COMMENTARY

The Push for Once-Daily HAART: A Call for Caution

Andrew D. Luber, PharmD

Disclosures

June 21, 2002

Introduction

To The Editor:

Advances in the management of HIV have resulted in significant declines in both mortality and AIDS-related opportunistic infections. As a result, the management of HIV-infected individuals has shifted from morbidity/mortality prevention to a chronic disease management model for many patients. With this change in treatment strategy, interventions to improve patient adherence and quality of life have become more prominent. Several recent articles on the Medscape HIV/AIDS Web site have reflected the growing focus of drug developers on once-daily antiretroviral agents and regimens, with varying degrees of success.[1,2,3,4,5] While the use of entirely once-daily antiretroviral regimens has been highly anticipated by both providers and patients, it should be appreciated that there are many potential pitfalls among all 3 classes of antiretroviral agents when constructing such regimens.

Clinical data suggest a concentration-dependent antiviral response to protease inhibitors (PIs): the higher the drug exposure above the inhibitory concentration (IC), the greater is the antiviral response.[6,7,8] One factor that can lower PI drug exposure is interpatient pharmacokinetic variability. Recent data comparing the pharmacokinetics, safety, and efficacy of once-daily and twice-daily lopinavir/ritonavir-containing highly active antiretroviral therapy (HAART) regimens showed decreased lopinavir trough levels in the once-daily treatment arm compared with the group who received the standard twice-daily dosing.[9] In addition, lopinavir levels showed substantially greater interpatient variability among patients receiving the once-daily regimen compared with the twice-daily cohort. Although this trial showed equivalent antiviral response rates between the 2 treatment arms at 48 weeks, it highlights a potential pitfall to once-daily PI-based regimens. In this cohort, all the patients were treatment-naive with wild-type viral isolates; thus, lopinavir concentrations were adequate to inhibit viral replication even among the patients in the once-daily treatment arm who had substantially lower lopinavir levels. However, the outcome may be different in a patient population with underlying resistance and an increased IC50 for lopinavir. Depending upon the degree of resistance and the level of drug exposure achieved in each individual patient, it is quite possible that in some cases drug exposure would be insufficient to maintain lopinavir levels above the IC50 of the resistant virus for the entire 24-hour dosing period.

This potential drawback of PIs has been previously demonstrated in the Merck 069 trial, which evaluated 3-times-daily vs twice-daily indinavir-containing HAART regimens. Preliminary pharmacokinetic data suggested that twice-daily indinavir would not provide sufficient drug levels to exceed the IC90 of wild-type viral isolates at 12 hours.[10] At 24 weeks, there was a significant difference between the arms in the proportion of patients with plasma HIV-1 RNA < 400 copies/mL (91% vs 64% in the 3-times-daily and twice-daily arms, respectively), leading Merck to discontinue the trial (Merck Research Laboratories, September 25, 1998).

Although it has not yet been fully investigated, increased interpatient variability associated with once-daily PI regimens is probably not unique to lopinavir/ritonavir. Pharmacokinetic data evaluating once-daily saquinavir/ritonavir have also shown wide interpatient variability, with some patients having saquinavir plasma levels below the IC50 values for wild-type viral isolates at 24 hours.[11]

Although the lopinavir/ritonavir trial described above showed equivalent antiviral response rates, it is important to note that there were very few patients evaluated in the 2 treatment arms (twice daily: n = 19; once daily: n = 17). In addition, the analysis was performed after only 48 weeks of treatment; there are currently no data on the durability of responses in the 2 treatment arms during a longer period of follow-up. Also, this trial evaluated once-daily vs twice-daily lopinavir/ritonavir when given in combination with twice-daily NRTIs. It remains to be proven whether results would be comparable for an entirely once-daily PI-based HAART regimen.

For all of these reasons, if PIs are to be used in once-daily HAART regimens, clinicians should carefully consider both the degree of underlying viral resistance (ie, by using phenotypic data) and PI drug exposure at 24 hours (ie, drug level monitoring).

Many investigational nonnucleoside reverse transcriptase inhibitors (NNRTIs) currently being developed have long half-lives that will allow for once-daily dosing. This gain in half-life, however, needs to be considered in the context of increased potential for sustained adverse events, possible drug-drug interactions, or both. For example, if a new NNRTI has a half-life of 100 hours and there is a significant adverse event or drug-drug interaction that raises the NNRTI drug levels, it will take 3-5 half-lives (13-21 days) for this to correct itself once the offending agent(s) is removed. Consequently, clinicians must remain vigilant to evaluate drug toxicities or interactions long after initiating the new NNRTI or changing concomitant medications.

The pharmacology of the nucleoside reverse transcriptase inhibitors (NRTIs) also requires careful scrutiny when evaluating once-daily regimens. Despite widespread use of these agents in clinical practice, limited data exist on how these agents interact with various cell lines in vivo. In order to diffuse into various tissue compartments and cell types, these agents must be present in the plasma. Once they enter HIV-infected cells they are converted to their active moieties, NRTI triphosphates. However, the triphosphate not only provides the antiviral activity, but also may be responsible for the mitochondrial toxicity associated with this class of agents.[12] When given in standard twice-daily dose regimens, NRTI levels in plasma peak and then decline before the next dose. When these agents are given in sustained-released formulations or when the total daily dose is administered at one time, plasma drug levels are more constant throughout the dosing interval.

With regard to NRTIs, it is not fully understood how various cells handle these agents when they are given "breaks" from exposure to the drug during a 24-hour period (ie, during twice-daily dosing) compared with when they are constantly exposed to drug (ie, during sustained-release or once-daily dosing). With the exception of zidovudine, in which the formation of the monophosphate moiety is a rate-limiting step, limited data are available on the intracellular pharmacokinetics for most of these agents. If the cells take up these agents via passive diffusion and do not have a rate-limiting step like zidovudine, whenever drug is available in the plasma it will pass through the cell membrane and be converted to the triphosphate. Consequently, it is possible that there could be more NRTI triphosphate within cells when given in a once-daily regimen compared with standard twice-daily regimens, and this could result in a greater incidence or more rapid development of long-term mitochondrial toxicities such as peripheral neuropathy or lipoatrophy. If, on the other hand, the cells use an active pump mechanism for some of these agents, this issue may not be so relevant. This is especially true if the NRTI pumps on the surface of the cell are saturable: If the pumps that are required for diffusion into the cell are occupied, then no matter how much drug is in the plasma, only a constant amount will enter the cell and be converted to NRTI triphosphate during the 24-hour period. Another confounding issue is the recent identification of cellular efflux pumps; how will these pumps operate in the presence of continuous NRTI exposure? Will there be upregulation of these pumps that will result in greater drug clearance over time? While these are unproven theoretical concerns, it is clear that a great deal more research is required to fully understand the ramifications of once-daily NRTI regimens and their interactions with, and within, various cell lines.

Finally, clinical data from other chronic disease states such as asthma, hypertension, and diabetes suggest that patient adherence improves only slightly, if at all, when comparing once-daily with twice-daily drug dosing.[13,14,15,16,17] Only limited data are available comparing the effects of these dosing strategies on patient adherence among HIV-infected patients receiving HAART.Early prospective, observational data suggest no difference in clinical outcomes among patients receiving once-daily or twice-daily HAART.[18]

In conclusion, once-daily HAART appears promising, but the apparently limited gain in patient adherence and our lack of understanding of the complex pharmacokinetic/pharmacodynamic interplay of these agents should lead clinicians to remain cautious about the use of these strategies in widespread clinical practice.

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