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Anitiretroviral Agents: adherence, PK
Written by Scott Penzak, PharmD, National Institutes of Health
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TOPICS:
Intervention For Depression
Non-Adherence & CD4s
Efavirenz: blood levels & CNS side effects
Tenofovir-DDI
Kaletra + Amprenavir
TDM
Twenty-five poster presentations were included in the session entitled "Antiretroviral Agents, Adherence, Pharmacokinetics, and Pharmacodynamics" at this year's ICAAC (Tuesday, December 18, 1:30-3:00 pm) in Chicago. While some of the data are interesting, by-and-large no presentations appear destined to have a major clinical impact.
Depression Reduces HAART's Effectiveness
Multiple studies and reviews have noted that depression can hinder adherence among patients with HIV infection.1 Moreover, additional studies have shown that cognitive and pharmacological therapy can improve depressive symptoms among patients with HIV infection.1 A study by Bangsberg and colleagues confirms these data.2 Depressive symptoms were measured in HIV infected patients by the Beck Depression Inventory (BDI) scale and categorized as < 15 (less depressive symptoms) and > 15 (more depressive symptoms). Adherence was assessed -by the use of MEMS caps and pill counts performed at the patient's place of residence- along with CD4+ count, duration of HAART, number of unstructured treatment interruptions > 30 days, and viral load < 400 copies/mL. Significant depressive symptoms (BDI > 15) were noted in 33/83 (40%) study participants. Subjects were followed up for 2.5 years. Patients with BDI > 15 were on HAART for a longer period of time (35 months) compared to those with BDI < 15 (p =.01). Patients with significant depression also had a significantly higher number of unstructured treatment interuptions (46%) compared to those without significant depression (24%; p = .01) and HIV-RNA was less than 400 copies/mL in 15% and 40% of patients with and without significant depression, respectively. Lastly, adherence was significantly greater by MEMS data (79% vs. 53%; p= .02) and pill counts (66% vs. 44%; p=.02) in patients without significant depression. Of note, gender, ethnicity, injection drug use and alcohol use were examined in bivariate and multivariate analyses and found not to be significant confounders. Data from this study are not particularly surprising. Because cognitive and pharmacologic interventions are typically safe and effective for the treatment of depression in patients with HIV infection, such patients should be routinely screened for depressive symptoms and treated as indicated -all the while being cognizant of potential drug-drug interactions between antiretroviral and antidepressant medications.
Non-Adherence & CD4 increases
The same group of investigators as above analyzed CD4+ counts over varying quartiles of adherence ( < 46%; 47-72%; 73-88%; > 88%) in 115 HIV-infected patients receiving > 3 antiretroviral (ARV) medications.3 HIV-RNA was also assessed. At 12 months, CD4+ counts increased 15-20% above baseline values in both the 73-88% and > 88% groups despite a greater decline in HIV-RNA in the > 88% group. These data show that CD4+ cell increases occur over a 12-month period with lower adherence levels than those required for reliable viral suppression. The authors note that findings from this study are consistent with epidemiological observations of delayed progression and mortality in the absence of outstanding adherence. However, beyond 12 months -presumably at some point- patients with poorer adherence (i.e. 73-88%) will experience virologic rebound and eventual declines in CD4+ cells. Thus, while these data are encouraging, patients should still strive to achieve adherence levels that are associated with reliable and durable viral suppression (> 90-95%).
Are Hi Efavirenz Blood Levels Associated With CNS Side Effects?
Several posters discussed the pharmacokinetics of efavirenz in relation to central nervous system (CNS) toxicity and viral suppression; long term adverse effects with efavirenz were also assessed.4-6 Nunez et. al. reported that plasma efavirenz concentrations > 3.5 mcg/mL were more frequent among subjects with CNS toxicity (13/15) compared to controls (17/36; p=.02).4 This data is in agreement with that recently reported by Marzolini et. al. in which efavirenz concentrations > 4 mcg/mL were associated with CNS toxicity among 130 HIV-infected patients.7 The authors suggest that the data from the 15 patients presented here support the introduction of therapeutic drug monitoring (TDM) for efavirenz in clinical practice. While this may eventually prove to be true, substantiating ARV efficacy along with reduced CNS symptoms with efavirenz doses below 600 mg daily are necessary before efavirenz TDM can be routinely recommended.
