antiretroviral drugs_ critical issues and recent advances

Indian J Pharmacol. 2012 May-Jun; 44(3): 288–298.

doi: 10.4103/0253-7613.96296

PMCID: PMC3371447

Antiretroviral drugs: Critical issues and recent advances

Mira Desai, Geetha Iyer, and R. K. Dikshit

Department of Pharmacology, B J Medical College, Ahmedabad, India

Correspondence to: Dr. Mira Desai, E-mail: [email protected]

Received March 1, 2012; Revised March 5, 2012; Accepted March 10, 2012.

Copyright : © Indian Journal of Pharmacology

This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported,

which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Human immunodeficiency virus (HIV) infection is now recognized as a chronic illness. Although the

success of highly active antiretroviral therapy is beyond question, several issues still persist. Since the

drugs cannot eradicate the virus, cure is not yet possible, and patients have to maintain a lifelong

adherence with the risk of toxic effects, drug-drug interactions and drug resistance. A clear

understanding of the viral replication and its interaction with host cell factors has led to the

development of a large number of effective antiretroviral drugs (ARVs). New drugs in the existing

class such as apricitabine, elvucitabine and etravirine have shown promising results against HIV

isolates resistant to first line drugs. These drugs have offered a new choice for patients with drug

resistant disease. However, the impact of their long term use on safety is yet to be assessed. Novel

drugs with unique mechanism of action such as CD4 receptor attachment inhibitors, maturation

inhibitors, pharmacokinetic enhancers, capsid assembly inhibitors and lens epithelium derived

growth factor inhibitors are still under development. Currently, ARVs, especially tenofovir and

emtricitabine, are also being evaluated for prevention of sexual transmission of HIV-1. The initial

results of an HIV prevention trial network are encouraging and have recommended the use of ARVs

for pre-exposure prophylaxis. Thus, ARVs form the key component of HIV prevention and treatment

strategy. This article discusses the challenges associated with HIV-1 treatment and updates several

major advances in the development of ARVs.

KEY WORDS: Antiretroviral drugs, challenges, recent advances

Introduction

A significant advancement in the understanding of an HIV replication and its pathogenesis has

helped in the identification of different pharmacological targets. This has resulted into availability of

a large number of antiretroviral (ARV) drugs. The antiretroviral therapy (ART) has evolved from

monotherapy with azidothymidine (AZT) to combination of 2 ARVs from nucleoside reverse

transcriptase inhibitors (NRTIs) to highly active antiretroviral therapy (HAART). The triple therapy

has resulted into significant improvement in an immune status, quality of life, and reduced morbidity

and mortality associated with HIV infection.[1] With the advent of the different drug regimens, the

disease scenario has changed from a ‘virtual death sentence’ to a ‘chronic manageable disease’. The

continued search for different drug combinations, preferential change in first line drugs and

Antiretroviral drugs: Critical issues and recent advances http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3371447/?report=printable

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HIV related factors

ARV related factors

identification of novel drugs has been a boon for an effective viral suppression. However, the success

of the drug treatment is achieved at the cost of life threatening adverse drug effects, drug-drug

interactions and an inconvenience of lifelong therapy. Since the disease has stepped into its 3

decade, there are several treatment-experienced patients living either with drug toxicity or facing the

threat of treatment failure due to a multi-drug resistance. Moreover, there is likelihood of newly

infected untreated patients harboring HIV mutants that are already resistant to commonly used ARV

drugs.[2] Thus, there are many critical issues associated with the use of ARV drugs that need to be

addressed. In addition, a great deal of attention has also been focused on prevention of an HIV

infection through sexual contact. This article is an attempt to discuss the key issues with ARV drugs,

review the new agents in existing classes and also the novel drugs under development.

Challenges with the Use of ARV Drugs

The critical issues associated with ART are related to the characteristic features of the virus (HIV),

ARV drugs and HIV positive patients. These factors are a major challenge for an effective long term

treatment.

HIV, a retrovirus, multiplies at a rate of approximately 10 copies per day. At such a high rate

of replication, the virus often commits mistakes and results into mutants.[3] High mutation

rate leads to development of multiple strains and threatens the development of drug resistance.

1.

Once infected, the virus becomes an integral part of host cell and survives the full life span of

infected host cell,[4] especially in T-lymphocytes and urogenital secretions. Surprisingly ,

despite a complete plasma viral load suppression for 6-12 months, the virus remains detectable

in seminal fluid and more often than not, these are drug resistant variants.[5] The existence of

virus in potential ‘reservoirs’ and the subsequent replication may cause relapse following

cessation of ART, necessitating lifelong treatment.[6] Different treatment strategies have been

tried for the persistent forms, but to date, no clinical or virological benefit has been reported.[7]

2.

Increasing reports of multi-drug resistant (MDR) virus in treatment-experienced patients are

also being encountered.[8]

3.

Attempts to eradicate the virus from the ‘reservoir’ have failed despite intensifying the ARV

treatment, implying that drugs cannot reach in adequate concentration in the latent reservoir

cells.[7]

1.

Each class of ARV drugs has the potential to cause toxicities, many of which are shared by

drugs likely to be used concomitantly in HIV positive patients. This complicates the treatment,

causes difficulty in causality assessment and may require treatment withdrawal in serious life

threatening reactions. Long term use of HAART has been reported to produce morphologic and

metabolic abnormality syndrome, especially hypertriglyceridemia (HTG).[9] This in turn has

increased the risk of cardiovascular (CVS) and cerebrovascular diseases in patients receiving

ART.[10]

2.

