International Association of Physicians in AIDS Care, February 2000 Journal
David J. Back, PhD; Sara E. Gibbons, MPhil; Saye H. Khoo, MB, MD, Department of Pharmacology & Therapeutics, University of Liverpool, Liverpool, UK; Concepta Merry, MB, PhD, Northwestern University Medical School, Comprehensive AIDS Center Chicago, Illinois, USA; Michael G. Barry, MB, PhD, Trinity Centre for Health Sciences, Department of Pharmacology & Therapeutics, St. James' Hospital Dublin, Ireland; Fiona Mulcahy, MB, MD, Department of Genitourinary Medicine, St. James' Hospital, Dublin, Ireland
| Introduction Arguments for Using TDM of PIs Potential Problems with TDM Where Do We Go from Here? References |
The introduction in 1995 of protease inhibitors (PIs) as a component of antiretroviral therapy dramatically decreased mortality and morbidity due to HIV infection,1 most clearly demonstrated by the reduction of opportunistic infections and hospital admissions. More recently, nonnucleoside reverse transcriptase inhibitors (NNRTIs) have shown impressive sustained antiviral effects.2,3 Currently a triple drug combination regimen containing nucleoside reverse transcriptase inhibitors (NRTIs) plus either a PI or an NNRTI constitutes the standard of care for patients commencing therapy.
However, in our overall enthusiasm for the advances made, we must remember that only around 50 percent of previously antiretroviral-naive patients commencing treatment will actually achieve maximal HIV viral suppression, with a viral load below the limit of quantification (BLQ) of 50 copies/mL.4 This figure is lower for patients who are treatment-experienced and subsequently switch therapy.
In addition observations from both clinical trials and large prospective studies show that subsequent virologic rebounds are frequent.5-7 For example, in a recent study from the Netherlands, 40 percent of patients had a virologic failure at 48 weeks, and over half of all patients receiving antiretroviral therapy required a switch in therapy during the first year of treatment.7 The number of patients who do not achieve adequate suppression of viral load despite extensive antiretroviral therapy is also increasing.
The many reasons for therapeutic failure include acquisition or emergence of resistant viral strains, incomplete adherence to therapy, and pharmacokinetic factors. Pharmacokinetic factors are particularly important in relation to PIs, drugs that are both metabolized by and act as modulators of CYP3A4.8 These activities cause considerable inter- and intraindividual variability in plasma levels and create a marked potential for drug interactions. The result may be reduced or elevated PI concentrations;8,9 reduced concentrations are potentially subtherapeutic, and elevated levels could predispose to adverse events.
Several studies have demonstrated a clear relationship between PI exposure and antiviral response.10-12 Dose-ranging monotherapy trials of ritonavir and indinavir have also demonstrated rapid emergence of antiviral resistance with lower than recommended doses.13,14 It is essential that patients receive the optimal dose of individual PIs within a regimen.
For these reasons, the role of therapeutic drug monitoring (TDM) for PIs has received increasing attention in recent months. Potential benefits as well as difficulties have been highlighted.15,16 There is little doubt that enthusiasm exists for TDM in HIV management in many quarters. But is such enthusiasm justified? Should we be more cautious? It is important to weigh the arguments for and against this new diagnostic technology.
For the NRTIs, establishing a relationship between plasma concentration and antiviral effect has been difficult simply because the intracellular triphosphate anabolite is the active moiety. Plasma concentrations of parent nucleoside and intracellular concentrations of triphosphates show only a weak correlation. Therefore meaningful NRTI data would require bedside cell separation, a technique that is time consuming, labor intensive, and costly. This effectively precludes the routine use of TDM of NRTIs in clinical practice.
Data from pharmacokinetic studies of the NNRTIs indicate that two of the drugs (efavirenz and nevirapine) have a prolonged half life, achieve adequate steady-state plasma concentrations during a dosing interval, and have less variable pharmacokinetics. For these reasons we currently focus attention on PIs.
1. Drug concentrations correlate with effect. This finding represents the strongest case for TDM. Although target plasma concentrations based on in vitro IC95 (concentration of drug giving 95 percent inhibition of virus) data have been defined, it is the association between plasma drug concentrations and virologic response observed in patient studies that provides us with the target values.