In contrast to the above findings, Fiske et. al. from Dupont Pharmaceuticals, found no relationship between efavirenz concentrations (AUC and Cmin) and CNS symptoms and HIV-RNA suppression.5 Pharmacokinetic data for efavirenz were retrospectively analyzed with respect to CNS symptoms in 524 patients, while data from 166 patients treated with efavirenz + lamivudine + zidovudine were evaluated to predict early ( 8 week) and later (48 week) virologic response. As noted, no significant associations were found between efavirenz plasma concentrations and virologic efficacy or CNS toxicity. It bears mentioning that at 48 weeks the median AUC in 6 patients whose HIV-RNA never dropped below 50 copies/mL was 150 M*hr compared to a median AUC of 173 M*hr in 93 patients responding to therapy with HIV-RNA < 50 copies/mL at 48 weeks. However, subjects with HIV-RNA that never declined to < 50 copies/mL were too few (n=6) to draw any statistical conclusions between the groups. Also of note, the patient population in this study was ARV nave; patient populations with prior treatment history may exhibit different concentration-effect relationships with efavirenz. In conclusion, these data are inconsistent with those reported by Nunez4 and Marzolini.8 Further study is necessary to reconcile these disparate findings and elucidate the relationship (if any) between efavirenz plasma concentrations and CNS toxicity and virologic response.
Fumaz and colleagues reported on the impact of CNS side effects and quality of life (QOL) and adherence with efavirenz.6 The study was prospective, randomized, and included 100 HIV positive patients who had experienced virologic failure with at least one protease inhibitor. Patients were randomized to switch to efavirenz plus 2 NRTIs or 2 NRTIs plus one or more new protease inhibitors. Data on adverse effects, QOL, and adherence were collected over 48 weeks. Numerous percentages for multiple adverse effects (e.g. dizziness; abnormal dreaming etc.) were reported, comprising a sea of numbers. Suffice it to say that most CNS side effects occurred in > 35% of patients 4 weeks after initiating therapy with efavirenz; this declined to < 15% at 48 weeks. Despite the incidence of adverse effects with efavirenz, QOL actually increased over the 48 week study period (p < .001); this was primarily due to the simplicity of efavirenz administration (once daily). Interestingly, there was no change from baseline in QOL among the group randomized to receive protease inhibitor therapy. At 48 weeks adherence was > 95% in 94% and 93% of efavirenz and protease inhibitor recipients, respectively. The results from this study provide clinicians with data to reassure patients that side effects with efavirenz -although prominent early in therapy- drop considerably over time. Moreover, the ease of efavirenz administration appears to overshadow its side effect profile; patients remain adherent over time and their quality of life improves.
Tenofovir + DDI
Turning our attention away from efavirenz, a drug interaction study between tenofovir disoproxil fumarate (TDF) and ddI (buffered formulation) was presented.8 Those who have familiarized themselves with the TDF package insert (Gilead) will recall this interaction. The study was conducted in 14 healthy volunteers and assessed the 2-way interaction between ddI and TDF under steady-state conditions. ddI exposure was increased approximately 40% with concurrent TDF, while TDF pharmacokinetics were unaffected. The authors speculate that the increase in ddI AUC with TDF may be the result of competition for renal elimination, although an effect on ddI absorption cannot be ruled out (particularly since ddI Cmax and AUC increased and half-life was unchanged with concurrent TDF). While theoretically possible that the increase in ddI exposure with TDF may predispose patients to ddI toxicities, this was not observed in a pooled safety analysis. A current study is planned to determine whether TDF modulates the pharmacokinetics of enteric-coated ddI.
Kaletra + Amprenavir
Meynard et. al. reported an interesting interaction between lopinavir-ritonavir (LPV-RTV) and amprenavir (APV).9 Plasma Cmin concentrations were determined in consecutive patients receiving:
- LPV-RTV 400 mg-100 mg twice daily (n=11)
- APV 600 mg twice daily + RTV 100 mg twice daily (n=36)
- LPV-RTV 400 mg-100 mg twice daily + APV 600 mg twice daily (n=10)
- LPV-RTV 400 mg-100 mg twice daily + APV 750 mg twice daily (n=5)
All patients received concurrent NRTIs without NNRTI therapy. APV median Cmins were:
- 1,755 ng/mL (607-3066): APV 600 mg twice daily + RTV 100 mg twice daily
- 778 ng/mL (190-2037): LPV-RTV 400 mg-100 mg twice daily + APV 600 mg twice daily
- 998 ng/mL (669-3066): LPV-RTV 400 mg-100 mg twice daily + APV 750 mg twice daily
Median lopinavir Cmins were:
- 3326 ng/mL (1316-6698): LPV-RTV 400 mg-100 mg twice daily
- 2226 ng/mL (518-8722): LPV-RTV 400 mg-100 mg twice daily + APV 600 mg twice daily
- 1716 ng/mL (347-4810): LPV-RTV 400 mg-100 mg twice daily + APV 750 mg twice daily
LPV-RTV appeared to markedly reduce APV exposure (by approximately 50%) in this study (p < .001). Unfortunately, the wide interpatient variability in APV concentrations and the small number of patients studied mandate that results from this study be interpreted cautiously. Nonetheless, these results support the use of a 750 mg twice daily dose of APV when given along with LPV-RTV as recommended by the LPV-RTV product information (Abbott). Administering APV 750 mg twice daily (with LPV-RTV) is expected to approximate the systemic APV exposure achieved with conventional APV dosing (1200 mg twice daily). When LPV-RTV is given concurrently with APV, it is probably -based on these data- not possible to achieve plasma APV concentrations comparable to those achieved with APV 600 mg twice daily plus RTV 100 mg twice daily. Also of note, is that fact that APV appeared to lower LPV-RTV concentrations; but again, interpatient variability in LPV concentrations was large. Future investigations assessing the interaction between LPV-RTV and APV are being conducted in crossover fashion in order to reduce the impact of interpatient variability (due to diet, concomitant drugs etc.) in the disposition of these agents. Nonetheless, results from this study have scientists speculating that lopinavir and amprenavir may induce the CYP3A4-mediated metabolism of each other; further study is necessary to confirm or refute such speculation.
