Educational Forum

Antiretroviral drugs: Critical issues and recent advances

Mira Desai, Geetha Iyer, R.K. Dikshit

ABSTRACT

Human immunodeficiency virus (HIV) 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 Department of Pharmacology, interactions and . A clear understanding of the viral replication and its B J Medical College, interaction with host cell factors has led to the development of a large number of effective Ahmedabad, India antiretroviral drugs (ARVs). New drugs in the existing class such as , and have shown promising results against HIV isolates resistant to first line drugs. Received: 01-03-2012 These drugs have offered a new choice for patients with drug resistant disease. However, Revised: 05-03-2012 the impact of their long term use on safety is yet to be assessed. Novel drugs with unique Accepted: 10-03-2012 mechanism of action such as CD4 receptor attachment inhibitors, maturation inhibitors, pharmacokinetic enhancers, capsid assembly inhibitors and lens epithelium derived growth Correspondence to: factor inhibitors are still under development. Currently, ARVs, especially tenofovir and Dr. Mira Desai, , are also being evaluated for prevention of sexual transmission of HIV-1. The E-mail: [email protected] 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 continued search for different drug combinations, preferential change in first line drugs and identification of novel drugs A significant advancement in the understanding of an HIV has been a boon for an effective viral suppression. However, replication and its pathogenesis has helped in the identification the success of the drug treatment is achieved at the cost of of different pharmacological targets. This has resulted into life threatening adverse drug effects, drug-drug interactions availability of a large number of antiretroviral (ARV) drugs. The and an inconvenience of lifelong therapy. Since the disease antiretroviral therapy (ART) has evolved from monotherapy has stepped into its 3rd decade, there are several treatment- with azidothymidine (AZT) to combination of 2 ARVs from experienced patients living either with drug toxicity or facing nucleoside reverse transcriptase inhibitors (NRTIs) to highly the threat of treatment failure due to a multi-drug resistance. active antiretroviral therapy (HAART). The triple therapy has Moreover, there is likelihood of newly infected untreated resulted into significant improvement in an immune status, patients harboring HIV mutants that are already resistant to quality of life, and reduced morbidity and mortality associated commonly used ARV drugs.[2] Thus, there are many critical with HIV infection.[1] With the advent of the different drug issues associated with the use of ARV drugs that need to regimens, the disease scenario has changed from a ‘virtual be addressed. In addition, a great deal of attention has also death sentence’ to a ‘chronic manageable disease’. The been focused on prevention of an HIV infection through sexual contact. This article is an attempt to discuss the key issues Access this article online with ARV drugs, review the new agents in existing classes and Quick Response Code: also the novel drugs under development. Website: www.ijp-online.com

DOI: 10.4103/0253-7613.96296 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.

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HIV related factors The use of over the counter drugs and herbal drugs may 1. HIV, a retrovirus, multiplies at a rate of approximately 1010 potentially compromise the management.[14] copies per day. At such a high rate of replication, the virus 4. Reduction of the plasma viremia to undetectable levels often commits mistakes and results into mutants.[3] High strongly correlates with strict adherence to ARV regimen mutation rate leads to development of multiple strains and that includes taking multiple drugs twice or thrice a day threatens the development of drug resistance. for rest of life. The recommended practice to combine 3 or 2. Once infected, the virus becomes an integral part of host more drugs from different classes of ART results in high pill cell and survives the full life span of infected host cell,[4] count that, along with toxicities, may cause inconvenience especially in T-lymphocytes and urogenital secretions. to the patient and poor adherence.[15] Surprisingly, despite a complete plasma 5. All classes of ARVs demonstrate the in vivo resistance. [2] suppression for 6-12 months, the virus remains detectable However, the rate of development of drug resistance in seminal fluid and more often than not, these are drug differs amongst them. Non--containing NRTI/ resistant variants.[5] The existence of virus in potential NtRTI combination regimens and NNRTIs have a low ‘reservoirs’ and the subsequent replication may cause genetic barrier to resistance; thereby, they require fewer relapse following cessation of ART, necessitating lifelong critical mutations to render the treatment ineffective. Drug treatment.[6] Different treatment strategies have been resistance is not only associated with rapid virologic failure tried for the persistent forms, but to date, no clinical or but also present the daunting task in designing an effective virological benefit has been reported.[7] treatment regimen. 3. Increasing reports of multi-drug resistant (MDR) virus 6. The limited availability of ARV drugs and safe alternatives in treatment-experienced patients are also being in resource poor countries further add to the problem. The encountered.[8] lack of monitoring for adverse events and poor access to ARV related factors therapeutic drug monitoring facilities also interfere with 1. Attempts to eradicate the virus from the ‘reservoir’ have effective ART management. failed despite intensifying the ARV treatment, implying that Host related factors drugs cannot reach in adequate concentration in the latent 1. Patients with pre-existing risk factors like obesity, fatty reservoir cells.[7] liver, psychiatric disorders, and abnormal liver and renal 2. Each class of ARV drugs has the potential to cause toxicities, functions are more likely to develop ADRs and require a many of which are shared by drugs likely to be used close monitoring. Presence of co-existing diseases like concomitantly in HIV positive patients. This complicates tuberculosis, anemia, diabetes mellitus and hyperlipidemia the treatment, causes difficulty in causality assessment and further complicate therapy, affect compliance, increase may require treatment withdrawal in serious life threatening chances of drug interactions and overlapping toxicity. reactions. Long term use of HAART has been reported Clinical manifestations of intercurrent illness like hepatitis to produce morphologic and metabolic abnormality A and malaria may often present as ARV drug toxicity and syndrome, especially hypertriglyceridemia (HTG).[9] This challenge the treatment. Hence, it becomes difficult to in turn has increased the risk of cardiovascular (CVS) and differentiate between complications of HIV disease and cerebrovascular diseases in patients receiving ART.[10] ARV toxicity as these may present with similar signs and 3. Clinically significant drug-drug interactions, frequently symptoms. seen in patients on ART, can adversely affect the patient 2. The success of HAART has increased the life expectancy of care and complicate ART. Interactions have been observed HIV patients. This has resulted into increased number of in 14% to 26% of HIV infected patients in USA and patients over 50 years, living with HIV.[16] It is likely that these Netherlands.[11,12] The therapeutic risk of interactions is elderly patients are exposed to broad range of concomitant due to potent induction or inhibition of cytochrome P450 along with ARV regimens. However, the choice (CYP450) isoenzyme, which also metabolizes a number of of these medications may not be always straightforward. other medications. On the other hand, the evaluation of The metabolic side effects of these ART increase the risk the potential interactions during clinical trials is mostly of CVS disease.[10] The selection of antihypertensive and incomplete and becomes evident only during drug therapy. antihyperlipidemic agents need extra care, and the most Further, the drugs belonging to same class also differ in appropriate drug may not always be a first line agent. their potential to cause the interactions. For example, first 3. Many ARVs are contraindicated or may require dose licensed , is predominantly modification or adjustment in special group of patients metabolized by UGT1A1- medicated glucoronidation with like pregnant women and children. Treatment of HIV-1 little potential to interact with CYP450 enzymes, whereas infected young pediatric patients is a daunting task due is largely metabolized by CYP3A4.[13] Moreover, to limited approval of appropriate pediatric drugs, dosage boosting effect is due to inhibition of CP450 formulations and fixed dose combinations. The safety and 3A4 enzyme, but it also inhibits other CYP isoenzymes correct dosing of key ARVs have not been established in and is an inducer of several liver enzymes, resulting into young children, and appropriate child adapted formulations complicated pharmacokinetic interactions with other drugs. do not exist. The drug treatment of co-existing medical disease (s) 4. A pre-treatment counseling of patient and family members and opportunistic can also complicate the ART. regarding the disease, strict adherence to drug treatment,

