The role of therapeutic drug monitoring in treatment of HIV infection

Looking back over the development of antiretroviral therapies (ART) for the treatment of HIV infection, probably the turning point in generating a belief that there were real grounds for optimism of ‘therapeutic success’ came with the introduction of protease inhibitors (PIs) in 1995. As a component of antiretroviral therapy, PIs produced a dramatic decrease in mortality and morbidity in HIV infection [1] most clearly demonstrated by the reduction of opportunistic infections and hospital admissions. Today, a triple drug combination regimen containing nucleoside reverse transcriptase inhibitors (NRTIs) plus PIs or non-nucleoside reverse transcriptase inhibitors (NNRTIs) constitutes the standard of care for patients commencing therapy (see Table 1). Table 1 Currently licensed antiretrovirals. Despite its success, combination ART still lacks sufficient potency and durability. Large prospective studies [2] suggest that up to 50% of HIV-positive patients will fail to achieve adequate suppression of plasma HIV RNA (i.e. < 50 copies/ml) with any of the current ART regimens. Even if this is achieved, viral rebound develops in a significant proportion of patients within 1 year of follow-up [3–5]. For example, in the Swiss cohort study [3], rebound HIV viraemia (from < 400 copies/ml to detectable) was approximately 10% per year in ART-naive patients commencing therapy and 20% in ART-experienced patients switching therapy. Although 80% of ART-naive patients achieved viral load below 400 copies/ml at 6 months, this was only sustained in 66% at 30 months and treatment changes were necessary in approximately half of patients by 24 months. In the Frankfurt cohort [4], over half of patients developed viral rebound within 12 months of achieving undetectable RNA. There are also a growing number of patients who fail treatment despite exposure to most antiretroviral agents and consequently receive salvage therapy, which may include ‘mega-ART’ regimens. Such regimens are associated with increased potential for toxicity and serious drug interactions. In this context, some of the most pressing clinical pharmacology questions are: Why do some patients fail treatment regardless of the regimen selected? How can existing therapies be improved or optimized? Will the new drugs in development show significant advantage? Treatment failure is clearly multifactorial, and may include the development of antiviral resistance, poor adherence to therapy and pharmacokinetic reasons. This review will focus on pharmacokinetic variability as an important consideration in treatment failure and current approaches to address the problem. Pharmacokinetic variability is particularly important in relation to PIs – a group of peptidomimetic drugs with considerable inter and intra-individual variability in plasma levels and marked potential for drug interactions leading to reduced or elevated PI plasma concentrations [6, 7]. Reduced concentrations will potentially compromise efficacy while elevated concentrations will predispose to adverse events. When considering the role of therapeutic drug monitoring (TDM) in antiretroviral therapy, the primary focus is therefore on PIs. However before proceeding to develop the arguments for TDM of PIs it is important to highlight the main issues around plasma concentrations of the other two main classes of antiretrovirals. For NRTIs, establishing a relationship between plasma concentration and antiviral effect has been difficult simply because it is the intracellular triphosphate anabolite that is the active moiety (Figure 1). Plasma concentrations of parent nucleosides and intracellular concentrations of triphosphates show only a weak correlation. Figure 2 displays data from studies with zidovudine (ZDV) and lamivudine (3TC) [8, 9]. Therefore meaningful data would require cell separation (i.e. to generate peripheral blood mononuclear cells, PBMCs), a technique which is time consuming, followed by analysis of the active triphosphate, a procedure that is currently available only in a handful of laboratories. This effectively precludes the routine use of TDM for NRTIs in clinical practice until such time as a more rapid throughput analytical system is developed. Figure 1 Activation pathways of nucleoside analogues. Figure 2 The relationship between intracellular nucleoside triphosphate and plasma concentration of parent drug for (a) zidovudine (ZDV) and (b) lamivudine (3TC) (○ 150 mg. • 300 mg). Note the weak correlation between area under the curve in cells ... Data from pharmacokinetic studies of NNRTIs indicate that two of the drugs, efavirenz and nevirapine, have a prolonged half-life, normally achieve adequate steady-state plasma concentrations during a dosing interval and have pharmacokinetics which are less variable than those of PIs. Although we would not entirely rule out a role for TDM of NNRTIs in some circumstances (e.g. in relation to CNS side-effects of efavirenz), presently attention is focused on PIs.