Clinically significant drug-drug interactions, frequently seen in patients on ART, can adversely

affect the patient care and complicate ART. Interactions have been observed in 14% to 26% of

HIV infected patients in USA and Netherlands.[11,12] The therapeutic risk of interactions is

due to potent induction or inhibition of cytochrome P450 (CYP450) isoenzyme, which also

metabolizes a number of other medications. On the other hand, the evaluation of the potential

interactions during clinical trials is mostly incomplete and becomes evident only during drug

therapy. Further, the drugs belonging to same class also differ in their potential to cause the

interactions. For example, first licensed integrase inhibitor, raltegravir is predominantly

3.

rd

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Host related factors

metabolized by UGT1A1- medicated glucoronidation with little potential to interact with

CYP450 enzymes, whereas elvitegravir is largely metabolized by CYP3A4.[13] Moreover,

ritonavir boosting effect is due to inhibition of CP450 3A4 enzyme, but it also inhibits other

CYP isoenzymes and is an inducer of several liver enzymes, resulting into complicated

pharmacokinetic interactions with other drugs. The drug treatment of co-existing medical

disease (s) and opportunistic infections can also complicate the ART. The use of over the

counter drugs and herbal drugs may potentially compromise the management.[14]

Reduction of the plasma viremia to undetectable levels strongly correlates with strict adherence

to ARV regimen that includes taking multiple drugs twice or thrice a day for rest of life. The

recommended practice to combine 3 or more drugs from different classes of ART results in high

pill count that, along with toxicities, may cause inconvenience to the patient and poor

adherence.[15]

4.

All classes of ARVs demonstrate the in vivo resistance.[2] However, the rate of development of

drug resistance differs amongst them. Non-thymidine-containing NRTI/NtRTI combination

regimens and NNRTIs have a low genetic barrier to resistance; thereby, they require fewer

critical mutations to render the treatment ineffective. Drug resistance is not only associated

with rapid virologic failure but also present the daunting task in designing an effective

treatment regimen.

5.

The limited availability of ARV drugs and safe alternatives in resource poor countries further

add to the problem. The lack of monitoring for adverse events and poor access to therapeutic

drug monitoring facilities also interfere with effective ART management.

6.

Patients with pre-existing risk factors like obesity, fatty liver, psychiatric disorders, and

abnormal liver and renal functions are more likely to develop ADRs and require a close

monitoring. Presence of co-existing diseases like tuberculosis, anemia, diabetes mellitus and

hyperlipidemia further complicate therapy, affect compliance, increase chances of drug

interactions and overlapping toxicity. Clinical manifestations of intercurrent illness like

hepatitis A and malaria may often present as ARV drug toxicity and challenge the treatment.

Hence, it becomes difficult to differentiate between complications of HIV disease and ARV

toxicity as these may present with similar signs and symptoms.

1.

The success of HAART has increased the life expectancy of HIV patients. This has resulted into

increased number of patients over 50 years, living with HIV.[16] It is likely that these elderly

patients are exposed to broad range of concomitant medications along with ARV regimens.

However, the choice of these medications may not be always straightforward. The metabolic

side effects of these ART increase the risk of CVS disease.[10] The selection of antihypertensive

and antihyperlipidemic agents need extra care, and the most appropriate drug may not always

be a first line agent.

2.

Many ARVs are contraindicated or may require dose modification or adjustment in special

group of patients like pregnant women and children. Treatment of HIV-1 infected young

pediatric patients is a daunting task due to limited approval of appropriate pediatric drugs,

dosage formulations and fixed dose combinations. The safety and correct dosing of key ARVs

have not been established in young children, and appropriate child adapted formulations do

not exist.

3.

A pre-treatment counseling of patient and family members regarding the disease, strict

adherence to drug treatment, regular follow-up, changing the life style and dietary measures

are essential elements for successful treatment. All these require deep understanding and

co-operation from HIV patients that may be challenging in developing countries.

4.


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I. Nucleoside reverse transcriptase inhibitors (NRTIs)

Pharmacological Targets for Antiretroviral Drugs

A thorough understanding of life cycle of an HIV has identified potential pharmacological targets to

interfere with viral replication.[17] The key molecular events include virus entry, nuclear import,

reverse transcription, genomic integration and viral maturation [Figure 1]. Prior to entry of HIV into

the host cell, the virus envelope glycoprotein gp120 attaches to CD4 receptor on the host cell

membrane, undergoes conformational changes and interacts with chemokine receptors, such as CCR5

or CXCR4. This in turn allows insertion of gp41 subunit in the host cell membrane, resulting in fusion

of viral and host cell membrane. These interactions take place before an HIV enters into the host cell.