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regular follow-up, changing the life style and dietary enzyme processes the viral DNA into the host genome to form measures are essential elements for successful treatment. the provirus. This step is an essential target for prospective All these require deep understanding and co-operation new and novel class of ARV drugs, the integrase inhibitors. from HIV patients that may be challenging in developing The integrase inhibitors prevent the integration of viral DNA countries. into host cell chromosomes, inhibiting viral protein production. The HIV protease enzyme covers the virus particles by protein Pharmacological Targets for Antiretroviral Drugs layers, resulting into a fully mature and infective virus. Targeting A thorough understanding of life cycle of an HIV has protease enzyme by Protease Inhibitors (PIs) has been an identified potential pharmacological targets to interfere with important target to disrupt the viral replication as it result into viral replication.[17] The key molecular events include virus entry, immature and defective virus. A final and important stage for nuclear import, reverse transcription, genomic integration and virus maturation involves protein precursor, Gag, that induces viral maturation [Figure 1]. Prior to entry of HIV into the host major structural and morphological changes in the HIV particle. cell, the virus envelope glycoprotein gp120 attaches to CD4 A class of drug that inhibits processing of Gag protein disrupts receptor on the host cell membrane, undergoes conformational the maturation process, known as maturation inhibitors. changes and interacts with chemokine receptors, such as CCR5 or CXCR4. This in turn allows insertion of subunit in the Existing Antiretroviral Drug Classes host cell membrane, resulting in fusion of viral and host cell Currently, there are 6 classes of ARV agents with 25 membrane. These interactions take place before an HIV enters drugs approved for single drug treatment and 12 as fixed into the host cell. The viral entry has been recognized as an dose combination by US-FDA [Tables 1 and 2]. These drugs attractive point of interest and led to a novel drug class known target 4 distinct proteins i.e. host cell receptor, reverse as entry inhibitors. Following an entry into the cell cytoplasm, transcriptase, integrase and protease to retard HIV replication. the viral protein is transported to the host cell nucleus. Reverse The conventional classes of ARVs are nucleoside reverse transcription of single stranded viral RNA into DNA takes transcriptase inhibitors (NRTIs), non-nucleoside reverse place within the pre-integrated complex in the nucleus of the transcriptase inhibitors (NNRTIs) and protease inhibitor host cell with the help of reverse transcriptase (RT) enzyme. (PIs). The recently approved newer groups include fusion Reverse transcriptase inhibitors interfere with RT activity either inhibitors, chemokine co receptor (CCR) antagonists and by competing with the natural substrates and incorporating integrase inhibitors. The agents with unique mechanisms into viral DNA to act as chain terminators in the synthesis of under development are CD4 attachment inhibitors, maturation proviral DNA or by allosteric inhibition of RT. HIV integrase inhibitors, lens epithelium derived growth factor inhibitors and capsid assembly inhibitors [Table 2]. Figure 1: Key molecular events in life cycle of Human Immunodeficiency I. Nucleoside reverse transcriptase inhibitors (NRTIs) Virus and pharmacological targets NRTIs were the first to be approved and form the backbone [18] Exposure to infected body fluids/blood of an HIV treatment. They are preferred as first line drugs (via sexual contact, vertical transmission) because of favorable pharmacokinetic profile, especially long intracellular half life, high oral and administration without regard to food, availability as fixed dose combinations Target 1 Binding of viral glycoproteins (gp120 and 41) to √ CCR5 inhibitors corresponding receptor on target cells (CD4 and (FDC) with convenient once or twice daily dosage schedule and √ coreceptor) Fusion Inhibitors [19] √ Attachment Inhibitors Virus entry into target cells (CD4 cells) by fusion of low risk for drug-drug interactions. √ Monoclonal antibodies viral and cell membranes However, NRTIs have low genetic barrier for drug resistance, and continued treatment is reported to accumulate mutations