For example, Gieschke and colleagues investigated the relationship between systemic exposure to saquinavir soft gel (400, 800, or 1200 mg three times daily) and plasma HIV RNA and CD4+ cell counts using empirical mathematical modeling to determine the area under the plasma concentration-time curve (AUC) that gives maximal viral suppression10 (Figure 1). In the ADAM study, plasma saquinavir and nelfinavir concentration ratios were strongly associated with the initial rate of HIV clearance.9 Studies of indinavir demonstrated a good relationship between indinavir exposure (AUC and trough [Cmin] levels) and virologic response.14 The Trilège study reported an association between low indinavir levels and treatment failure,17 although a similar US study (ACTG 343) failed to observe this association.18 Several other US19 and Dutch20,21 studies found an association between indinavir levels (using AUC, peak concentration [Cmax], Cmin, or concentration ratios) and virologic response in both adults and children.
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Figure 1. Calculating the optimal dose of a PI.The relationship between plasma HIV RNA and systemic exposure to different doses of saquinavir soft gel can be used to determine the area under the plasma concentration-time curve (AUC) that gives maximal viral suppression. |
The evidence, therefore, is that maintaining therapeutic levels is potentially critical for PIs, not just in preventing drug resistance, but also in preventing cross-resistance to other PIs. Exposure of a patient to subtherapeutic levels of a PI may result in the stepwise accumulation of mutations in the HIV protease and subsequent resistance to both the prescribed drug and other class members.
Recently results from the VIRADAPT study confirm the importance of maintaining therapeutic drugs concentrations.22 This randomized controlled trial compared genotyping to standard of care (SOC) to guide planning of a new regimen after virologic failure. The investigators also retrospectively analyzed plasma samples for PI concentrations and categorized patients as having optimal or suboptimal concentrations based on trough concentrations above or below the IC50 of the drug. The results provide evidence that both genotyping and optimal PI concentrations are beneficial. For example, six months after the switch to a new regimen, there was only a 0.23-log drop in viral load among patients receiving SOC with suboptimal drug concentrations, but a 1.3-log drop among patients having both genoty-ping and optimal drug concentrations.
2. Plasma drug concentrations vary from individual to individual. PI concentrations may vary more than 10-fold between patients.23 Figure 2 shows PI trough concentrations in our own patient cohort. A number of features are worth noting, beginning with the marked interpatient variability in trough concentrations. For example, a high proportion of patients receiving the original hard gel formulation of saquinavir had a Cmin below the target IC95 value of 100 ng/mL, although some patients had a Cmin above this value. Plasma concentrations of saquinavir with the soft gel formulation are much higher. Indinavir, ritonavir, and nelfinavir show similar variability. The effect of gastrointestinal disease, food, or other drugs and possibly the efflux transporter P-glycoprotein24,25 are all important considerations in relation to plasma concentrations.
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| Figure 2. Highly variable PI trough concentrations. Trough concentrations of saquinavir (SQV), indinavir (IND), and nelfinavir (NLF) vary considerably in patients after dosing regimens of 600 mg tid, 800 mg tid (1200 mg bid), and 750 mg tid respectively. (Data from the Liverpool HIV Pharmacology Group.) |
3. Drug interactions are complex. PIs are substrates for cytochrome P450 (CYP)3A4. Drugs that inhibit (CYP)3A4, such as other PIs, azole antifungals, and macrolide antibiotics, may therefore elevate PI concentrations. Conversely, the induction of CYP3A4 by drugs such as some NNRTIs, rifampicin, and rifabutin may decrease PI concentrations. Patients taking a failing regimen are typically given at least two new drugs and in salvage therapy increasingly complex combinations of as many as four to eight agents which may include PI-PI combinations plus an NNRTI. Such regimens create a considerable potential for complex drug interactions and toxicity. For a complete listing of the important drug interactions in HIV therapy see our group's Web site, http://www.liv.ac.uk/hivgroup.
