Treatment failure of nelfinavir-containing triple therapy can largely be explained by low nelfinavir plasma concentrations.

The relationship between plasma concentrations of nelfinavir and virologic treatment failure was investigated to determine the minimum effective concentration of nelfinavir. Plasma samples were prospectively collected from treatment-naive patients who began taking nelfinavir, 1,250 mg BID + two nucleoside reverse transcription inhibitors (NRTIs). Nelfinavir concentration ratios were calculated by dividing each individual nelfinavir level by the time-adjusted population value. Virologic failure was defined as either no response (a detectable viral load after 6 months) or a relapse (detectable viral load after being undetectable, or an increase in viral load >1 log above nadir). Forty-eight patients were included with a median follow-up period of 8 months. The median concentration ratio of nelfinavir was 0.98 (interquartile range, 0.76-1.47). Virologic failure was observed in 29% of the patients. In a univariate analysis, the nelfinavir concentration ratio appeared to be the single determinant that was related to virologic failure (P = 0.039). Patients with a median ratio <0.90 had a relative risk of 3.0 (95% CI, 1.2-7.6) for virologic failure. Using this threshold, virologic failures were detected with 64% sensitivity and 74% specificity (P = 0.014). Virologic failure of nelfinavir-containing triple therapy can be explained, to a large extent, by low plasma levels of nelfinavir.

Therapeutic drug monitoring of HIV-protease inhibitors to assess noncompliance.

OBJECTIVE: To determine plasma concentration ratio limits (CORALS) for HIV-protease inhibitors outside of which random plasma concentrations reflect partial compliance or noncompliance. In the absence of a gold standard for measuring compliance and to avoid complex techniques, measuring plasma concentrations may be an objective and easy way to check noncompliance. METHODS: Pharmacokinetic curves after observed ingestion were recorded in patients on steady-state indinavir 800 mg TID (n = 22), ritonavir 400 mg/saquinavir 400 mg BID (n = 22, ritonavir; n = 17, saquinavir hard-gel capsules), or nelfinavir 750 mg TID (n = 4) or 1250 mg BID (n = 4). Concentration ratios were calculated by dividing the measured concentration by the median population value at the corresponding sampling time. Limits were based on the minimum P(05) (5th percentile) and maximum P(95) of these ratios found during the sampling interval. With these limits the authors determined (1) the proportion of patients falsely judged as noncompliers after observed ingestion, (2) discrimination between compliers and noncompliers, and (3) the absolute percentage of noncompliers. To judge the last two elements, two sets of random plasma samples were included: (1) samples sent in by the physician on suspicion of noncompliance (indinavir, n = 42; nelfinavir, n = 22;) or from a study population stating imperfect compliance in a questionnaire (ritonavir/saquinavir, n = 11); (2) control samples sent in routinely for monitoring therapeutic levels (indinavir, n = 41; nelfinavir, n = 201) or drawn from patients who stated perfect compliance in the questionnaire (ritonavir/saquinavir, n = 35). RESULTS: The following CORALS were found: indinavir <0.23 or >3.3; nelfinavir <0.36 or >2.1; ritonavir <0.18 or >1.9; saquinavir <0.28 or >2.3. In 31% to 55% of the patients suspected of noncompliance a plasma concentration ratio outside these limits was found. If a ratio was outside the limits, there was a 68% to 88% chance that that plasma sample belonged to a patient suspected of noncompliance, compared with the controls (all Chi-squared tests < 0.05). Compared with observed ingestion, these chances ranged from 87% to 92%. CONCLUSION: By using concentration ratio limits (CORALS), plasma samples of protease inhibitors with values outside these limits are highly indicative of partial or noncompliance.

Therapeutic drug monitoring of indinavir and nelfinavir to assess adherence to therapy in human immunodeficiency virus-infected children.

INTRODUCTION: Adherence to highly active antiretroviral therapy is required to obtain an optimal long term virologic response rate of HIV-1-infected children. Plasma concentrations of protease inhibitors (PIs) outside the limits of the reference values indicate nonadherence to antiretroviral therapy in adults. We studied during a 2-year follow-up period routinely taken plasma protease inhibitor concentrations to assess adherence to antiretroviral therapy in HIV-1-infected children. METHODS: In 40 children (ages 3 months to 18 years) blood samples were taken at regular outpatient visits every 12 weeks after the start of highly active antiretroviral therapy and analyzed for plasma concentrations of indinavir or nelfinavir by high performance liquid chromatography and for plasma HIV-1 RNA load. The percentage of samples fulfilling the criteria for adherence was assessed for each child by three methods. For each sample a concentration ratio was calculated by dividing the concentration in that sample by the time-adjusted population value. According to Method 1 concentration ratios below or above concentration ratio limits (CORALs) of population data obtained in adults were highly indicative of nonadherence. Because many children have high PI levels, Method 2 evaluated plasma samples of PIs with only the lower CORAL. According to Method 3 only children with plasma samples below the limit of quantification (0.04 mg/l) were considered noncompliant. Differences in adherence rate between virologic responders and virologic nonresponders and between adherence rates and the two protease inhibitors were analyzed. The cumulative incidence of HIV-1 RNA levels >500 copies/ml in children was calculated. RESULTS: Thirty-one children started treatment with indinavir, and nine children started treatment with nelfinavir. The median adherence rates for indinavir as determined by methods 1, 2 and 3 were 54% [interquartile range (IQR), 25 to 69%], 67% (IQR 50 to 92%) and 80% (IQR 63 to 100%), respectively. For nelfinavir median adherence rates of 60% (IQR 39 to 75%), 100% (IQR 67 to 100%) and 100% (IQR 100 to 100%) were observed. Adherence rates calculated with Method 2 were significantly higher in virologic responders ( = 0.04). Adherence rates calculated with Methods 2 and 3 were significantly lower in children using indinavir compared with those using nelfinavir ( = 0.02 and = 0.02, respectively). CONCLUSION: Calculation of adherence rates using the lower limit of CORALs of indinavir or nelfinavir in children may be a useful measurement for the assessment of nonadherence to antiretroviral therapy in children.