Target 2 that causes resistance and cross-resistance to agents within the √ Nucleoside and class. Moreover, the current drugs in this class are associated Nucleotide Reverse Transcriptase Inhibitors Formation of viral cDNA with the help of [9] reverse transcriptase with bone marrow suppression and high mitochondrial toxicity. √ Nonnucleoside Reverse Transcriptase Inhibitors The potential to cause serious and irreversible toxicity increases with long term use of . Hence, the recent WHO Target 3 [20] √ Integrase inhibitors Integration of cDNA into host genome by guidelines recommend a gradual phase out of stavudine. integrase enzyme 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 Replication of viral particles : genetic and structural proteins been revised by the US Department of Health and Human

Host Cell Services (DHHS) where tenofovir (TDF) and emtricitabine (FTC) combination is the preferred NRTI component in an initial Target 4 [18,21] √ Protease inhibitors Viral expression and maturation by regimen. This combination has shown superior virologic and protease enzyme immunologic response as compared to AZT + 3TC and is also effective against with lower rate of lipotrophy Target 5 [22] Budding of mature and highly infectious as compared to stavudine and AZT. Although nephrotoxicity √ Maturation inhibitors viral particles has been a concern with TDF, it is rare in treatment-naive patients but requires a periodic monitoring of renal function.

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Table 1:

Antiretroviral drugs approved by the US FDA

Categories NRTIs NNRTIs PIs Entry Inhibitors Integrase (CCR5 and Fusion Inhibitors inhibitors) Treatment naïve patients (AZT) Ritonavir (RTV) - - Stavudine (d4T) (NVP) (IDV) (3TC) Delviradine (SQV) (ddI) (DLV) (NFV) (ddC) (EFV) (APV) (ABC) () (FPV) (ATV) Treatment experienced Tenofovir (TDF)* Etravirine (TPV) * Raltegravir* patients Emtricitabine (FTC)* (ETV) * (DRV) Prevention of vertical Zidovudine Nevirapine - - - transmission (WHO Lamivudine Efavirenz guidelines) Tenofovir Emtrictabine Children Zidovudine Nevirapine Ritonavir Enfuvirtide - Stavudine Nelfinavir Lamivudine Darunavir Didanosine Emtricitabine Abacavir For post exposure Zidovudine (AZT) Efavirenz Indinavir Enfuvirtide - prophylaxis Stavudine (d4T) Nelfinavir Lamivudine (3TC) Ritonavir Didanosine (ddI) Saquinavir Emtricitabine (FTC) Fosamprenavir Tenofovir (TDF) Atazanavir Ritonavir/ For pre exposure Tenofovir and prophylaxis Emtricitabine in MSM *Approved for both treatment naïve and treatment experienced patients MSM – Men who have sex with men NRTI = Nucleoside Reverse Transcriptase Inhibitors; NNRTI = Non Nucleoside Reverse Transcriptase Inhibitors; PI = Protease Inhibitors

Table 2: myocardial infarction.[23] The new agents apricitabine and Fixed dose combinations of Antiretroviral drugs approved by elvucitabine are currently being evaluated against HIV-1 isolates [24] US FDA resistant to conventional NRTIs. a) Apricitabine (AVX754, formerly SPD754) Approved for adult use Approved for pediatric use Apricitabine is a analogue, active against HIV-1,

Zidovudine + Lamivudine Zidovudine + Lamivudine isolates resistant to lamivudine, zidovudine and other NRTIs. Zidovudine + Lamivudine + Nevirapine Stavudine + Lamivudine Interestingly, the preclinical studies have failed to demonstrate Stavudine + Lamivudine Ritonavir + Lopinavir mitochondrial toxicity or any effect on mitochondrial DNA in high Stavudine + Lamivudine + Nevirapine doses.[25] It has been observed that apricitabine was effective Abacavir + Lamivudine in 50 treatment-experienced patients, failing to respond to Zidovudine + Abacavir + Lamivudine lamivudine or emtricitabine containing regimen. A phase II Lamivudine + Tenofovir trial of 600 mg-800 mg apricitabine at 24 weeks demonstrated Lamivudine + Tenofovir + Efavirenz higher antiviral activity as compared to lamivudine containing Tenofovir + Emtricitabine regimen.[26] The drug seems to be promising against NRTIs- Tenofovir + Emtricitabine + Efavirenz Ritonavir + Lopinavir resistant HIV strains for treatment-experienced patients. Amprenavir + Ritonavir b) Elvucitabine Elvucitabine is also a new cytidine analogue, active Even abacavir (ABC) has been stepped down to alternative against HIV 1, and is compared to lamivudine. A phase II option on an initial therapy due to reports of high virologic trial at 48 weeks showed similar efficacy and safety profile in failure, hypersensitivity and cardiovascular risk, especially treatment-naive patients as compared to 3TC.[27]

