Peter L Anderson
Department of Clinical Pharmacy
School of Pharmacy
University of Colorado Health Sciences Center
The promise and goal of combination antiretroviral therapy is to transform HIV infection from a progressive fatal disease to a chronic manageable condition. However, the lustre of this high promise has been tarnished by adverse effects associated with chronic antiretroviral therapy, such as hyperlipidaemia and hyperinsulinaemia (and potential sequelae), lactic acidaemia, peripheral neuropathy and body fat maldistribution.(1,2) Additionally, maximal long-term suppression of HIV-RNA to <50 copies/ml of plasma is not realised by up to 50% of patients.(3) A consequence of submaximal suppression of HIV-RNA can be the selection of drug-resistant HIV mutants, which can eventually limit any future therapeutic options and can be passed on in new infections.(4,5) One method that has been advocated to combat poor drug response by improving adherence is to develop safe and well-tolerated once-daily combination regimens.
One of the most important reasons for combination antiretroviral failure is inadequate potency of the regimen.(6) This was demonstrated when triple therapies with saquinavir hard-gelatin capsules (unboosted with ritonavir) were proven to be inferior to triple therapies with other protease inhibitors that were more bioavailable.(6,7) Additional studies indicate that adverse drug–drug and drug–diet interactions and variable pharmacokinetics can also lower the intrinsic potency of combination antiretroviral regimens, leading to therapy failure.(8–10) However, the most notable and widespread source of inadequate regimen potency is imperfect adherence.(11)
Many factors are associated with reduced adherence, such as younger age, regimen complexity, active substance abuse, mental health illnesses, patient’s perception of the importance of medical care and adherence, lack of adherence aids (eg, pill boxes or alarms) and antiretroviral toxicity/tolerability.(12–14) The pharmacist/healthcare team can intervene to improve adherence by earning patients’ trust, referring them to the appropriate health professional for substance abuse and/or mental health illnesses, and by making sure that they use adherence aids. Drug-specific factors, such as regimen complexity and antiretroviral toxicity/tolerability, also influence adherence.(12–14) Importantly, toxicity/tolerability are vital for at least two reasons: their impact on adherence and response, and their direct influence on quality of life.
Remarkably, studies suggest that some combination antiretroviral regimens cannot withstand even small deviations from 100% adherence. For example, in the case of protease inhibitor regimens, a decrease in protease inhibitor adherence from >95% to 90–95% resulted in a drop in response (defined as HIV-RNA <400 copies/ml) from 81% to 64%.(15,16) It seems reasonable to conclude that missed protease inhibitor doses exposed patients to suboptimal drug exposures because typical drug exposures during routine dosing narrowly exceeded the exposures necessary for a sustained efficacious response.(6) Additionally, the half-lives of the drugs must have been relatively short, such that the drug exposure fell below a level associated with a high probability of response after the missed dose. Theoretically, antiretroviral drugs that greatly exceed the exposures necessary for an effective response and have a very long half-life should remain effective even during a missed dose. A drug with these characteristics is termed “forgiving”, as the pharmacological profile allows for missed doses. A “forgiving” drug must also be safe and tolerable for a favourable pharmacological profile.
In general, the pharmacological profile of a once-daily antiretroviral or antiretroviral combination regimen is best defined by the following questions:
- Has the once-daily drug or drug combination been shown to be safe and tolerable in a large number of biologically diverse patients over the long term?
- Do well-conducted (large, randomised, multicentre, long-term, etc) clinical trials demonstrate suppression of plasma HIV-RNA, CD4 cell recovery and/or protection from opportunistic infections that are comparable to those observed with established therapies?
Drugs and drug combinations that satisfy these questions have usually been approved by regulatory agencies. Once-daily antiretrovirals generally falling into this category are: efavirenz, fosamprenavir/ritonavir, atazanavir, atazanavir/ritonavir, tenofovir, emtricitabine, lamivudine and abacavir.(12) Didanosine (enteric-coated) and stavudine (extended-release) are approved for once-daily dosing, but these agents have unpredictable long-term safety issues associated with their mitochondrial toxicity profiles.(17) It should also be noted that many of the once-daily antiretrovirals listed above lack extended follow-up data.(18)
Several twice- and thrice-daily antiretrovirals are currently being investigated for once-daily use, especially protease inhibitors with ritonavir boosting. In this case, the following questions may help predict the once-daily pharmacological profile:
- Is there evidence that the agents are relatively safe and tolerable in biologically diverse patients with other dosing strategies?
- Does once-daily dosing provide drug exposures that significantly exceed those necessary for a high probability of response?
- Is the half-life long enough to sustain effective drug exposures even for a missed dose?
Several of these investigational ritonavir-boosted protease inhibitors provide marginal drug exposures that narrowly exceed those associated with sustained viral response. Additionally, these agents have relatively short half-lives and, therefore, have marginal to poor “forgiveness”. These agents may be good candidates for therapeutic drug monitoring (TDM), given this rather tenuous pharmacological profile. TDM guidelines for patients with wild-type virus are available from several sources.(12,19)
There are obviously other critically important issues to consider for once-daily antiretroviral therapy. It is vital that all once-daily agents can be administered at the same time (ie, the agents must have no differences in dietary requirements).(18) For example, efavirenz and didanosine are recommended on an empty stomach, whereas atazanavir, saquanivir/ritonavir and lopinavir/ritonavir should be taken with food.(12) Additionally, other significant pharmacological considerations are associated with many once-daily antiretrovirals. This includes some drug combinations that should not be coadministered (eg, triple once-daily nucleoside analogues), drug–drug interactions that require dose adjustments (eg, tenofovir plus atazanavir), patient conditions that affect antiretroviral choices or doses (eg, no efavirenz in early pregnancy or dose adjustments for renal/liver disease) and overlapping toxicities that require special consideration or monitoring (eg, abacavir and nevirapine hypersensitivities). (12,18) It is imperative that the pharmacist/healthcare team carefully reviews all antiretroviral regimens for drug interactions, and that appropriate monitoring and interventions are carried out where indicated. Several outstanding drug information resources are available for guidance.(12,20)
Table 1 provides an overall pharmacological summary of the current once-daily antiretroviral agents.(12,17,18,20–23) The table illustrates several potentially favourable once-daily drug combinations for antiretroviral-naive subjects. Some drugs and drug combinations should not be offered at this time, whereas some investigational protease inhibitors may be TDM candidates because of marginal pharmacological profiles for once-daily dosing.(12,19) Finally, it is always necessary to consider the art of antiretroviral therapy. Drug regimens should be designed according to the individual and TDM information must be integrated with other clinical and patient information.
Once-daily antiretroviral therapy is upon us. Pharmacist input and patient monitoring for antiretroviral therapies are especially important given the challenging pharmacological issues associated with this disease.
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- HIV Drug Interactions Web site. Liverpool HIV Pharmacology Group (LHPG); University of Liverpool, UK. Available from: www.hiv-druginteractions.org
- Bristol-Myers Squibb Company. BMS-232632: Atazanavir Briefing Document May-2003. Available from: www.fda.gov/ohrms/dockets/ac/03/briefing/3950B1_01_bristolmyerssquibb-atazanavir.pdf
- Aarnoutse RE, Droste JA, van Oosterhout JJ, et al. Br J Clin Pharmacol 2003;55:115-25.
- Mascolini M. Available from: www.NATAP.org
- British HIV Association (BHIVA) Writing Committee on behalf of the BHIVA Executive Committee. HIV Med 2003; 4 Suppl 1:1-41. Available from: www.bhiva.org/guidelines.htm