The viral entry has been recognized as an attractive point of interest and led to a novel drug class

known as entry inhibitors. Following an entry into the cell cytoplasm, the viral protein is transported

to the host cell nucleus. Reverse transcription of single stranded viral RNA into DNA takes place

within the pre-integrated complex in the nucleus of the host cell with the help of reverse transcriptase

(RT) enzyme. Reverse transcriptase inhibitors interfere with RT activity either by competing with the

natural substrates and incorporating into viral DNA to act as chain terminators in the synthesis of

proviral DNA or by allosteric inhibition of RT. HIV integrase enzyme processes the viral DNA into the

host genome to form the provirus. This step is an essential target for prospective new and novel class

of ARV drugs, the integrase inhibitors. The integrase inhibitors prevent the integration of viral DNA

into host cell chromosomes, inhibiting viral protein production. The HIV protease enzyme covers the

virus particles by protein layers, resulting into a fully mature and infective virus. Targeting protease

enzyme by Protease Inhibitors (PIs) has been an important target to disrupt the viral replication as it

result into immature and defective virus. A final and important stage for virus maturation involves

protein precursor, Gag, that induces major structural and morphological changes in the HIV particle.

A class of drug that inhibits processing of Gag protein disrupts the maturation process, known as

maturation inhibitors.

Existing Antiretroviral Drug Classes

Currently, there are 6 classes of ARV agents with 25 drugs approved for single drug treatment and 12

as fixed dose combination by US-FDA [Tables 1 and 2]. These drugs target 4 distinct proteins i.e. host

cell receptor, reverse transcriptase, integrase and protease to retard HIV replication. The conventional

classes of ARVs are nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse

transcriptase inhibitors (NNRTIs) and protease inhibitor (PIs). The recently approved newer groups

include fusion inhibitors, chemokine co receptor (CCR) antagonists and integrase inhibitors. The

agents with unique mechanisms under development are CD4 attachment inhibitors, maturation

inhibitors, lens epithelium derived growth factor inhibitors and capsid assembly inhibitors [Table 2].

NRTIs were the first to be approved and form the

backbone of an HIV treatment.[18] They are preferred as first line drugs because of favorable

pharmacokinetic profile, especially long intracellular half life, high oral bioavailability and

administration without regard to food, availability as fixed dose combinations (FDC) with convenient

once or twice daily dosage schedule and low risk for drug-drug interactions.[19]

However, NRTIs have low genetic barrier for drug resistance, and continued treatment is reported to

accumulate mutations that causes resistance and cross-resistance to agents within the class.

Moreover, the current drugs in this class are associated with bone marrow suppression and high

mitochondrial toxicity.[9] The potential to cause serious and irreversible toxicity increases with long

term use of stavudine. Hence, the recent WHO guidelines recommend a gradual phase out of

stavudine.[20] However, in developing countries, it is still widely used as first-line treatment because

of its low cost and an easy availability. Recently, the guidelines for the industrialized nations have

been revised by the US Department of Health and Human Services (DHHS) where tenofovir (TDF)


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a) Apricitabine (AVX754, formerly SPD754)

b) Elvucitabine

c) Amdoxovir

II. Non-nucleoside reverse transcriptase enzyme inhibitors (NNRTIs)

a) Etravirine (TMC 125)

and emtricitabine (FTC) combination is the preferred NRTI component in an initial regimen.[18,21]

This combination has shown superior virologic and immunologic response as compared to AZT + 3TC

and is also effective against hepatitis B virus with lower rate of lipotrophy as compared to stavudine

and AZT.[22] Although nephrotoxicity has been a concern with TDF, it is rare in treatment-naive

patients but requires a periodic monitoring of renal function. Even abacavir (ABC) has been stepped

down to alternative option on an initial therapy due to reports of high virologic failure,

hypersensitivity and cardiovascular risk, especially myocardial infarction.[23] The new agents

apricitabine and elvucitabine are currently being evaluated against HIV-1 isolates resistant to

conventional NRTIs.[24]

Apricitabine is a cytidine analogue, active against HIV-1,

isolates resistant to lamivudine, zidovudine and other NRTIs. Interestingly, the preclinical studies

have failed to demonstrate mitochondrial toxicity or any effect on mitochondrial DNA in high

doses.[25] It has been observed that apricitabine was effective in 50 treatment-experienced patients,

failing to respond to lamivudine or emtricitabine containing regimen. A phase II trial of 600 mg-800

mg apricitabine at 24 weeks demonstrated higher antiviral activity as compared to lamivudine

containing regimen.[26] The drug seems to be promising against NRTIs-resistant HIV strains for

treatment-experienced patients.

Elvucitabine is also a new cytidine analogue, active against HIV 1, and is compared to

lamivudine. A phase II trial at 48 weeks showed similar efficacy and safety profile in treatment-naive

patients as compared to 3TC.[27]

Amdoxovir is an investigational compound, having activity against HIV-1 isolates. It is

particularly designed and developed for use against the first line NRTI resistant HIV mutants with an

improved safety and efficacy. It is well-tolerated and shown to act synergistically in combination with

low and standard doses of AZT by significant reduction in viral load as compared to amdoxovir

alone.[28]

NNRTIs are an integral part of initial

treatment regimen along with 1 or 2 NRTIs and a PI.[29] In developing countries, nevirapine or

efavirenz is commonly included in an initial regimen due to their efficacy, low cost and convenient

dosage schedule. Nevirapine is also safe in pregnancy and has been extensively used to prevent

vertical transmission. However, nevirapine-based regimen has been reported to cause fatal cutaneous

hypersensitivity and hepatotoxicity.[30] In resource-rich countries, efavirenz is now preferred over

nevirapine in initial regimen as it is available as once a day formulation or as FDC along with

tenofovir and emtricitabine (TDF + FTC). Efavirenz has short term CNS side effects and is also

teratogenic. Moreover, both the drugs are a substrate for cytochrome enzyme (CYP 3A4) that results

into frequent interactions with drugs metabolized through same pathway.[18] Like NRTIs, NNRTIs

also have low genetic barrier to drug resistance. Even a single mutation may result into cross-

resistance.[8] Interestingly, virus isolates resistant to AZT or ddI can get selected and have shown

resistance to nevirapine or delaviridine.[31] It is also estimated that 5% to 7% of newly infected

patients already have NNRTI-resistant mutants. Hence, patients who fail to respond to one NNRTI

are not prescribed other NNRTI in future regimen. The limitations associated with first generation

NNRTIs have resulted into search for new agents that can take care of the critical issues.