Indian Journal of Pharmacology | June 2012 | Vol 44 | Issue 3 291 Desai, et al.: Advances in antiretroviral drugs c) conventional NNRTIs, lack of antagonism with other ARV drugs Amdoxovir is an investigational compound, having activity and fewer adverse reactions are some important characteristics against HIV-1 isolates. It is particularly designed and developed of rilpivirine.[34] for use against the first line NRTI resistant HIV mutants with c) RDEA806 an improved safety and efficacy. It is well-tolerated and shown This is a new NNRTI that has shown activity against HIV-1 to act synergistically in combination with low and standard resistant mutant in phase II trials. Unlike other NNRTIs, it does doses of AZT by significant reduction in viral load as compared not inhibit or induce cytochrome enzyme system.[35] to amdoxovir alone.[28] III. Protease inhibitors (PIs) II. Non-nucleoside reverse transcriptase enzyme inhibitors PIs have high genetic barrier for drug resistance, and the (NNRTIs) use of low dose ritonavir as boosting agent is now considered NNRTIs are an integral part of initial treatment regimen as first line option for patients who do not respond to or tolerate [29] along with 1 or 2 NRTIs and a PI. In developing countries, an initial treatment regimen.[18,21] However, the mutations that nevirapine or efavirenz is commonly included in an initial arise from selection pressure from any PI can grant cross- regimen due to their efficacy, low cost and convenient resistance to other drugs in the same class. Most of the PIs dosage schedule. Nevirapine is also safe in pregnancy and except nelfinavir are available with ritonavir boosting and have has been extensively used to prevent vertical transmission. been approved and preferred options for an initial ART by the However, nevirapine-based regimen has been reported to US Department of Health and Human Services and International [30] cause fatal cutaneous hypersensitivity and . AIDS society USA guidelines.[18,21] Low dose ritonavir as In resource-rich countries, efavirenz is now preferred over boosting agent has not only increased the utility of PIs-based nevirapine in initial regimen as it is available as once a day regimen but also opened a new area of research for novel formulation or as FDC along with tenofovir and emtricitabine class of drugs. The limitations of PIs include insulin resistance, (TDF + FTC). Efavirenz has short term CNS side effects and dyslipidemia, hypertriglyceridemia, high risk of coronary artery is also teratogenic. Moreover, both the drugs are a substrate disease and clinically significant interactions with antifungals, for cytochrome enzyme (CYP 3A4) that results into frequent antimycobacterials, hormonal contraceptives, HMG-coenzyme interactions with drugs metabolized through same pathway. [18] reductase inhibitors, antihistaminics, anticonvulsants, Like NRTIs, NNRTIs also have low genetic barrier to drug psychotropics, ergot alkaloids and sedatives.[11] resistance. Even a single mutation may result into cross- resistance.[8] Interestingly, virus isolates resistant to AZT or a) Atazanavir (ATV) ddI can get selected and have shown resistance to nevirapine Atazanavir is a second generation PI and is claimed to have [36] or delaviridine.[31] It is also estimated that 5% to 7% of newly a 20 times more potent antiviral activity than other PIs. infected patients already have NNRTI-resistant mutants. Hence, Boosted ATV has been preferred over LPV/r in treatment-naive patients who fail to respond to one NNRTI are not prescribed and experienced patients due to once a day administration, other NNRTI in future regimen. The limitations associated with convenient dosage schedule and minimal effect on lipid first generation NNRTIs have resulted into search for new agents profile.[37] The drug has similar pharmacological actions as that can take care of the critical issues. other PIs, including metabolism by cytochrome P450. It has also been reported to elevate serum transaminase levels and cause a) Etravirine (TMC 125) hyperbilirubinemia, prolong PR interval and asymptomatic Etravirine (ETV), a second generation NNRTI, has been heart block.[38] Rare but serious ADRs like S.J. syndrome and approved by US-FDA. An evaluation of its efficacy, safety hepatotoxicity have also been reported. H receptor blockers and tolerability in treatment-experienced patients has been 2 promising. It has significant activity against first generation and proton pump inhibitors should be avoided as ATV requires NNRTI-resistant HIV-1 virus with some activity against HIV- acidic pH for complete absorption. 2. [32] The drug is specially developed with a high genetic barrier b) Tipranavir (TPV) to resistance with unique genotypic resistance profile.[33] It is Tipranavir is a second generation PI, approved for use in specially recommended for patients with documented NNRTI patients with PI resistant strains.[39] Its combination with NNRTIs resistance.[32] The long half life, high barrier to resistance and and NRTIs is additive while with fusion inhibitor, enfuviritide, it good antiviral efficacy of etravirine make it a major force in is observed to have the synergistic action. A phase III clinical this class of drugs. However, it is also a substrate and inhibitor trial of ritonavir-boosted 500 mg TPV showed superior virologic of several CYP 3A4 enzymes, and therefore, contraindicated and immunologic response as compared to ritonavir-boosted for use with anticonvulsants, antimycobacterials and other peptidomimetic PIs.[40] It requires 15-20 mutations in HIV NNRTIs.[18] It also requires dosage adjustment if used with drugs, protease gene to develop resistance to TPV as compared to few metabolized by CYP enzyme system. mutations to peptidomimetic PIs.[41] It can be administered with b) Rilpivirine (TMC 278) high fat meal and is metabolized by CYP 450 that may result Rilpivirine, an addition in the list of NNRTI, has also shown into interactions. in vitro activity against HIV resistant strains. It has been c) Darunavir (DRV) evaluated as an alternative to efavirenz in a phase III clinical Darunavir, a new non-peptidic PI, has been developed and trial in the dose of 25 mg per day with TDF/FTC regimen. studied for treatment-experienced patients with PI-resistant The convenient dosage schedule, high genetic barrier to drug mutations. The results of phase III clinical trials of riotnavir- resistance, effectiveness against HIV strains resistant to boosted darunavir (100 mg+600 mg twice daily) showed an

