teaser
Kay Seden MRPharmS
Research and Clinical Trials Pharmacist
NIHR Biomedical Research Centre, Royal Liverpool & Broadgreen University Hospitals Trust and the University of Liverpool, UK
The introduction of highly active antiretroviral therapy (HAART) in the mid-1990s has led to considerably increased life expectancy for HIV patients, and improved quality of life. The need for life long treatment with combination therapy and an ageing population of HIV patients has led to new challenges in terms of managing drug-drug interactions (DDIs) between antiretrovirals (ARVs) and co-administered medicines, minimising long term toxicities such as lypodystropy, and improving acceptability of regimens for long term treatment and improved adherence.
Treatment with ARVs aims to reduce HIV viral load to an undetectable level in the blood, and to increase CD4 cell count, thereby improving immune response and reducing the likelihood of mortality and morbidity resulting from opportunistic infections and AIDs-defining illness. Treatment largely consists of a combination of at least three ARV agents, now selected from six drug classes that inhibit the HIV cycle at distinct stages of replication. Conventionally these were nucleos(t)ide reverse transcriptase inhibitors (N(t)RTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs). Newer classes are now licensed, such as the fusion inhibitors (enfuvirtide), integrase inhibitors (raltegravir), and CCR5 receptor antagonists (maraviroc). Standard first line regimens consist of a nucleoside backbone of two agents, for example tenofovir disoproxil fumarate and emtricitabine, along with an NNRTI such as efavirenz, or a boosted PI such as atazanavir or darunavir.
As PIs are rapidly metabolized by the cytochrome P450 CYP3A subfamily in the intestine and liver, they are usually administered with low dose ritonavir, itself a PI, which is a potent inhibitor of CYP3A4. This coadministration therefore ‘boosts’ levels of PIs, acting to increase systemic exposure and the short half-lives observed with unboosted PIs on oral administration.
As effective preventative strategies such as vaccines and microbicides are unlikely to become available in the foreseeable future, suppressive treatment with ARVs remains the mainstay of HIV management.
Challenges
ARVs are among the most therapeutically risky drugs for drug-drug interactions (DDIs), due to potent inhibition or induction of liver enzymes, such as the CYP450 isoenzymes, which metabolise a broad array of other medications. DDIs involving PIs and NNRTIs are more likely to be attributable to hepatic metabolic pathways than DDIs involving nucleoside or nucleotide reverse transcriptase inhibitors, which in some cases can be due to competition for renal tubular secretion.
Due to the increasing ability to significantly alter the natural history of HIV infection, patients are more likely to be exposed to a broader range of concomitant medication. Hence, HIV can be viewed as a chronic condition, which will eventually need to be managed alongside chronic conditions associated with ageing. Acceptability of regimens to patients is therefore important. Adverse events such as diarrhoea or psychological effects may have an impact on patient adherence. Pill burden may also be an important factor, with combined triple agent formulations such as Atripla®, which allows one tablet daily dosing, improving adherence in some patients. Long term toxicities of ARVs are also important, as chronic treatment with some agents, along with HIV disease state, may cause, for example, metabolic disorders, lipid abnormalities, and increased cardiovascular risk.
Another important aspect of HIV treatment is the development of resistance. Viral resistance mutations may be present in treatment naive HIV-infected patients, or may develop during the course of treatment if viral load is detectable in the presence of ARVs. Resistance mutations may reduce susceptibility of the virus to a single agent, or in some cases to several agents in a class, thereby significantly reducing available treatment options.
This article will briefly summarise some of the new ARVs in late stage clinical development and discuss how the challenges of current ARV therapy are being addressed. Some of the future challenges and innovations of HIV treatment will also be mentioned.
New agents in development
As ARV treatment is chronic, is susceptible to single agent and class resistance, and includes agents with a high propensity for DDIs, there is constant requirement for novel agents. Figure 1 summarises some key desirable characteristics for novel ARVs. Although no single agent is likely to possess every ideal characteristic, newly developed agents can be expected to exhibit benefits over the other licensed drugs in their class as summarised below.
There are new agents in development for all of the current classes of ARVs; those in the later stages of clinical development are summarised below.
NRTIs
Apricitabine (ATC) was in phase III development, and demonstrated activity in both treatment-naïve and treatment-experienced HIV-1-infected patients. With an intracellular half life of approximately seven hours, the dosing regimen is likely to be 800mg twice daily. As a deoxycytidine analogue, ATC is renally eliminated, and therefore, in common with other NRTIs, has little potential for interaction via CYP450 metabolism pathways. However, there is potential for competition for intracellular phosphorylation, which is required for activity, when administered with other cytidine analogue NRTIs lamivudine (3TC) and emtricitabine (FTC).