Etravirine (ETV), a second generation NNRTI, has been approved by US-FDA.

An evaluation of its efficacy, safety and tolerability in treatment-experienced patients has been

promising. It has significant activity against first generation NNRTI-resistant HIV-1 virus with some

activity against HIV-2.[32] The drug is specially developed with a high genetic barrier to resistance

with unique genotypic resistance profile.[33] It is specially recommended for patients with


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b) Rilpivirine (TMC 278)

c) RDEA806

III. Protease inhibitors (PIs)

a) Atazanavir (ATV)

b) Tipranavir (TPV)

c) Darunavir (DRV)

documented NNRTI resistance.[32] The long half life, high barrier to resistance and good antiviral

efficacy of etravirine make it a major force in this class of drugs. However, it is also a substrate and

inhibitor of several CYP 3A4 enzymes, and therefore, contraindicated for use with anticonvulsants,

antimycobacterials and other NNRTIs.[18] It also requires dosage adjustment if used with drugs,

metabolized by CYP enzyme system.

Rilpivirine, an addition in the list of NNRTI, has also shown in vitro activity

against HIV resistant strains. It has been evaluated as an alternative to efavirenz in a phase III

clinical trial in the dose of 25 mg per day with TDF/FTC regimen. The convenient dosage schedule,

high genetic barrier to drug resistance, effectiveness against HIV strains resistant to conventional

NNRTIs, lack of antagonism with other ARV drugs and fewer adverse reactions are some important

characteristics of rilpivirine.[34]

This is a new NNRTI that has shown activity against HIV-1 resistant mutant in phase II

trials. Unlike other NNRTIs, it does not inhibit or induce cytochrome enzyme system.[35]

PIs have high genetic barrier for drug resistance, and the use of low dose

ritonavir as boosting agent is now considered as first line option for patients who do not respond to or

tolerate an initial treatment regimen.[18,21] However, the mutations that arise from selection

pressure from any PI can grant cross-resistance to other drugs in the same class. Most of the PIs

except nelfinavir are available with ritonavir boosting and have been approved and preferred options

for an initial ART by the US Department of Health and Human Services and International AIDS

society USA guidelines.[18,21] Low dose ritonavir as boosting agent has not only increased the utility

of PIs-based regimen but also opened a new area of research for novel class of drugs. The limitations

of PIs include insulin resistance, dyslipidemia, hypertriglyceridemia, high risk of coronary artery

disease and clinically significant interactions with antifungals, antimycobacterials, hormonal

contraceptives, HMG-coenzyme reductase inhibitors, antihistaminics, anticonvulsants, psychotropics,

ergot alkaloids and sedatives.[11]

Atazanavir is a second generation PI and is claimed to have a 20 times more potent

antiviral activity than other PIs.[36] Boosted ATV has been preferred over LPV/r in treatment-naive

and experienced patients due to once a day administration, convenient dosage schedule and minimal

effect on lipid profile.[37] The drug has similar pharmacological actions as other PIs, including

metabolism by cytochrome P450. It has also been reported to elevate serum transaminase levels and

cause hyperbilirubinemia, prolong PR interval and asymptomatic heart block.[38] Rare but serious

ADRs like S.J. syndrome and hepatotoxicity have also been reported. H receptor blockers and proton

pump inhibitors should be avoided as ATV requires acidic pH for complete absorption.

Tipranavir is a second generation PI, approved for use in patients with PI resistant

strains.[39] Its combination with NNRTIs and NRTIs is additive while with fusion inhibitor,

enfuviritide, it is observed to have the synergistic action. A phase III clinical trial of ritonavir-boosted

500 mg TPV showed superior virologic and immunologic response as compared to ritonavir-boosted

peptidomimetic PIs.[40] It requires 15-20 mutations in HIV protease gene to develop resistance to

TPV as compared to few mutations to peptidomimetic PIs.[41] It can be administered with high fat

meal and is metabolized by CYP 450 that may result into interactions.