292 Indian Journal of Pharmacology | June 2012 | Vol 44 | Issue 3 Desai, et al.: Advances in antiretroviral drugs improved virologic response and hence the drug was approved Search is also on to find new drugs acting on host cell receptors, for patients with multi-drug resistant HIV infection.[42] Several which may provide a greater variety and opportunity to disrupt other studies have also observed greater virologic and viral replication. New classes with unique mechanism of action, immunologic benefit with DRV as compared to standard PIs for which are currently under development, are CD4 receptor treatment-experienced patients with PI resistant mutations.[43] attachment inhibitors, maturation inhibitors, pharmacokinetic Darunavir has also been tested in treatment-naive patients. enhancers, capsid assembly inhibitors and lens epithelium A phase III clinical study, comparing darunavir (800 mg) plus derived growth factor inhibitors [Table 3]. ritonavoir (100 mg) once a day or LPV/r once or twice a day I. Entry inhibitors along with TDF plus FTC, showed similar viral suppression with HIV-1 entry into the host cell is a multistep process, involving [44] minimal gastrointestinal and lipid side effects at 48 weeks. attachment of virus to CD4 and chemokine receptors (CCR5 or Hence, darunavir is now the preferred ritonavir-boosted PI for CXCR4). A complex interaction between host cell receptors and treatment–naive patients in developed countries.[18] However, viral glycoprotein brings both viral and host cell membranes in the incidence of lipid abnormalities with DRV use is similar close proximity, resulting into fusion [Figure 2]. This knowledge to other PIs. Tipranavir and darunavir have been approved has helped in identifying novel drug classes like fusion inhibitors as they have superior virologic and immunologic response and chemokine receptor antagonists. Pharmacologically, as compared to riotnavir-boosted PI. Both the drugs are sequential inhibition of the successive steps of viral entry specially recommended for use in treatment-experienced pathway by combination of fusion inhibitor and chemokine patients, especially in presence of multi-drug resistant virus and documented treatment failure.[40] Figure 2: Multistep process of viral entry pathway d) (GW 640385) 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.

Table 3:

List of novel antiretroviral drugs and HIV targets

Drug Group Name of the drug Target Current status Fusion Inhibitors Enfuvirtide gp41 subunit of envelop protein Approved in 2003 CCR5 inhibitors Maraviroc Small molecule CCR5 receptor antagonist Approved in 2007 Trials discontinued due to hepatotoxicity Trials discontinued due to poor antiviral activity PRO140 Monoclonal antibody against CCR5 receptors Completed phase II clinical trials Integrase inhibitors Raltegravir Integrase enzyme Approved in 2007 Elvitegravir Undergoing phase III clinical trials Attachment inhibitors Monoclonal antibody against CD4 receptors Completed phase II clinical trials of host cells Maturation inhibitors gag structural protein Completed phase II trials Lens epithelium CX00287 Block the interaction of LEDGF/p75 with Under development derived growth factor integrase enzyme of HIV-1, prevents inhibitors integration of proviral DNA Capsid Inhibitors PF-3450071 Inhibitor of HIV-1gag polypeptide assembly Under development PF-3450074 and also dismantles assembled HIV-1 caspid assembly tubes