Importantly, ATC has been found to be active in the presence of mutations in HIV reverse transcriptase that confer resistance to other NRTIs, meaning it has potential as a treatment option in patients who have previously failed NRTI-containing regimens.1 Development has recently been halted.
Elvucitabine, an L-cytosine NRTI about to enter phase III trials, has an intacellular triphosphate half life of approximately 20 hours, allowing once daily dosing. Elvucitabine also exhibited potentially more potent activity against a variety of nucleoside resistant viral isolates, particularly those resistant to zidovudine and tenofovir. It is not metabolised by CYP450 enzymes, nor is it an inducer or inhibitor of CYP450. It has been hypothesised that Ritonavir may increase the bioavailability of elvucitabine via inhibition of P-glycoprotein efflux transporter in the gut wall.2
NNRTIs
Rilpivirine is an NNRTI in phase III development with a long half life, allowing once daily dosing. It has been developed from the same series as etravirine, identified from structure-activity relationship screening due to activity against virus resistant to the first generation NNRTIs, efavirenz and nevirapine. Rilpivirine appears to be well tolerated, with less CNS disturbance than efavirenz, and has non-teratogenic potential. Absorption is, however, pH dependent. As a result, AUC is increased approximately 45% when given with food, and drugs which increase stomach pH, for example proton pump inhibitors, may decrease exposure to rilpivirine. In common with the other NNRTIs, rilpivirine is metabolised by CYP3A4, making it susceptible to interaction with inducers and inhibitors of this enzyme; it has been found to induce CYP3A4.3
Lersivirine is in phase II development as a once daily tablet. It binds reverse transcriptase in a novel manner, resulting in a unique resistance profile. Like rilpivirine, its solubility is pH dependent, although a study has shown a lack of clinically relevant effect of antacid coadministration.
Metabolism is predominantly via glucuronidation, notably by UGT2B7, although CYP3A4 is also involved to a relevant extent. It is thought to modestly induce CYP3A4.4
Integrase inhibitors
Elvitegravir (EVG) is currently in phase III trials and also in phase II trials as a one pill once-a-day combination. EVG is metabolised by CYP3A4, and its half life is significantly increased when coadministered with a pharmacoenhancer such as ritonavir or GS9350 (Cobicistat), as described below. EVG is active against virus which is resistant to NRTIs, NNRTIs and PIs; however, the mutations selected by EVG confer cross resistance to raltegravir, an integrase inhibitor in current clinical use.5
S/GSK1349572, currently in phase III trials, is designed to retain activity against raltegravir and elvitegravir resistant virus. It is metabolised predominantly by UGT1A1, with minor involvement of CYP3A4, making DDIs via this route unlikely. It has a long half life, which allows once daily dosing without requirement for a pharmacoenhancer. Its exposure is significantly decreased when coadministed with antacids,5 and there is also potential for interaction with atazanavir, which is an inhibitor of UGT1A1.
CCR5 antagonists
Vicriviroc is a CCR5 antagonist which was in phase III development, and like the licensed CCR5 antagonist maraviroc, is active only against HIV virus which carries the CCR5 co-receptor. Unlike maraviroc, however, vicriviroc has a long half life conducive with once daily dosing. Metabolism is via CYP3A4, CYP2C9 and CYP3A5, making DDIs an important consideration. Vicriviroc failed to show superiority to placebo in phase III trials when added to regimens of treatment experienced patients with virological failure. Phase III studies in treatment naive patients and patients who are virologically suppressed have recently been halted, and it is unclear whether development will continue.6
Novel PK enhancers
Cobicistat (GS-9350) is a new potent mechanism-based inhibitor of human CYP3A isoforms, in development to increase the systemic exposure of coadministered agents that are metabolised by CYP3A enzymes, as an alternative to ritonavir. Currently in phase III trials as a single agent, and also as a ‘Quad’ pill combined with elvitegravir, emtricitabine and tenofovir; cobicistat has no antiviral activity. Potential benefits of cobicistat compared to ritonavir include a more favourable adverse event and toxicity profile, which may aid improved adherence. Unlike ritonavir, the physicochemical properties of cobicistat are amenable to coformulation with other agents, which is important for future combination therapies which decrease pill burdens of ARV regimens. Cobicistat also has less potential than ritonavir to exhibit significant undesirable drug interactions, including inhibition or induction of other CYP450 enzymes, phase II conjugating enzymes, and drug transporters.7
The future of ARV therapy
Novel regimens
Novel regimens, which differ from standard triple therapy, are under investigation with a view to simplifying dosing, reducing pill burden, and reducing toxicity, particularly that observed with NRTI treatment. Challenges include comparable viral load suppression to conventional triple therapy, comparable penetration into sanctuary sites such as the CNS, and a sufficient barrier to resistance while fewer agents are being administered.