Darunavir, a new non-peptidic PI, has been developed and studied for treatment-

experienced patients with PI-resistant mutations. The results of phase III clinical trials of riotnavir-

boosted darunavir (100 mg+600 mg twice daily) showed an improved virologic response and hence

the drug was approved for patients with multi-drug resistant HIV infection.[42] Several other studies

have also observed greater virologic and immunologic benefit with DRV as compared to standard PIs

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d) Brecanavir (GW 640385)

I. Entry inhibitors

i) Chemokine receptor inhibitors

a) CCR5 receptor inhibitors

for treatment-experienced patients with PI resistant mutations.[43] Darunavir has also been tested in

treatment-naive patients. A phase III clinical study, comparing darunavir (800 mg) plus ritonavoir

(100 mg) once a day or LPV/r once or twice a day along with TDF plus FTC, showed similar viral

suppression with minimal gastrointestinal and lipid side effects at 48 weeks.[44] Hence, darunavir is

now the preferred ritonavir-boosted PI for treatment–naive patients in developed countries.[18]

However, the incidence of lipid abnormalities with DRV use is similar to other PIs. Tipranavir and

darunavir have been approved as they have superior virologic and immunologic response as compared

to riotnavir-boosted PI. Both the drugs are specially recommended for use in treatment-experienced

patients, especially in presence of multi-drug resistant virus and documented treatment failure.[40]

Brecanavir, a new PI, has shown high activity against the PI resistant

strains of HIV-1 virus. Co-administration with ritonavir markedly increases an oral bioavailability.

However, its development has been stopped due to failure of drug formulation to achieve the effective

blood levels.

New Antiretroviral Drug Classes

The intricate details of viral entry and maturation process have identified new classes of ARV drugs,

especially entry inhibitors (chemokine receptor and fusion inhibitors) and integrase inhibitors. A few

of them are approved for clinical use, and many more are in pipeline. These drugs achieve high level

of viral suppression in patients with multi-drug resistant HIV-1, especially in a failing regimen.

Currently, their status is limited as add on therapy in highly treatment-experienced patients. Search

is also on to find new drugs acting on host cell receptors, which may provide a greater variety and

opportunity to disrupt viral replication. New classes with unique mechanism of action, which are

currently under development, are CD4 receptor attachment inhibitors, maturation inhibitors,

pharmacokinetic enhancers, capsid assembly inhibitors and lens epithelium derived growth factor

inhibitors [Table 3].

HIV-1 entry into the host cell is a multistep process, involving attachment of virus to

CD4 and chemokine receptors (CCR5 or CXCR4). A complex interaction between host cell receptors

and viral glycoprotein brings both viral and host cell membranes in close proximity, resulting into

fusion [Figure 2]. This knowledge has helped in identifying novel drug classes like fusion inhibitors

and chemokine receptor antagonists. Pharmacologically, sequential inhibition of the successive steps

of viral entry pathway by combination of fusion inhibitor and chemokine receptor blocker would result

into synergism.

The chemokine receptors, CCR5 and CXCR4 belong to G protein

coupled receptor family and help in activation and migration of T cells. HIV-1 isolates bind to a

specific co-receptor known as HIV tropism in order to gain an entry into host cell.[45] Commonly, R5

strains bind with CCR5 and X4 binds with CXCR4.[45] However, initially HIV-1 isolates use a single

co-receptor (most commonly CCR5), but as the disease progresses, other co-receptors (such as

CXCR4, CCR3 and CCR2b) are also detected. An interaction between HIV-1 and CCR5 can be

prevented by small molecule antagonists, monoclonal antibodies and modified natural CCR5 ligands.

Aplaviroc was the first CCR5 inhibitor and has been followed by maraviroc

and vicriviroc. Further evaluation of aplaviroc and vicriviroc has been discontinued due to adverse

reactions and poor antiviral activity, respectively. Initially, maraviroc was approved for use in

treatment-experienced patients, based on the results of phase III trials (MOTIVATE 1 and 2) with

better suppression of viral load at 48 and 96 weeks (150 mg to 300 mg once or twice a day) as

compared to placebo.[46,47] Investigations in treatment-naïve patients have demonstrated it to be

similar to efavirenz,[48] and therefore, the approval was expanded to include ART naïve patients with


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b) CXCR4 chemokine receptor inhibitors

ii) CCR5 antibodies

iii) Fusion inhibitors

a) Enfuvirtide (T-20)

b) Sifuviritide

CCR5 tropic virus. The drug is well-tolerated with minimal side effects like abdominal pain, asthenia

and postural hypotension. Maraviroc is a substrate for the CYP 3A4, and therefore, dose adjustment is

necessary when co-administered with other drugs that use the same pathway. A tropism testing is

also necessary prior to use of maraviroc as patients with CXCR4 or mixed HIV-1 do not respond well.

In addition, resistance patterns have already been observed with CCR5 inhibitors, either through

selection of minority variants of CXCR4 or a dual/mixed tropic virus or by development of

mutations.[49] This is potentially dangerous as CXCR4 tropic virus is associated with greater and

faster decline in CD4 counts.

AMD-070 is an investigational compound with potent in vitro

antiviral activity against wild type X4 virus but with no action against R5 tropic virus. The

development of CXCR4 compound has been slow as unlike CCR5, which is present in more than 50%

of HIV infected patients, X4 is found in mixtures with R5.[50] Hence, simple inhibition of CXCR4

may not be sufficient to decrease the plasma viral load substantially. On the other hand, combination

of CXCR4 and CCR5 would be more effective. Preliminary studies with AMD3100 showed inhibition

of the X4 component of the virus population, but further development of this parenterally

administered drug as an antiretroviral agent was discontinued due to QTc prolongation.

