US Pharm. 2006;1:HS-5-HS-12.

The HIV-protease inhibitors (PIs) are of substantial importance in the management of HIV infection. The addition of PIs to the anti-HIV armamentarium in the mid-1990s led to the use of combination antiretroviral treatment known as highly active antiretroviral therapy (HAART) in HIV-infected patients.1,2 The latest Department of Health and Human Services (HHS) guidelines for use of antiretroviral agents in antiretroviral-naïve adults call for use of either a PI or a non-nucleoside reverse transcriptase inhibitor (NNRTI) combined with two nucleoside reverse transcriptase inhibitors (NRTIs).3 In the past decade, the PIs have had a major role in the success of HAART by suppressing viral load to undetectable levels for impressive time lengths in HIV-infected patients, contributing to a decrease in AIDS incidence in industrialized nations.4 Currently, there are eight PI products marketed in the United States (table 1).




Despite their obvious usefulness for treatment of HIV infection, PIs are associated with several negative aspects, including viral resistance, metabolic abnormalities (dyslipidemia, insulin resistance, and lipodystrophy), and problematic medication adherence secondary to a large pill burden.5-7 In addition, the pharmacokinetic profiles of individual PIs are generally unfavorable, as evidenced by limited oral bioavailability and a short plasma half-life.6,8 Fortunately, a decade of experience with PItherapy has led to strategies that partially overcome some of the negative aspects of this important class of anti-HIV drugs. Of the negative aspects associated with PIs, viral resistance, undesirable pharmacokinetic properties, and poor medication adherence are closely related to one another. This article will discuss these three issues, with an emphasis on the role of PI boosting in improving the PI component of HAART.

Viral Resistance and Testing
As with nearly all antimicrobial agents, the use of antiretroviral agents for treatment of HIV infection is associated with resistance. Viral resistance occurs when HIV RNA mutates, leading to altered antiretroviral target sites that resist antiviral drugs. For example, viral resistance may occur via substitution or insertion of nucleotides into the HIV protease gene, resulting in substituted or additional amino acids in HIV protease, which, in turn, block PIs from binding to and inhibiting their target.9 The development of viral resistance is associated with reduced likelihood of suppressing viral replication in HIV-infected patients undergoing HAART. For most antiretroviral agents, including the PIs, clinically significant viral resistance requires the selection of multiple mutations in a viral strain (the NNRTIs are a major exception to this rule, as clinically significant resistance may occur from a single nucleotide point mutation, resulting in a single amino acid mutation). 10 The risk of viral resistance to PIs may be related to the level of patient adherence to HAART. At both very high and very low levels of adherence, the risk of resistance may be less, while intermediate levels may be associated with the greatest risk of resistance.11

Viral fitness, a measure of the ability of HIV to replicate in a given environment, is an important concept related to assessing the effect of viral resistance. Viral resistance may allow HIV to continue to replicate in the presence of an antiretroviral agent but often at a cost to the virus only in terms of a decline in viral fitness. In other words, viral resistance may have less of an effect on disease progression and mortality than previously believed, due to mutations that lead to less virulent strains of HIV.10 Interestingly, there is scant evidence suggesting that viral resistance is a major determinant in disease progression and mortality in patients receiving HAART. Indeed, recent evidence has shown a lack of correlation between viral resistance and disease progression or mortality.12

While the implications of viral resistance on disease progression and mortality are unclear at this point, many clinicians believe that the success of antiretroviral treatment may be impaired by the emergence of viral resistance. As a result, it may be appropriate for the viral resistance characteristics of the HIV strain infecting a patient to be assessed for viral resistance. Resistance testing yields information regarding which antiretroviral agents are resistant to the HIV infection particular to a specific patient. When used appropriately, viral resistance testing can improve the virologic outcome of HIV-infected patients. 13 There are two types of assays used to assess HIV resistance to antiretroviral agents: genotypic and phenotypic.3

Genotypic assays look for specific mutations in viral genes coding for antiretroviral targets. For example, a genotypic assay searches for known mutations in HIV protease when assessing resistance of HIV to PIs. Results from a genotypic assay, generally available after one to two weeks, are analyzed based on current knowledge of viral mutations at the level of viral genes and then used to guide the clinician in selecting optimal drug therapy. There are several online databases of genetic mutations associated with viral resistance in HIV that may guide the clinician in interpreting results from genotypic assays, including the International AIDS Society–USA (IAS-USA) database (www.iasusa.org/resistance_mutations), and the Stanford University HIV Drug Resistance Database (hivdb.stanford.edu).

Phenotypic assays are conceptually similar to traditional antibacterial-resistance testing and involve measuring the ability of HIV to grow at various concentrations of antiretroviral agents. Automated and recombinant commercially available phenotyping assays report the drug concentration that inhibits 50% and 90% of HIV replication (the mean inhibitory concentration; IC50 and IC 90). Phenotypic assays take about two to three weeks to complete and are more expensive than genotypic assays.