4. Drug concentrations may correlate with excessive toxicity. Reversible liver toxicity is seen with high doses of PIs or dual PI combinations. High peak plasma concentrations of indinavir are associated with renal stones.26 Similarly, high Cmax values of ritonavir are related to circumoral paraesthesia.27 We have successfully changed ritonavir dosing regimens (for example, to 300 mg four times daily) to overcome this effect.27 Emerging data suggest an association between PI levels and plasma triglycerides.28,29
5. Clearance is reduced by liver dysfunction. Pre-existing liver impairment, particularly with coexisting chronic hepatitis B or C infection, is not uncommon in individuals with HIV infection. Wide variability in the pharmacokinetics of nelfinavir in a small group of patients has been demonstrated,30 and liver dysfunction is likely to affect the disposition of all PIs. In the ANRS EP11 study of over 1200 patients receiving PIs, most cases of serious liver toxicity (greater than grade 3) occurred in patients coinfected with hepatitis C virus.31
6. Better tools are needed to assess adherence. Incomplete adherence to therapy because of the complexity of drug regimens is a major problem. HIV treatment appears to be very unforgiving in this respect; therapeutic failure is very closely associated with failure to adhere to prescribed therapy. Although the plasma half-life of PIs is comparatively short (two to eight hours), monitoring plasma drug levels may be useful for selected patients suspected of nonadherence.32 TDM may identify poor adherence, although adequate plasma drug levels would not automatically imply good adherence, since adequate levels tell you only that the patient has taken a recent dose of medication. Therefore, in our view, using TDM as a marker of adherence is probably not appropriate; there is simply too much variability to make it useful.
7. Antiretroviral therapy is expensive. Adding PI therapy to the previous standard of care results in an average additional drug cost per patient of US$5000 to $7000 per annum. It is essential that dosing regimens are optimized to ensure maximum therapeutic benefit from these expensive drugs.
One of the major problems with TDM is knowing the target concentration. Minimum target PI concentrations have largely been defined on the basis of monotherapy concentration-effect modeling or in vitro IC95 data for laboratory or clinical isolates of HIV, with allowance made for protein binding. But how are these values affected by other antiretroviral agents in a given combination? Are data derived from studies using PI monotherapy, or complex four-drug regimens including dual PIs, appropriate to the general clinic population of HIV-positive patients?
In using a single target trough concentration, we assume that all patients have viral isolates with the same susceptibility. In reality many patients with resistant isolates require higher concentrations. Interindividual variability in drug absorption (for example, with diet or according to disease stage) or changing patterns of adherence may confuse the picture and give TDM a poorer predictive value.
Finally, there is little agreement concerning the best measure to use: AUC, Cmax, Cmin, or concentration ratios. AUCs clearly represent the most robust measure, but there are logistical difficulties in instituting their use on a wide scale. As a result, the Pharmacology Committee of the US AIDS Clinical Trials Group (ACTG) recently issued guidelines stating that routine TDM is not recommended "except in the context of supervised clinical studies designed to assess the utility of TDM."33
Antiretroviral therapy is failing in increasing numbers of patients because the durability of therapy, though improved, appears to be limited. Although newer PIs, NNRTIs, and NRTIs are being evaluated, there are no imminent plans for introducing a new major class of compounds into phase III studies. Clearly there is a need for better drugs that achieve high plasma concentrations reliably without associated toxicity.
This urgent need to improve efficacy and preserve treatment options has led to the use of ritonavir as a pharmacoenhancer34,35 and to calls from leading experts36 and patient advocacy groups for routine TDM by clinicians. Despite the lack of definitive studies to evaluate the clinical benefits of and indications for TDM, some national treatment guidelines (for example, from the British HIV Association37) have incorporated TDM as an option for the management of HIV infection.
Clearly, the "want" for TDM is widespread while the "need" has yet to be fully established. Questions such as "Does TDM improve patient outcome?" and "Is it cost-effective?" urgently need to be addressed. Assessing the costs of PIs and of monitoring their levels is a health service issue of great immediacy. It is clear that randomized controlled trials to assess TDM are urgently required. Results of one such study, the ATHENA trial in the Netherlands, should be reported in 2000. Without such studies there will be mounting demand for instituting TDM, in a situation analogous to clinical use of viral resistance assays. Some health authorities will probably refuse funding because of the lack of data while others may be pressured into providing TDM. Eventually, TDM may be introduced without adequate assessment.
However, if controlled trials show that TDM is clinically beneficial, it will assist clinicians in optimizing the management of HIV-positive patients and in delaying the onset of virologic failure while preserving future treatment options. We must also remember that expert interpretation of a concentration is absolutely critical to understanding what the results actually mean. This is not therapeutic drug measurement but therapeutic drug monitoring. It is our view that TDM must comprise a full monitoring service that not only measures drug concentrations, but also assesses all the other factors that may affect these concentrations. We must offer the clinician and patient both a valid interpretation and the option of dose modification if considered appropriate.
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This information is designed to support, not replace, the relationship that exists between you and your doctor.