PRO140 is a humanized monoclonal antibody against chemokine receptor CCR5,

which inhibits R5 tropic HIV-1 at low concentration that does not affect natural action of CCR5.[51] It

received fast track status by the FDA in 2006. PRO140 acts by binding to an extracellular site on the

CCR5 co-receptor and prevents fusion of HIV-1 membrane with host cell and the subsequent infection

of healthy host cells.[45] In vitro studies have shown synergism between CCR5 inhibitors and

antibodies.[52]

A proof of concept study with a single intravenous infusion of PRO140 showed potent, rapid and

dose-dependent reduction of viral load of more than 10 fold, lasting for 2-3 weeks.[52] Significant

antiviral activity was also observed in a randomized, double blind trial as compared to placebo.[53]

Subcutaneous PRO140 has also been investigated with similar results. A Cochrane review on PRO140

concluded that although preliminary studies look promising, an evidence is insufficient, and larger

trials would be required to provide conclusive proof of efficacy in HIV infected patients.[54]

Enfuvirtide is the only fusion inhibitor approved by US FDA for treatment-

experienced patients who failed other antiretroviral therapy. It is a synthetic peptide and is

structurally similar to a section of gp41. It blocks the conformational changes in gp41 and hence

blocks an entry of virus in the host cell. An advantage of enfuvirtide over CCR5 inhibitors is that it

targets both R5 and X4 tropic virus. Enfuvirtide along with optimal background treatment (OBT) has

demonstrated significant antiviral activity in treatment-experienced patients at 24 weeks as compared

to patients receiving OBT alone.[55] It was also assessed as a part of multi-drug antiretroviral

regimen and has shown a greater decline in viral RNA load when combined with darunavir/ritonavir

(POWER 1 and 2), tipranavir,[56] tenofovir and zidovudine.[57] Hence, it is important as add on

therapy. An evaluation of enfuviritide in treatment-experienced children, adolescents and for

prevention of mother to child HIV transmission has been encouraging. The common ADRs are local

reaction due to subcutaneous administration and bacterial pneumonia.[55] Parenteral administration

of the drug, local site reactions, cost and inconvenience associated with its use place the drug in a

reserve category for patients when all treatment fails. Resistance to enfuviritide develops within a few

weeks due to mutation of HR1 region of gp41 as well as HR2 indicate low genetic barrier.[57]

Sifuviritide, an investigational fusion inhibitor, is more potent against HIV-1 than

enfuviritide. However, in vitro studies have reported an HIV variant resistant to sifuviritide due to


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c) T1249

II. Integrase inhibitors

a) Raltegravir

b) Elvitegravir (formerly GS-9137 and JTK-303)

c) GSK-1349572

III. Pharmacokinetic enhancers

specific mutations at gp120. The mutant viruses also demonstrated variable degrees of cross-

resistance to enfuvirtide, some of which are preferentially more resistant to sifuviritide.[58]

T1249, a second generation fusion inhibitor, is shown to be effective even against enfuvirtide

resistant HIV-1 strains as well as HIV-2 and simian immunodeficiency virus (SIV).

Integrase inhibitors inhibit strand transfer of viral DNA to host cell DNA. The

first agent ‘raltegravir’ has been approved by US-FDA for both treatment-experienced and naïve

patients. The rational for prescribing this drug in treatment-naïve patients is to preserve NNRTI and

PI for future regimens. The second drug ‘elvitegravir’ is undergoing phase III trials.

Raltegravir demonstrated significant antiviral activity against HIV isolates resistant to a

variety of antiretroviral drugs such as protease inhibitors, NRTIs and NNRTIs.[59] It is as effective as

efavirenz in reducing viral RNA count at 48 and 96 weeks.[60] Even in treatment-experienced

patients with documented virologic failure, a combination of raltegravir, etravirine and

darunavir/ritonavir demonstrated a decrease in HIV RNA count to <50 cells/ml in 90% and 86%

patients at 24 and 48 weeks, respectively.[61] Raltegravir is also shown to be non-inferior to

enfuvirtide in patients with multi-drug resistant HIV-1 infection who are averse to subcutaneous

injections of enfuvirtide.[61] Unlike PIs, it improves lipid profile, and the chances of interactions are

few as compared to other antiretrovirals.[62] Co-administration with atazanavir and tenofovir can

increase drug levels of raltegravir as both inhibit UGT1A1, which metabolizes raltegravir. This

interaction could be beneficial as the dose of raltegravir required can be decreased. Raltegravir has

potential for use at all stages of HIV treatment in treatment-experienced and naïve patients due to

significant antiviral activity, short term safety and tolerability and fewer chances for interactions.

Elvitegravir is a quinolone derivative with potent antiviral

activity. A difference between raltegravir and elvitegravir is that the former is metabolized by

glucuronidation and the latter is first metabolized by CYP 3A4/5. The clinical importance of this fact

is that co-administration of elvitegravir with ritonavir or any pharmacoenhancer results in almost 20

fold increase in plasma concentration, requiring only once-daily dose. A 10 day monotherapy in both

treatment-naïve and experienced patients (elvitegravir with ritonavir) has shown significant

reduction in HIV RNA levels. A randomized, phase II trial in treatment-experienced patients showed

that elvitegravir is as effective as boosted PI regimen at 48 weeks.[63]

However, integrase inhibitors have a low genetic barrier to resistance i.e. even a single mutation can

cause a decrease in susceptibility.[64] Failure of therapy due to resistance to raltegravir has been

demonstrated even in phase III trials.[65] Out of 105 patients who experienced virologic failure in the

BENCHMARK studies, 64 patients had genotypic experience of an integrase resistance.