There is considerable promise for improving patient care through the use of HIV resistance testing. However, there are also limitations associated with these assays. The HIV resistance assays are relatively expensive to perform, and there is a lack of consistent quality assurance among them. Another important limitation to resistance testing is the likelihood of failure to detect a resistant species that constitutes a low percentage of the circulating viral species in a patient. 3 For example, if a patient is infected with a resistant strain of HIV that constitutes only 10% to 20% of the circulating strains, there is a relatively high probability that the resistant strain will not be detected by the available assays.3 Resistant strains, by their nature, are selected for and amplified relative to nonresistant strains in the presence of antiretroviral agents to which they are resistant. As such, HIV strains resistant to PIs are most detectable during or soon after termination of HAART; therefore, resistance testing should be performed while the patient is still taking the PI(s) or within four after therapy termination. The HHS has provided additional recommendations for HIV resistance testing.3 Of note, viral resistance testing is recommended in the case of virologic failure (lack of HIV RNA response to HAART) as a means of ascertaining the role of resistance and to guide clinicians in designing alternate HAART regimens.

Once a patient's viral resistance to a specific HAART regimen leads to virologic failure, some experts recommend changing each drug in the regimen, including each PI, unless there are no valid alternatives.14 In the scenario of virologic failure secondary to resistance, the HHS guidelines recommend using resistance testing to identify at least two or more agents that are considered fully active as replacement agents when subsequent HAART regimens are designed.3 Clearly, replacing only one agent of the entire HAART regimen to combat virologic failure secondary to viral resistance is not recommended and may lead to rapid viral resistance to the new agent in the modified HAART regimen. 15

PI Boosting
The terms PI boosting and boosted PI therapy are firmly embedded in the lexicon of HIV treatment. Put simply, PI boosting creates and uses a clinically significant drug-drug interaction to benefit patients receiving HAART. PIs are metabolized substantially by cytochrome 3A4 (CYP3A4), the most important isoform contributing to drug metabolism in the large family of drug-metabolizing enzymes known as CYP450. Therefore, inhibition of CYP3A4 activity by an inhibitor will increase the elimination half-life of PIs and exposure of the patient to the PI by reducing first-pass metabolism and hepatic clearance. Most PI boosting is accomplished by the use of a low, subtherapeutic dose of the PI ritonavir as the pharmacokinetic booster in addition to a therapeutic dose of a second PI (often referred to as the primary PI in this scenario). Of the PIs, ritonavir is the most potent inhibitor of CYP3A4 and is used more often as a low-dose pharmacokinetic booster rather than in therapeutic doses as the primary PI. In addition, ritonavir inhibits P-glycoprotein (P-gp), a transmembrane efflux protein that transports PIs out of cells. Inhibition of P-gp by ritonavir may increase penetration of PIs into viral sanctuary sites. Finally, therapeutic dosing of ritonavir (e.g., 600 mg twice a day) as the sole PI is not recommended and is known for lower tolerability relative to the lower doses used for pharmacokinetic boosting (e.g., 100 mg twice a day), further increasing the appeal of ritonavir as a PI-boosting agent.16

The rationale for PI boosting is mostly based on the poor pharmacokinetic profile of most PIs. Specifically, most PIs have variable and/or limited oral bioavailability and a short elimination half-life, which may lead to subtherapeutic systemic exposure. 6,8,16 Low systemic exposure to PIs may result in exacerbation of viral resistance and a decrease in treatment success. In addition, the PIs must achieve adequate blood concentrations to function as effective anti-HIV therapy. The need for adequate blood concentrations plus the poor pharmacokinetic profile of the PIs result in a large pill burden (the number and frequency of dosage units the patient must take each day) that contributes to poor medication adherence. The large pill burden associated with unboosted (standard) PI therapy is further exacerbated by the high number of potential drug-drug interactions that require separation of dosage administration when combined with certain other antiretroviral agents or other HIV-related medications.

PI boosting results in a lower pill burden, which is likely to enhance medication adherence. In some cases (e.g., in treatment-naïve patients), two- or three-times-daily PI dosing may be lowered to once-daily dosing when low-dose ritonavir is used as a PI booster. Ritonavir may be useful as a PI booster for most, but not all, of the PIs. Lopinavir may be administered only with ritonavir because the two drugs are formulated together. Saquinavir, indin­ avir, atazanavir, amprenavir, fosampren­ avir, and tipranavir all have improved pharmacokinetic properties when administered with low-dose ritonavir. Tipranavir is not recommended for use in HAART unless it is boosted with ritonavir.3 The pharmacokinetic enhancement of low-dose ritonavir on nelfinavir is modest since nelfinavir is mostly metabolized by CYP2C19.16 In addition, nelfinavir may be effectively administered as a single PI agent with twice-daily dosing; therefore, boosting this PI with ritonavir is less likely to be of significant clinical benefit. Typical unboosted and boosted dosing regimens of the currently approved PI inhibitors are summarized in table 2.