PI monotherapy
Boosted protease inhibitors have a relatively high potency and high genetic barrier to resistance, making this class a suitable candidate for monotherapy. Initial treatment with PI monotherapy has been found to be less efficacious than conventional triple therapy; however, safety and efficacy of switching to PI monotherapy from conventional triple therapy in stable patients has been demonstrated in relatively short term studies. Until long term data is available, PI monotherapy is likely to be a strategy used in a minority of patients, for example those experiencing significant NRTI toxicity.8
Nucleoside sparing
In addition to boosted PI monotherapy, PIs with a second agent are being investigated as ‘nucleoside sparing’ regimens. Among those studied are boosted lopinavir with efavirenz,9 boosted atazanavir with maraviroc (the phase IIb A4001078 trial) and unboosted atazanavir with raltegravir (the phase III SPARTA trial).
Better than once daily dosing?
Multi-agent combination tablets which offer one pill, once daily dosing may improve adherence, therefore improving clinical response, and reducing the likelihood of developing resistance. Reduction of the dosing intervals of currently licensed ARVs is a strategy which is also being investigated, for example a prolonged release formulation of nevirapine is being investigated and has shown non-inferior efficacy to standard twice daily dosing.10
Drugs in development with long terminal half lives such as elvucitabine,2 may in the future lead to dosing regimens which do not necessitate medication to be taken daily, but rather, for example three times weekly. In addition to favourable drug characteristics, innovations in formulation technology are likely to facilitate delivery of ARVs in the future. Nanotechnology may allow controlled and targeted delivery of ARVs, potentially reducing toxicity of treatment, allowing longer dosing intervals and specific targeting of drug to viral reservoir sites such as the central nervous system (CNS), or to specific sites of viral replication, for example the nuclei of T-cells.11
A nanosuspension formulation of rilpivirine is being investigated for potential as a once monthly intramuscular or subcutaneous depot injection.12
New drugs for hepatitis C: New challenges for co-infection
Due to the inherent complexity of ARV therapy, the treatment of co-infection can pose challenges. For example, some agents used in tuberculosis, malaria and fungal infection can interact significantly with ARV regimens. An example of co-infection for which treatment may become increasingly complicated is hepatitis C (HCV).
Therapy for chronic HCV conventionally involves ribavirin and pegylated interferon alpha, but recent advances in the development of agents that act specifically to inhibit hepatitis C virus (STAT-C) are set to fundamentally change the way that patients will be treated.
New agents directed against HCV polymerase, protease and other targets will initially be added to standard of care with pegylated interferon-α and ribavirin; however future therapy, similarly to HAART, is likely to comprise combinations of agents which act at distinct stages of viral replication and have differing resistance profiles. There is evidence that interactions between ARV regimens and new STAT-C drugs may be anticipated, which will need to be considered when HIV/HCV coinfection is managed in the future.13
Pharmacogenetic testing
Pharmacogenetic testing currently has an application in ARV treatment, in the ability to predict patients likely to have a severe hypersensitivity reaction to abacavir (ABC). Treatment with ABC is not initiated until patients have been screened for the presence of the HLA B*5701 allele, the presence of which was found to be associated with increased likelihood of hypersensitivity.
There is potential for further pharmacogenetic applications, as various genes have been associated with ARV toxicity and differing pharmacokinetic properties in individuals. An example is efavirenz, an important component of first line therapy, which exhibits considerable interindividual variability in plasma levels and clinical effects when standard 600mg doses are administered. Genes associated with metabolic pathways of efavirenz, such as CYP2B6 516TT, CYP2A6*9, CYP2A6*9 and/or *17, UGT2B7*1a and *2 carriers have been significantly associated with altered pharmacokinetics.14
Determining carriers of such genes prior to initiating treatment could allow individualisation of dosing according to phenotype, reducing the risk of sub-therapeutic levels or risk of toxicity. However, before such associations can be developed for clinical use, other factors must be taken into account, such as clinical need, the potential impact of the intervention and cost effectiveness.
Conclusion
The future of HIV therapy is changing, with the availability of new drugs, new classes of drugs, and the investigation of novel regimens and treatment strategies.
These innovations aim to improve HIV treatment by addressing key pharmacological issues such as DDI potential, toxicity, forgiveness, drug resistance, and penetration of drug into viral sanctuary sites. Patients will benefit from a greater range of treatment options, simplified regimens, fewer long term toxicities and potentially more individualised therapy.
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