GSK-1349572 (S/GSK-1349572), an investigational second generation integrase

inhibitor for oral treatment of HIV infection, displayed in vitro activity against integrase-resistant

HIV-1 isolates from patients experiencing virological failure while receiving raltegravir. The

pharmacokinetic profile of GSK-1349572 supports once-daily dosing without boosting with ritonavir.

In phase I and II clinical trials, side effects reported are similar to placebo and not related to the dose

or duration of treatment. Phase IIb trials of GSK-1349572 are being conducted in antiretroviral-naïve

and in experienced patients. With the high demand for second-generation integrase inhibitors for

antiretroviral experienced patients and once-daily dosing without ritonavir-boosting for

treatment-naïve patients, GSK-1349572 has the potential to become a highly valued product.[66]

The current strategy is to exploit the pharmacokinetic profile of one ARV

drug to enhance the therapeutic effect of the concomitant ARV drug. This has opened the possibility of

pharmacokinetic enhancers without having anti-HIV activity. Ritonavir is already being used


9 of 23 12/02/2013 2:01 PM

Cobicistat (GS-9350), SPI-452

IV. CD4 receptor attachment inhibitors

a) Ibalizumab (TNX-355)

V. HIV maturation inhibitors

a) Bevirimat (formerly PA-457)

VI. Lens epithelium derived growth factor inhibitor

extensively to boost other PIs. Surprisingly, it has been observed that ritonavir can also boost drugs in

other classes such as, elvitegravir (an integrase inhibitor) and vicriviroc (a CCR5 inhibitor). However,

ritonavir is associated with gastrointestinal intolerance, dyslipidemia and diabetes. Pharmacokinetic

enhancers are a major step towards identifying ritonavir alternatives.

Cobicistat and SPI-452 are 2 compounds under investigation.[67,68]

Cobicistat has no anti-HIV activity but is a potent inhibitor of CYP3A. It increases the blood level of

certain ARV drugs, allowing once-daily dosing. It is found to be safe and well-tolerated in escalating

single and multiple dose-ranging studies in healthy volunteers. It is under trial as a standalone

boosting agent for PIs, especially atazanavir and integrase inhibitor elvitegravir as FDC and found to

be comparable with ritonavir.[69] It also has a low potential to cause lipid and glucose abnormalities

than ritonavir. SPI-452 is another investigational pharmacokinetic enhancer without anti-HIV

activity. It is being investigated to increase the exposure of darunavir and atazanavir. Both the drugs

have been shown to enhance the plasma levels of PIs.[69]

The attachment of outer membrane gp120 to CD4 receptor is

inhibited by investigational compounds that constitute the new class of CD4 receptor attachment

inhibitors.

Ibalizumab, a humanized monoclonal IgG4 antibody against CD4 receptors,

was granted fast track status by US-FDA in 2003. It inhibits viral entry by attaching with

extracellular domain of CD4 receptors. The binding site is distinct from gp120 and is designed in a

way so as not to interfere with immunological function of CD4 receptors. Its novel mechanism of

action leads to potent antiviral activity in spite of HIV tropism and an unlikely cross-resistance with

other antiretrovirals.[70] A single dose, proof of concept study showed efficacy and tolerability of a

range of doses (0.3 mg/kg to 2 5 mg/kg). The greatest effect in reducing viral load and increase in

CD4 count is seen at 25 mg/kg. Adverse effects have been observed to be headache, rashes, nasal

congestion and urticaria. Similar efficacy was also seen in phase Ib study with once and twice a week

regimens.[71] A phase Ib study was found to decrease the HIV-RNA copy initially for 2 weeks,

however, the levels increased back towards baseline, indicating reduced susceptibility. It has also

shown synergistic effect with fusion inhibitors. Parenteral administration of the agent may be a

problem for regular use. The drug is under further evaluation.

This is an emerging class of drugs that targets internal structural protein

precursor Gag, which is vital in final stage of virus development for a mature and infectious virion.

Bevirimat is a novel agent that acts on the last and important stage of

HIV maturation before it buds from host cell. The primary target of the drug is gag polyprotein

precursor, the main structural protein of the assembly and budding of the viral particles. It prevents

the cleavage of the precursor protein to a mature viral capsid protein. This disrupts gag processing

and results in defective, immature, non-infectious viral particle.[72] The pharmacokinetic profile is

favorable with long half life and once a day dosing. A preliminary phase IIb trial in patients with

resistance to 3 antiretroviral drug classes has shown decline in plasma HIV-RNA level. The initial

results are encouraging, and it seems that maturation inhibitors may find a place in HIV therapeutics

in coming years. Bevirimat has been granted the fast track status by the FDA in 2005.

HIV-1 can integrate their DNA at different sites in host

DNA. During the pre-integration complex, the HIV integrase interacts and binds with host cell

factors. Researchers have identified lens epithelium derived growth factor (LEDGF) that directs HIV-1

DNA integration to different sites in host genome.[73] This interaction has been an interesting target

for antiviral therapy. Researchers used rational design to identify small molecules to fit the


10 of 23 12/02/2013 2:01 PM

VII. Capsid assembly inhibitors

a) PF-3450071 and PF-3450074

a) Microbicides

b) HIV Vaccine

interaction by a series of 2 - (quinoline-3-yl) acetic acid derivatives. These compounds have been

investigated as lens epithelium derived growth factor inhibitor.[74] It has been observed that

CX00287 moderately inhibits LEDGF and HIV replication in vitro. Further research is going on.