Indian Journal of Pharmacology | June 2012 | Vol 44 | Issue 3 293 Desai, et al.: Advances in antiretroviral drugs receptor blocker would result into synergism. shown synergism between CCR5 inhibitors and antibodies.[52] i) Chemokine receptor inhibitors A proof of concept study with a single intravenous The chemokine receptors, CCR5 and CXCR4 belong to G infusion of PRO140 showed potent, rapid and dose-dependent protein coupled receptor family and help in activation and reduction of viral load of more than 10 fold, lasting for 2-3 migration of T cells. HIV-1 isolates bind to a specific co-receptor weeks.[52] Significant antiviral activity was also observed in known as HIV tropism in order to gain an entry into host a randomized, double blind trial as compared to placebo.[53] cell.[45] Commonly, R5 strains bind with CCR5 and X4 binds Subcutaneous PRO140 has also been investigated with similar with CXCR4.[45] However, initially HIV-1 isolates use a single co- results. A Cochrane review on PRO140 concluded that although receptor (most commonly CCR5), but as the disease progresses, preliminary studies look promising, an evidence is insufficient, other co-receptors (such as CXCR4, CCR3 and CCR2b) are and larger trials would be required to provide conclusive proof also detected. An interaction between HIV-1 and CCR5 can of efficacy in HIV infected patients.[54] be prevented by small molecule antagonists, monoclonal iii) Fusion inhibitors antibodies and modified natural CCR5 ligands. a) Enfuvirtide (T-20) a) CCR5 receptor inhibitors Enfuvirtide is the only fusion inhibitor approved by US Aplaviroc was the first CCR5 inhibitor and has been followed FDA for treatment-experienced patients who failed other by maraviroc and vicriviroc. Further evaluation of aplaviroc and antiretroviral therapy. It is a synthetic peptide and is structurally vicriviroc has been discontinued due to adverse reactions and similar to a section of gp41. It blocks the conformational poor antiviral activity, respectively. Initially, maraviroc was changes in gp41 and hence blocks an entry of virus in the approved for use in treatment-experienced patients, based host cell. An advantage of enfuvirtide over CCR5 inhibitors is on the results of phase III trials (MOTIVATE 1 and 2) with that it targets both R5 and X4 tropic virus. Enfuvirtide along better suppression of viral load at 48 and 96 weeks (150 mg with optimal background treatment (OBT) has demonstrated to 300 mg once or twice a day) as compared to placebo.[46,47] significant antiviral activity in treatment-experienced patients Investigations in treatment-naïve patients have demonstrated at 24 weeks as compared to patients receiving OBT alone.[55] it to be similar to efavirenz,[48] and therefore, the approval It was also assessed as a part of multi-drug antiretroviral was expanded to include ART naïve patients with CCR5 tropic regimen and has shown a greater decline in viral RNA load virus. The drug is well-tolerated with minimal side effects like when combined with darunavir/ritonavir (POWER 1 and 2), abdominal pain, asthenia and postural hypotension. Maraviroc tipranavir,[56] tenofovir and zidovudine.[57] Hence, it is important is a substrate for the CYP 3A4, and therefore, dose adjustment as add on therapy. An evaluation of enfuviritide in treatment- is necessary when co-administered with other drugs that use experienced children, adolescents and for prevention of mother the same pathway. A tropism testing is also necessary prior to child HIV transmission has been encouraging. The common to use of maraviroc as patients with CXCR4 or mixed HIV-1 do ADRs are local reaction due to subcutaneous administration not respond well. In addition, resistance patterns have already and bacterial pneumonia.[55] Parenteral administration of the been observed with CCR5 inhibitors, either through selection drug, local site reactions, cost and inconvenience associated of minority variants of CXCR4 or a dual/mixed tropic virus or with its use place the drug in a reserve category for patients [49] by development of mutations. This is potentially dangerous when all treatment fails. Resistance to enfuviritide develops as CXCR4 tropic virus is associated with greater and faster within a few weeks due to mutation of HR1 region of gp41 as decline in CD4 counts. well as HR2 indicate low genetic barrier.[57] b) CXCR4 chemokine receptor inhibitors b) Sifuviritide AMD-070 is an investigational compound with potent in vitro Sifuviritide, an investigational fusion inhibitor, is more potent antiviral activity against wild type X4 virus but with no action against HIV-1 than enfuviritide. However, in vitro studies have against R5 tropic virus. The development of CXCR4 compound reported an HIV variant resistant to sifuviritide due to specific has been slow as unlike CCR5, which is present in more than mutations at gp120. The mutant viruses also demonstrated 50% of HIV infected patients, X4 is found in mixtures with variable degrees of cross-resistance to enfuvirtide, some of [50] R5. Hence, simple inhibition of CXCR4 may not be sufficient which are preferentially more resistant to sifuviritide.[58] to decrease the plasma viral load substantially. On the other hand, combination of CXCR4 and CCR5 would be more effective. c) T1249 Preliminary studies with AMD3100 showed inhibition of the X4 T1249, a second generation fusion inhibitor, is shown to be component of the virus population, but further development of effective even against enfuvirtide resistant HIV-1 strains as well this parenterally administered drug as an antiretroviral agent as HIV-2 and simian immunodeficiency virus (SIV). was discontinued due to QTc prolongation. II. Integrase inhibitors ii) CCR5 antibodies Integrase inhibitors inhibit strand transfer of viral DNA to PRO140 is a humanized monoclonal antibody against host cell DNA. The first agent ‘raltegravir’ has been approved chemokine receptor CCR5, which inhibits R5 tropic HIV-1 at by US-FDA for both treatment-experienced and naïve patients. low concentration that does not affect natural action of CCR5.[51] The rational for prescribing this drug in treatment-naïve patients It received fast track status by the FDA in 2006. PRO140 acts is to preserve NNRTI and PI for future regimens. The second by binding to an extracellular site on the CCR5 co-receptor drug ‘elvitegravir’ is undergoing phase III trials. and prevents fusion of HIV-1 membrane with host cell and the a) Raltegravir subsequent infection of healthy host cells.[45] In vitro studies have Raltegravir demonstrated significant antiviral activity

