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5 Newer Classes: Entry Inhibitors and Integrase Inhibitors

5 Newer Classes: Entry Inhibitors and Integrase Inhibitors

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4.5 Newer Classes: Entry Inhibitors and Integrase Inhibitors



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HIV Entry Mechanism

2. Co-receptor

interaction



HIV



HIV



Chemokine

Receptor

Inhibitors



gp41



HIV



3a. Anchorage

gp120



1. CD4

Attachment



CXCR4

CCR5



R5 or X4



CD4



gp41



Cell

3c. Fusion

Complete



HIV



HIV



Fusion

Inhibitors



HIV 3b. coil-coil

interaction



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 [57]. 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 [58]. 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 [20].

4.5.2

Integrase Inhibitors



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



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Viral DNA Synthesis



2

In-Dependint

Processing

of 3'Ends



Nuclear

Entry



1

Assembly on Viral DNA in a

Nucleoprotein Complex



mbrane

Nuclear Me

3a

Target

DNA

Binding



X

3b

Concerted

Target DNA

Cleavage

and joining



Gap Repall

Strand Transfer

Inhibitors

Mature

Provirus

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” [61] (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) [62]. However, the majority of patients who

experienced virologic failure also developed drug resistance to raltegravir [63].

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 [20].

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



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 [22], while four-NRTI regimens have not yet been studied extensively [23] 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 [30] and/or increased

rates of drug resistance at virologic failure [42], 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 [66].

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).



Stage of

NRTIs

development

Phase III

Phase II

Phase I/II



rilpivirine

apricitabine

BILR-355

dexelvucitabine UK-453,061

amdoxovir

IDX-899

elvucitabine



Phase I



NNRTIs



RDEA-806



PIs



Entry

inhibitors



Integrase

inhibitors



vicriviroc

ibalizumab

PRO 140

HGS004



elvitegravir



Maturation

inhibitors



bevirimat

GSK

MPC-9055

compounds



PRO 542

PPL-100 PF-232798

INH-1001

SPI-256 SCH-532706

TBR 652

TRI-1144



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half-life that allows dosing as infrequently as once a month [67]. Additional newer

formulations of antiretroviral agents may allow infrequent dosing of antiretroviral

therapy.

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 [52].

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 [68], 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 [65].

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.



4.7

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 [20]. Although the optimum time to start antiretroviral therapy in patients with

active TB is not known, a number of clinical trials are under way [70]. 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



References



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 [29]. 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 [70].



4.8

Conclusions



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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