Capsid assembly inhibitors are a new class of drugs for treating HIV

infection. Virus capsid is made up of identical, symmetrically arranged protein blocks that maintain

the structure of the virus particle. It plays an important role in early and late stages of viral replication

and is essential for the survival and infectivity of the virus. Hence, virus capsid has been recognized as

a potential target for new class of ARV drugs. The molecule that inhibits the interactions between

structural proteins would affect the integrity and survival of the virus.

PF-3450071 and PF-3450074 act early in the HIV-1 replication cycle at a

step following HIV-1 envelope-mediated entry. Both the compounds were evaluated in single cycle

infection assays and in the viral production-infectivity assay, using NFV (PI) and EFV (NNRTI) as

late stage and early stage inhibitor controls. Both of them inhibited the production of infectious

virus.[75]

Preventive Measures for HIV Infection

Until recently, the prevention of HIV-1 infection has centered on the pregnant women to prevent

mother to child transmission of virus. The use of AZT and NVP to prevent neonatal HIV-1 infection

achieved considerable success in resource-rich countries. The idea of HIV-1 treatment as preventive

measure generated tremendous interest as it is believed to prevent or reduce the rate of sexual

transmission of virus to uninfected partner. A number of population-based prevention studies are

currently under pilot or at planning stage.[76,77] In addition to drug treatment, the current HIV

prevention measures also include behavioral messages such as, “ABC” approach (Abstinence, Be

faithful, Condom use). However, they have limited impact on the incidence rate of HIV in women. A

search for prevention techniques that can be easily used by women, effective in presence of seminal

fluid, compatible with latex and acceptable to all partners is underway.

Microbicides are used for an application in vagina and rectum to prevent transmission

of sexual transmitted diseases including HIV. They are also called topical pre-exposure prophylaxis

(PrEP). Agents that can disrupt viral membrane, surfactants, especially 9-non-oxynol, anionic

polymers etc., have been tested, but results have generally been disappointing. Tenofovir disoproxil

has been tested in a gel formulation as a vaginal microbicide. In vitro and in vivo studies have

demonstrated its efficacy both as pre-exposure and post-exposure prophylaxis. The CAPRISA004 trial

has shown tenofovir to decrease an HIV infection in uninfected women by 39% when applied

vaginally in 2 doses over a period of 24 hours.[78] Efficacy of an oral tenofovir with emtricitabine has

also been tested with positive results i.e. 44% reduction in HIV transmission.[79] CDC has already

recommended the use of this combination for prophylaxis. Similarly, trials studying the efficacy and

safety of combined oral and topical tenofovir are also going on. An NNRTI being developed as a

vaginal gel is dapivirine, which has demonstrated efficacy in in vitro studies.[80] However, the

advent of PrEP has raised issues like the use of drugs in uninfected individuals, increased chances of

risky sexual behavior (complacency), an adherence of the patient, resistance to antiretrovirals,

acceptability of drugs with substantial ADRs and cost of the regimen that need to be addressed.[78]

Hence, PrEP can only be an adjunct along with behavioral change therapy.

The development of vaccine against an HIV is considered to be worthwhile as majority

of the patients live in developing countries and cannot afford treatment, lifelong therapy, side effects

and problems of multi-drug resistance. While a lot of research is being done, it is not without pitfalls.

None of the vaccines tested so far has been successful, the main problems being diversity of the virus,


11 of 23 12/02/2013 2:01 PM

an ability of the virus to elude the immune system and lack of animal models.[81] The STEP study

tested the efficacy of recombinant Ad5 HIV-1 vaccine (viral vector carrying HIV-1 gag, pol and env

antigens), but lack of efficacy and an increased HIV-1 acquisition in some subjects lead to premature

termination of the trial.[82]

Conclusion

Current antiretroviral drugs are highly effective, but drug resistance, drug-drug interactions, long

term adverse events and compliance continue to be a challenge. New agents in conventional classes

have revived the hopes for treatment-naïve and experienced patients. Promising new agents offer new

choices as second line treatment options for treatment-experienced patients. However, an impact of

their long term use on drug safety and drug-drug interactions is yet to be assessed. Several agents in

entirely novel classes are under an investigation. However, none of the new agents have shown to

eradicate the virus and is free from adverse events. Hence, there is a need for continuing search for

novel drugs and to optimally utilize the available drugs to combat multi-drug resistant strains and

eliminate virus replication. Parallel to HIV treatment, ARVs have also been shown to reduce the rate

of sexual transmission of HIV-1. Thus, ARVs are recommended for pre-exposure prophylaxis to

prevent HIV transmission through sexual contact. Making available an effective microbicide or

vaccine that prevents HIV-1 acquisition still remains a major area of further research.

Footnotes

Source of Support: Nil

Conflict of Interest: None declared.

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Figures and Tables


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Figure 1

Key molecular events in life cycle of Human Immunodeficiency Virus and pharmacological targets


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Table 1

Antiretroviral drugs approved by the US FDA


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Table 2

Fixed dose combinations of Antiretroviral drugs approved by US FDA


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Table 3

List of novel antiretroviral drugs and HIV targets


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Figure 2

Multistep process of viral entry pathway

Articles from Indian Journal of Pharmacology are provided here courtesy of Medknow Publications


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antiretroviral drugs_ critical issues and recent advances

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