294 Indian Journal of Pharmacology | June 2012 | Vol 44 | Issue 3 Desai, et al.: Advances in antiretroviral drugs against HIV isolates resistant to a variety of antiretroviral the concomitant ARV drug. This has opened the possibility of drugs such as protease inhibitors, NRTIs and NNRTIs.[59] It pharmacokinetic enhancers without having anti-HIV activity. is as effective as efavirenz in reducing viral RNA count at 48 Ritonavir is already being used extensively to boost other and 96 weeks.[60] Even in treatment-experienced patients with PIs. Surprisingly, it has been observed that ritonavir can also documented virologic failure, a combination of raltegravir, boost drugs in other classes such as, elvitegravir (an integrase etravirine and darunavir/ritonavir demonstrated a decrease inhibitor) and vicriviroc (a CCR5 inhibitor). However, ritonavir is in HIV RNA count to <50 cells/ml in 90% and 86% patients associated with gastrointestinal intolerance, dyslipidemia and at 24 and 48 weeks, respectively.[61] Raltegravir is also shown diabetes. Pharmacokinetic enhancers are a major step towards to be non-inferior to enfuvirtide in patients with multi-drug identifying ritonavir alternatives. resistant HIV-1 infection who are averse to subcutaneous (GS-9350), SPI-452 [61] injections of enfuvirtide. Unlike PIs, it improves lipid Cobicistat and SPI-452 are 2 compounds under profile, and the chances of interactions are few as compared investigation.[67,68] Cobicistat has no anti-HIV activity but is a [62] to other antiretrovirals. Co-administration with atazanavir potent inhibitor of CYP3A. It increases the blood level of certain and tenofovir can increase drug levels of raltegravir as both ARV drugs, allowing once-daily dosing. It is found to be safe and inhibit UGT1A1, which metabolizes raltegravir. This interaction well-tolerated in escalating single and multiple dose-ranging could be beneficial as the dose of raltegravir required can be studies in healthy volunteers. It is under trial as a standalone decreased. Raltegravir has potential for use at all stages of HIV boosting agent for PIs, especially atazanavir and integrase treatment in treatment-experienced and naïve patients due to inhibitor elvitegravir as FDC and found to be comparable with significant antiviral activity, short term safety and tolerability ritonavir.[69] It also has a low potential to cause lipid and glucose and fewer chances for interactions. abnormalities than ritonavir. SPI-452 is another investigational b) Elvitegravir (formerly GS-9137 and JTK-303) pharmacokinetic enhancer without anti-HIV activity. It is Elvitegravir is a quinolone derivative with potent antiviral being investigated to increase the exposure of darunavir and activity. A difference between raltegravir and elvitegravir is that atazanavir. Both the drugs have been shown to enhance the the former is metabolized by glucuronidation and the latter is plasma levels of PIs.[69] first metabolized by CYP 3A4/5. The clinical importance of this IV. CD4 receptor attachment inhibitors fact is that co-administration of elvitegravir with ritonavir or The attachment of outer membrane gp120 to CD4 receptor any pharmacoenhancer results in almost 20 fold increase in is inhibited by investigational compounds that constitute the plasma concentration, requiring only once-daily dose. A 10 day new class of CD4 receptor attachment inhibitors. monotherapy in both treatment-naïve and experienced patients (elvitegravir with ritonavir) has shown significant reduction a) Ibalizumab (TNX-355) in HIV RNA levels. A randomized, phase II trial in treatment- Ibalizumab, a humanized monoclonal IgG4 antibody against experienced patients showed that elvitegravir is as effective as CD4 receptors, was granted fast track status by US-FDA in boosted PI regimen at 48 weeks.[63] 2003. It inhibits viral entry by attaching with extracellular However, integrase inhibitors have a low genetic barrier domain of CD4 receptors. The binding site is distinct from to resistance i.e. even a single mutation can cause a decrease gp120 and is designed in a way so as not to interfere with in susceptibility.[64] Failure of therapy due to resistance to immunological function of CD4 receptors. Its novel mechanism raltegravir has been demonstrated even in phase III trials.[65] of action leads to potent antiviral activity in spite of HIV tropism Out of 105 patients who experienced virologic failure in the and an unlikely cross-resistance with other antiretrovirals.[70] BENCHMARK studies, 64 patients had genotypic experience A single dose, proof of concept study showed efficacy and of an integrase resistance. tolerability of a range of doses (0.3 mg/kg to 2 5 mg/kg). The c) GSK-1349572 greatest effect in reducing viral load and increase in CD4 count GSK-1349572 (S/GSK-1349572), an investigational second is seen at 25 mg/kg. Adverse effects have been observed to generation integrase inhibitor for oral treatment of HIV infection, be headache, rashes, nasal congestion and urticaria. Similar displayed in vitro activity against integrase-resistant HIV-1 efficacy was also seen in phase Ib study with once and twice a [71] isolates from patients experiencing virological failure while week regimens. A phase Ib study was found to decrease the receiving raltegravir. The pharmacokinetic profile of GSK- HIV-RNA copy initially for 2 weeks, however, the levels increased

1349572 supports once-daily dosing without boosting with back towards baseline, indicating reduced susceptibility. It has ritonavir. In phase I and II clinical trials, side effects reported also shown synergistic effect with fusion inhibitors. Parenteral are similar to placebo and not related to the dose or duration of administration of the agent may be a problem for regular use. treatment. Phase IIb trials of GSK-1349572 are being conducted The drug is under further evaluation. in antiretroviral-naïve and in experienced patients. With the V. HIV maturation inhibitors high demand for second-generation integrase inhibitors for This is an emerging class of drugs that targets internal antiretroviral experienced patients and once-daily dosing structural protein precursor Gag, which is vital in final stage of without ritonavir-boosting for treatment-naïve patients, GSK- virus development for a mature and infectious virion. 1349572 has the potential to become a highly valued product.[66] a) Bevirimat (formerly PA-457) III. Pharmacokinetic enhancers Bevirimat is a novel agent that acts on the last and important The current strategy is to exploit the pharmacokinetic stage of HIV maturation before it buds from host cell. The profile of one ARV drug to enhance the therapeutic effect of primary target of the drug is gag polyprotein precursor, the