TDM
Lastly, several studies evaluated the concentration-effect relationship of protease inhibitors and the potential for TDM.10-11 One examined indinavir plasma concentrations and correlated Cmax and AUC with renal toxicity and virologic response, respectively.10 A separate study concluded that a higher risk of viral rebound is associated with lower plasma concentrations of nelfinavir but not indinavir.11 Both studies concluded that TDM is necessary in routine clinical practice. Neither study provided particularly new or interesting information nor did either incorporate resistance testing to determine virtual phenotypes or inhibitory quotients (IQ). In general, the data for TDM presented at this years ICAAC paled in comparison to other conferences (8th Conference on Retroviruses and Opportunistic Infections and 2nd International Workshop on Clinical Pharmacology of HIV Therapy) that have taken place over the past year.
References
1. Penzak SR, Reddy YS, Grimsley SR. Depression in patients with HIV infection. Am J Health Syst Pharm 2000;57:376-86.
2. Bangsberg DR, Perry S, Charlebois ED et. al. Depression symptoms (DS) predict HAART adherence, duration, unstructured treatment interruption and viral suppression. In: Abstracts of the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago, IL, USA. December 16-19, 2001 [I-1721].
3. Bangsberg DR, Perry S, Deeks SG et. al. Rising CD4+ cell counts in spite of incomplete adherence over 12 months. In: Abstracts of the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago, IL, USA. December 16-19, 2001 [I-1722].
4. Nunez M, Gonzalez De Requena D, Gallego L et. al. Impact of efavirenz plasma levels on the development of severe central nervous system toxicity. In: Abstracts of the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago, IL, USA. December 16-19, 2001 [I-1724].
5. Fiske WD, Joshi AS, Labriola DF. An assessment of population pharmacokinetic parameters of efavirenz on nervous system symptoms and suppression of HIV-RNA. In: Abstracts of the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago, IL, USA. December 16-19, 2001 [I-1727].
6. Fumaz CR, Tuldra A, Ferrer M et. al. Impact of central nervous system disorders (CNSD) on quality of life (QOL) and adherence (ADH) to treatment (tt) of HIV-1+ patients (pts) treated with efavirenz (EFZ). In: Abstracts of the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago, IL, USA. December 16-19, 2001 [I-1726].
7. Marzolini C, Telenti A, Decosterd LA et. al. Efavirenz plasma levels can predict treatment failure and central nervous system side effects in HIV-1 infected patients. AIDS 2001;15:71-75.
8. Flaherty J, Kearney B, Wolf J et. al. Coadministration of tenofovir DF (TDF) and didanosine (ddI): a pharmacokinetic (PK) and safety evaluation. In: Abstracts of the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago, IL, USA. December 16-19, 2001 [I-1729].
9. Meynard JL, Poirer JM, Guiard-schmid JB. Impact of ABT 378/r on the amprenavir (APV) plasma concentrations in HIV-experienced patients treated by the association APV-ABT 378/r. In: Abstracts of the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago, IL, USA. December 16-19, 2001 [I-1736].
10. Gatti G, DiBiagio A, DePascalis CR et. al. The relationship between systemic exposure to indinavir and response (virologic efficacy and renal toxicity). In: Abstracts of the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago, IL, USA. December 16-19, 2001 [I-1732].
11. LeMoing V, Peytavin G, Ecobichon JL et. al. Plasma levels of indinavir and nelfinavir at time of viral response may have a different impact on the risk of further viral failure in HIV-infected patients. In: Abstracts of the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago, IL, USA. December 16-19, 2001 [I-1733].
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