Antiretroviral Drugs_ Critical Issues and Recent Advances
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Transcript of 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
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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
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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
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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,
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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
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