these studies. Whilst raltegravir is metabolized by glucuronidation, concomitant administration with rifampin causes a 40–60% decrease in
raltegravir concentrations, thus complicating the concomitant treatment of TB .
In summary, drugs with new mechanisms of action, such as HIV entry inhibitors
and integrase inhibitors, have demonstrated signiﬁcant virologic activity in patients
with resistance to NRTIs, NNRTIs, and PIs. Consequently, new drugs have revolutionized the goals and management of treatment-experienced patients, setting a new
standard of virologic response: HIV RNA levels suppressed to <50 copies mlÀ1 [20,
21]. Unfortunately, these newer drugs are limited by their higher cost, the need for
parenteral administration of enfuvirtide the restriction of activity to R5 virus (only)
and the need for the tropism assay, in the case of maraviroc, and a low barrier to
resistance for raltegravir. Signiﬁcant drug–drug interactions of maraviroc or raltegravir with rifampin also further complicate the use of these drugs.
4.6 Newer Strategies
While current combination antiretroviral therapy regimens are highly effective, their
limitations of convenience, tolerability, toxicity, drug–drug interactions and activity
against drug-resistant viral strains continue to prompt the search for new strategies
and newer antiretroviral agents. The current preferred initial therapy for HIV
infection is a regimen consisting of two NRTIs in combination with an NNRTI or
a ritonavir-boosted PI [20, 21] (Table 4.3), on the basis of results from large
randomized, comparative clinical trials [7, 14, 30, 41, 45, 47]. Studies comparing
preferred NNRTI-based regimens with PI regimens have demonstrated distinct
beneﬁts to both strategies [42, 44], and support either approach.
Newer strategies for treatment-na€ıve patients include some novel approaches. AllNRTI regimens have the potential to avoid drug–drug interactions, particularly with
the hepatically metabolized NNRTIs and PIs and TB drugs. However, three-NRTI
regimens are less potent than NNRTI-based regimens , while four-NRTI regimens have not yet been studied extensively  and could have toxicity problems of
their own. An NRTI-sparing approach to avoid NRTI-related toxicities also has been
explored, typically consisting of an NNRTI together with a ritonavir-boosted PI.
However, these regimens have been associated with toxicity  and/or increased
rates of drug resistance at virologic failure , continue to have signiﬁcant
drug–drug interaction issues, and have not been adopted widely.
Newer compounds may challenge the existing drugs and treatment paradigms
(Table 4.4). When combined with dual NRTIs, an investigational NNRTI – rilpivirine –
showed comparable virologic responses to efavirenz but was associated with fewer
rashes and central nervous system toxicity in a Phase II study for up to 96 weeks .
Rilpivirine is currently under investigation in large Phase III studies. Rilpivirine is
also available in an investigational nanoparticle formulation with a prolonged drug
Table 4.4 Investigational antiretroviral agents in clinical development (partial list only).
j 4 HIV/AIDS Drugs
half-life that allows dosing as infrequently as once a month . Additional newer
formulations of antiretroviral agents may allow infrequent dosing of antiretroviral
Newer drugs approved for treatment-experienced patients also may offer beneﬁts
to treatment-na€ıve patients as part of combination regimens. For example, darunavir
was non-inferior virologically to lopinavir/ritonavir and had fewer side effects .
Maraviroc was non-inferior to efavirenz as part of a three-drug regimen for the HIV
RNA <400 copies mlÀ1 endpoint, but not for <50 copies mlÀ1 , although tropism
assay sensitivity most likely played a role. A raltegravir-based regimen had comparable virologic responses to an efavirenz-based regimen over 96 weeks, and a
statistically signiﬁcantly more rapid time to virologic suppression [64, 69]; similarly
designed Phase III raltegravir studies provided similar preliminary results .
With the development of these newer agents in treatment-na€ıve patients, new
potentially paradigm-shifting strategies could be tested that could spare several
classes of drugs. For example, the combination of a PI with an integrase inhibitor or a
CCR5 antagonist could spare both NRTIs and NNRTIs. Similarly, a standard
combination regimen of NRTIs and an NNRTI could be used ﬁrst and then, after
regimen failure, a new regimen consisting of a PI with an integrase inhibitor or a
CCR5 antagonist could be used. This would deﬁne a sequence of two fully potent
antiretroviral therapy regimens with distinct mechanisms of action and nonoverlapping drug resistance proﬁles, although drug–drug interactions (including those
with TB medications) would complicate these new approaches. Consequently, pilot
studies investigating such possibilities are currently in progress.
For patients with signiﬁcant treatment experience, the current guidelines recommend reviewing the treatment history, performing drug-resistance testing, and
designing a regimen with two (or preferably three) fully active agents in the next
regimen [20, 21]. A number of investigational compounds in existing classes
(NRTIs, NNRTIs, PIs), in newer approved classes (CCR5 antagonists, integrase
inhibitors), or in investigational classes (CD4 attachment inhibitors, CXCR4
antagonists, maturation inhibitors) have demonstrated activity against drugresistant viruses, and may be particularly useful for treatment-experienced patients
if they are proved safe and effective (Table 4.4). Today, the pipeline for new
antiretroviral agents appears full.
Concomitant Treatment of HIV Infection and Tuberculosis
The current guidelines emphasize that the treatment of HIV-infected patients with
active TB should follow the same principles as for HIV-infected patients without
TB . Although the optimum time to start antiretroviral therapy in patients with
active TB is not known, a number of clinical trials are under way . Neither are
the optimal antiretroviral regimens to treat HIV-infected patients with TB known,
although NRTI combinations that do not cause peripheral neuropathy (e.g.,
abacavir/lamivudine, tenofovir/emtricitabine, or zidovudine/lamivudine), in
combination with a NNRTI with manageable drug interactions and a lower potential
for overlapping hepatotoxicity (e.g., efavirenz), have demonstrated virologic outcomes that are not different from those in treated HIV-infected patients without
TB . The treatment of HIV and TB can be successfully managed, and the
integration of care and treatment for both infections is clearly critical. In addition,
clinical trials are in progress that will continue to deﬁne the optimal strategies for
concomitant treatment .
The development of effective antiretroviral therapy changed the natural history of
HIV disease, with dramatic decreases in morbidity and mortality worldwide. Today,
the life expectancy of HIV-infected people receiving treatment is approaching that of
the general population. With effective treatment, HIV has been transformed into a
chronic, manageable disease; consequently, more convenient, more tolerable and
less-toxic medications are critical for long-term adherence and clinical responses.
More recently, the development of new drugs in existing classes with activity against
drug-resistant virus (e.g., NNRTIs, PIs), and of drugs with new mechanisms of action
(HIV entry inhibitors, integrase inhibitors), has offered greatly improved treatment
options for individuals with treatment experience and/or drug-resistant viral strains.
Newer compounds and strategies continue to be tested and will ensure further
progress in the ﬁeld. The concomitant treatment of HIV infection and TB is
complicated by overlapping drug toxicities, drug–drug interactions, and the inconvenience of multidrug regimens. However, effective comanagement strategies are
possible, and clinical trials are either planned or under way to ensure further progress
in this area.
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