Is PI-boosted therapy less prone to cause viral resistance than unboosted PI therapy? Kempf and colleagues recently compared incidence of viral resistance from weeks 24 to 108 of therapy with ritonavir/lopinavir plus stavudine and lamivudine versus nelfinavir plus stavudine and lamivudine in a double-blind, randomized, phase III study.7 In the 51 ritonavir/lopinavir subjects, no phenotypic or genotypic resistance to lopinavir/ritonavir was detected; however, primary mutations related to nelfinavir resistance were observed in 43 of 96 (45%) nelfinavir-treated subjects, suggesting that PI boosting may decrease the incidence of viral resistance.7 In an additional recent study, MacManus and colleagues demonstrated the absence of protease resistance at 48 weeks of fosamprenavir therapy boosted with ritonavir.17 Therefore, evidence shows that PI boosting contributes to a reduction in the risk of viral resistance to HAART.

Are PI-boosted HAART regimens effective? Several studies, which have been reviewed in the literature, have shown that PI boosting with ritonavir is associated with clinically important suppression of HIV RNA levels for lengthy periods in both treatment-naïve and treatment-experienced patients.8,18 In addition, some PIs would likely be ineffective components of HAART regimens if they were not boosted by ritonavir. For example, lopinavir and tipranavir are not indicated for use other than with low-dose ritonavir. Therefore, the addition of low-dose ritonavir as a pharmacokinetic booster leads to efficacious HAART regimens and, for some PIs, must be used to ensure efficacy.2,6,8,19

When should PI-boosted HAART regimens be used? In some cases, PI-boosted HAART regimens should be used for initial therapy in treatment-naïve patients. For example, if a PI-containing HAART regimen is used for initial therapy, the HHS guidelines state that lopinavir/ritonavir is the preferred PI. In addition, for patients who experience virologic failure--defined as incomplete (repeated HIV RNA >400 copies/mL after 24 weeks or >50 copies/mL by 48 weeks in a treatment-naïve patient initiating therapy) or lack of HIV RNA response to antiretroviral therapy, during initial therapy with a PI-containing HAART regimen--the HHS guidelines recommend including a low-dose ritonavir in subsequent PI-containing HAART regimens regardless of whether the initial HAART regimen contained low-dose ritonavir.3 As mentioned previously, the selection of the boosted PI in HAART regimens in patients who experience virologic failure should be based on results from viral resistance testing.

Are there disadvantages to PI boosting? While PI boosting has many benefits, it is also associated with several negative aspects. Ritonavir is a potent inhibitor of CYP3A4-catalyzed drug metabolism and may readily precipitate potentially life-threatening drug-drug interactions, even when used at lower pharmacokinetic-boosting doses. 3,6 When managing PI-boosted patients, pharmacists should consult detailed references, such as the HHS guidelines, that outline potentially serious drug-drug interactions involving ritonavir. PI boosting results in consistent and sustained therapeutic blood levels of PIs, which may lead to a higher incidence of adverse effects common to this drug class. For example, PI-boosted therapy may be associated with a higher risk of dyslipidemia, insulin resistance, and body shape changes secondary to fat redistribution. 8,20

Improving Medication Adherence
Adherence to therapy may be thought of as a collaborative agreement between the health care providers and patients to achieve a desired therapeutic result.21 Consistent medication adherence is important for any anti-infective treatment to ensure adequate antimicrobial activity and decrease the risk of drug resistance. Adherence to HAART is no exception; however, the complexity of the typical HAART regimen lends itself to greater adherence challenges as compared with most other antiinfective drug regimens.3,6 HAART regimens consist of three or more medications that are sometimes given multiple times per day on a chronic basis. For certain antiretroviral combinations within a given HAART regimen, the timing of administration of individual antiretrovirals with respect to one another may be critical to avoid drug interactions. In addition, HAART is often associated with a large pill burden. Multiple studies have documented that a lack of medication adherence to HAART leads to virologic failure, disease progression, and increased mortality. 10,21 Several strategies are promoted in the literature to improve medication adherence in patients receiving HAART.

When possible, simplification and reduction in pill burden of HAART is recommended to maximize medication adherence.3 The use of PI boosting is an important contribution to decreasing the pill burden associated with HAART, which may lead to improved medication adherence. PI boosting allows for the PI component of HAART to be administered less frequently due to improved pharmacokinetics. There are several PIs that can now be administered once daily when boosted with ritonavir, which otherwise would need to be administered twice daily.22 Drug manufacturers are also developing combination products that allow for decreased pill burden and regimen simplification. For example, Kaletra (lopin­ avir/ritonavir) contains lopinavir formulated with low-dose ritonavir in one dosage form.

To improve medication adherence with HAART, HHS guidelines recommend several strategies, including reviewing, anticipating, and treating side effects; using a team approach with nurses, pharmacists, and peer counselors; and engaging family and friends to participate and help in medication adherence.3 Pharmacists interested in learning more about HAART medication adherence strategies should consult the HHS recommendations at www.aidsinfo.nih.gov/guidelines.

Summary
HAART has significantly contributed to a reduction in AIDS incidence, disease progression, and mortality in developed nations. However, the PI component of HAART contributes to viral resistance and poor medication adherence, in part due to its undesirable pharmacokinetic properties. The development of several clinical strategies, such as viral resistance testing and PI pharmacokinetic boosting, have led to improvements in the use of PIs as part of HAART in HIV-positive patients.

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