Indian Journal of Pharmacology | June 2012 | Vol 44 | Issue 3 295 Desai, et al.: Advances in antiretroviral drugs main structural protein of the assembly and budding of the viral presence of seminal fluid, compatible with latex and acceptable particles. It prevents the cleavage of the precursor protein to a to all partners is underway. mature viral capsid protein. This disrupts gag processing and a) Microbicides [72] results in defective, immature, non-infectious viral particle. Microbicides are used for an application in vagina and rectum The pharmacokinetic profile is favorable with long half life and to prevent transmission of sexual transmitted diseases including once a day dosing. A preliminary phase IIb trial in patients with HIV. They are also called topical pre-exposure prophylaxis (PrEP). resistance to 3 antiretroviral drug classes has shown decline Agents that can disrupt viral membrane, surfactants, especially in plasma HIV-RNA level. The initial results are encouraging, 9-non-oxynol, anionic polymers etc., have been tested, but and it seems that maturation inhibitors may find a place in HIV results have generally been disappointing. therapeutics in coming years. Bevirimat has been granted the has been tested in a gel formulation as a vaginal microbicide. fast track status by the FDA in 2005. In vitro and in vivo studies have demonstrated its efficacy both as VI. Lens epithelium derived growth factor inhibitor pre-exposure and post-exposure prophylaxis. The CAPRISA004 HIV-1 can integrate their DNA at different sites in host DNA. trial has shown tenofovir to decrease an HIV infection in During the pre-integration complex, the HIV integrase interacts uninfected women by 39% when applied vaginally in 2 doses and binds with host cell factors. Researchers have identified over a period of 24 hours.[78] Efficacy of an oral tenofovir with lens epithelium derived growth factor (LEDGF) that directs emtricitabine has also been tested with positive results i.e. 44% HIV-1 DNA integration to different sites in host genome.[73] This reduction in HIV transmission.[79] CDC has already recommended interaction has been an interesting target for antiviral therapy. the use of this combination for prophylaxis. Similarly, trials Researchers used rational design to identify small molecules studying the efficacy and safety of combined oral and topical to fit the interaction by a series of 2 - (quinoline-3-yl) acetic tenofovir are also going on. An NNRTI being developed as a acid derivatives. These compounds have been investigated as vaginal gel is dapivirine, which has demonstrated efficacy in lens epithelium derived growth factor inhibitor.[74] It has been in vitro studies.[80] However, the advent of PrEP has raised observed that CX00287 moderately inhibits LEDGF and HIV issues like the use of drugs in uninfected individuals, increased replication in vitro. Further research is going on. chances of risky sexual behavior (complacency), an adherence of VII. Capsid assembly inhibitors the patient, resistance to antiretrovirals, acceptability of drugs Capsid assembly inhibitors are a new class of drugs for with substantial ADRs and cost of the regimen that need to be treating HIV infection. Virus capsid is made up of identical, addressed.[78] Hence, PrEP can only be an adjunct along with symmetrically arranged protein blocks that maintain the behavioral change therapy. structure of the virus particle. It plays an important role in b) HIV Vaccine early and late stages of viral replication and is essential for the The development of vaccine against an HIV is considered survival and infectivity of the virus. Hence, virus capsid has been to be worthwhile as majority of the patients live in developing recognized as a potential target for new class of ARV drugs. countries and cannot afford treatment, lifelong therapy, side The molecule that inhibits the interactions between structural effects and problems of multi-drug resistance. While a lot of proteins would affect the integrity and survival of the virus. research is being done, it is not without pitfalls. None of the a) PF-3450071 and PF-3450074 vaccines tested so far has been successful, the main problems PF-3450071 and PF-3450074 act early in the HIV-1 being diversity of the virus, an ability of the virus to elude the replication cycle at a step following HIV-1 envelope-mediated immune system and lack of animal models.[81] The STEP study entry. Both the compounds were evaluated in single cycle tested the efficacy of recombinant Ad5 HIV-1 vaccine (viral infection assays and in the viral production-infectivity assay, vector carrying HIV-1 gag, pol and env antigens), but lack of using NFV (PI) and EFV (NNRTI) as late stage and early stage efficacy and an increased HIV-1 acquisition in some subjects inhibitor controls. Both of them inhibited the production of lead to premature termination of the trial.[82] infectious virus.[75] Conclusion Preventive Measures for HIV Infection Current antiretroviral drugs are highly effective, but drug Until recently, the prevention of HIV-1 infection has centered resistance, drug-drug interactions, long term adverse events on the pregnant women to prevent mother to child transmission and compliance continue to be a challenge. New agents in of virus. The use of AZT and NVP to prevent neonatal HIV-1 conventional classes have revived the hopes for treatment- infection achieved considerable success in resource-rich naïve and experienced patients. Promising new agents offer countries. The idea of HIV-1 treatment as preventive measure new choices as second line treatment options for treatment- generated tremendous interest as it is believed to prevent or experienced patients. However, an impact of their long term reduce the rate of sexual transmission of virus to uninfected use on drug safety and drug-drug interactions is yet to be partner. A number of population-based prevention studies are assessed. Several agents in entirely novel classes are under currently under pilot or at planning stage.[76,77] In addition to drug an investigation. However, none of the new agents have shown treatment, the current HIV prevention measures also include to eradicate the virus and is free from adverse events. Hence, behavioral messages such as, “ABC” approach (Abstinence, Be there is a need for continuing search for novel drugs and to faithful, Condom use). However, they have limited impact on optimally utilize the available drugs to combat multi-drug the incidence rate of HIV in women. A search for prevention resistant strains and eliminate virus replication. Parallel to HIV techniques that can be easily used by women, effective in treatment, ARVs have also been shown to reduce the rate of

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