Assessment of adherence to HIV protease inhibitors: comparison and combination of various methods, including MEMS (electronic monitoring), patient and nurse report, and therapeutic drug monitoring.

BACKGROUND: Adherence to protease inhibitor-containing antiretroviral therapy is crucial, but difficult to measure. OBJECTIVE: To compare and combine various methods of measuring adherence to the strict protease inhibitor-containing regimens. METHODS: The following methods were used: medication event monitoring system (MEMS) caps (electronic monitoring), therapeutic drug monitoring, pill count, pharmacy refill data, questionnaires, diaries (for registration of food patterns and special events related to the use of MEMS), adherence assessment by the physician and clinical nurse specialist, and in-depth interviews. In addition, ultrasensitive viral load and resistance testing was performed. RESULTS: Twenty-eight patients were included; data could be evaluated in 26. According to MEMS data, 25% of the patients took fewer than 95% of all doses, and two thirds of the patients took fewer than 95% of the doses on time. Only 43% of the patients showed good adherence with food restrictions. Methods that showed significant correlations with MEMS results were patients' self-reported adherence; therapeutic drug monitoring, indicating plasma levels outside predefined ranges; and estimation of adherence by a clinical nurse specialist, especially by in-depth interview. CONCLUSION: Diary-corrected MEMS data gave a detailed insight into patients' adherence patterns. Patients' self-report and therapeutic drug monitoring were significantly correlated with the MEMS data, and the clinical nurse specialist may also play a role in identifying patients who are imperfectly adherent.

Pros and cons of therapeutic drug monitoring of antiretroviral agents.

Therapeutic drug monitoring has the promise to become a part of routine patient care in the treatment of HIV infection. It is known that plasma drug concentrations of protease inhibitors and non-nucleoside reverse transcriptase inhibitors are better predictors of antiviral response or toxicity than drug dose is. Furthermore, high interpatient variability is significant. In addition, therapeutic drug monitoring may be used as a direct and objective instrument to measure non-adherence. This review describes possibilities and limitations of therapeutic drug monitoring in HIV treatment.

The influence of efavirenz on the pharmacokinetics of a twice-daily combination of indinavir and low-dose ritonavir in healthy volunteers.

OBJECTIVE: This study evaluated the effect of multiple-dose efavirenz on the steady-state pharmacokinetics of the combination of indinavir (800 mg) and low-dose ritonavir (100 mg) twice a day, in which ritonavir is used to increase indinavir plasma concentrations. METHODS: Eighteen healthy male volunteers participated in this multiple-dose, 1-arm, 2-period interaction study. They took a combination of 800 mg indinavir and 100 mg ritonavir with food for 15 days. From days 15 to 29, a once-daily administration of 600 mg efavirenz was added to the combination. Pharmacokinetics of indinavir and ritonavir on days 15 and 29 were compared. RESULTS: Fourteen volunteers completed the study. The addition of efavirenz resulted in significant reductions (P <.01) in indinavir area under the curve (AUC, -25%), trough concentration (C(min), -50%), and maximum concentration (C(max), -17%). All indinavir C(min) levels on day 29 remained equivalent to or above the mean C(min) value described for the regimen of 800 mg indinavir three times a day, without ritonavir (0.15 mg/L). Changes in ritonavir AUC, C(min), and C(max) were -36%, -39%, and -34%, respectively. Pharmacokinetics of efavirenz on day 29 were comparable with published data. CONCLUSIONS: The addition of efavirenz to a combination of 800 mg indinavir and 100 mg ritonavir twice daily results in significant decreases in AUC, C(max), and especially C(min) of indinavir. The dose of indinavir or ritonavir should be increased to maintain similar indinavir drug levels after addition of efavirenz to the indinavir-ritonavir combination. Dose modifications may not be needed in antiretroviral-naive human immunodeficiency virus-infected patients if the reference C(min) of the regimen of 800 mg indinavir 3 times a day is considered to be adequate.