Personalizing HIV therapy, mission impossible?

Sustained HIV suppression depends on a number of factors including therapy adherence, management of side effects, viral resistance and individual characteristics of patients and therapeutic settings. Treatment response rates range up to 90% in therapy naïve patients but decline to approximately 50% in patients who received several antiretrovirals during treatment history. Furthermore, HIV protease inhibitors (PI) and non nucleoside reverse transcriptase inhibitors (NNRTI) plasma concentrations display high inter- and intra individual variability and the therapeutic window is comparably narrow. In this therapeutic setting the personalization of dosing regimens has been suggested in many cases to tailor the ARV plasma concentrations with the intention to maximize therapy success and minimize side effects in the individual. However, personalizing therapy by modifying the dosing regimen bears the danger of losing therapeutic efficacy, increasing side effects or causing viral resistance. This topical review identifies pharmacokinetic and pharmacodynamic models of antiretroviral therapy appraising the potential application to HIV therapy and discusses its future in the light of new drug classes and fix-dose combinations

Drug-drug interactions between phenprocoumon or acenocoumarol and the direct thrombininhibitor argatroban : a clinical phase-I trial with healthy volunteers

In dieser klinischen Phase I-Studie an 39 gesunden, männlichen Probanden im Alter zwischen 18 und 45 Jahren wurde die Fragestellung untersucht, wie ein Übergang von intravenöser Blutgerinnungshemmung mit dem direkten Thrombinhemmer Argatroban und den oralen Antikoagulantien Phenprocoumon und Acenocoumarol in der klinischen Praxis zu kontrollieren ist. Bei den bisher verwendeten Laboruntersuchungen, wie der aPTT existieren Interaktionen zwischen Argatroban und oraler Antikoagulation, welche nicht notwendigerweise die wirkliche in vivo Situation reflektieren, was durch eine ex vivo-in vitro-Interferenz des Gerinnungsassays verursacht wird. APTT Reagenzien aktivieren die intrinsische Gerinnungskaskade zu einem sehr frühen Zeitpunkt (gleich zu Beginn derselben bei Faktor XI). Dadurch werden die Interaktionen zwischen der oralen Antikoagulation und den Rückkopplungsmechanismen zwischen beiden Gerinnungswegen, welche durch die orale Antikoagulation teilweise erschöpft sind, begreifbar. Ebenso wurde die Interaktion zwischen anderen direkten Thrombinhemmern und der oralen Antikoagulation am Beispiel Napsagatran mit Warfarin beschrieben 35: Die Gabe von Napsagatran alleine führte zur Erhöhung von aPTT und Prothrombinzeit (PT), die zusätzliche Einmaldosis Warfarin erhöhte die AUEC (Fläche unter der Effekt-Kurve) für die PT zusätzlich um das vierfache und für die aPTT um 45%. Obwohl die PT unter dem Einfluss direkter Thrombinhemmer verlängert ist, wird sie nicht als Parameter des Monitorings der Wirkung therapeutischer Dosierungen von Argatroban und anderen direkten Thrombinhemmern bei der Thrombosephrophylaxe und Behandlung tiefer Beinvenethrombosen empfohlen 39. Die aPTT wird hingegen, neben ihrem Einsatz zur Überwachung der klinischen Therapie direkter Thrombinhemmer 40,41, auch als pharmakodynamischer Schlüsselparameter in Phase-I-Studien derselben eingesetzt 42,43. Da jedoch höhere Konzentrationen der Thrombinhemmer die aPTT-Werte für die Kalibrierung verändern und darüber hinaus verschiedene aPTT-Reagenzien mit unterschiedlicher Empfindlichkeit gegenüber den Thrombinhemmern angeboten werden, ist die aPTT nicht der ideale Parameter zur Überwachung der Wirkung direkter Thrombinhemmer. Die ECT ist hierfür wesentlich spezifischer 40,41. Dennoch werden validierte ECT-Assays nicht kommerziell vertrieben, was deren Einsatz in der Klinik bisher unmöglich macht. Insofern ist es notwendig geworden, eine Empfehlung für den Übergang von intravenöser auf orale Antikoagulation mit dem bisherigen Instrument der INR zu finden. Auch wenn dies aus den o.g. Gründen nicht optimal ist, mag es zulässig sein, die Nomogramme für Acenocoumarol und Phenprocoumon in einfache Regeln zu übersetzen, ohne daß ein Sicherheitsproblem in der Klinik entsteht. Vorausgesetzt, ein Vorhersagefehler von 3,0 bestehen kann. Dies ist in der Praxis aufmerksam zu kontrollieren. Argatroban ist also für HIT Typ II-Patienten, die unter klinischen Bedingungen antikoaguliert werden müssen, eine gut steuerbare Alternative, bei welcher auch die anschließende Umstellung auf orale Antikoagulation kontrolliert sicher handhabbar ist.This clinical phase I - study with 39 healthy male volunteers was performed to evaluate the safety and efficacy of an intravenous anticoagulation with the direct thrombin inhibitor argatroban. The study was designed to simulate different situations in a clinical setting where a transition from intravenous to oral anticoagulation is needed. We investigated healthy subjects with either three different doses argatroban alone or in combination with the oral anticoagulants acenocoumarol and phenprocoumon. A comparison of INR, aPTT, ECT and bleeding time was performed in order to find a suitable solution for the clinical monitoring of the anticoagulation effects of the described drugs. As a main result of the study the regression analysis allows the differentiation between argatroban doses and the ISI of the PT-reagent as well as the used oral anticoagulants. Thus we could use the nomogram for a certain argatroban dosage of either 1,2 or 3 µg/kg/min and the ISI of the inhouse laboratory to conclude from the in vivo assessed INR to the 'real' INR value and control therapy in patients. But a complicated method might not be useful in practice. Therefore it can be more suitable to translate the nomograms of acenocoumarol and phenprocoumon into general rules, without creating a safety problem. Assuming that a prediction error of < ± 0.6 is acceptable, the nomograms of acenocoumarol and phenprocoumon allow a prediction of the real coagulation conditions up to a dose of 2.0 µg/kg/min, if an ISI of 1-2 of the PT-reagent is used. Actual guidelines describe a stop of the infusion therapy with heparines, if the INR has reached 2.0. Yet we do propose an easy-to-use and safe rule for the calculation of the 'real' INR for the transition from argatroban to oral anticoagulation : 1. The i.v. application of argatroban can be stopped, if under simultaneous oral anticoagulation INR has reached 4.0 for an appropriate period. This applies to an ISI of 1-2 of the PT reagent. In this case the real INR will be in between 2.2 and 3.7. 2. The clinician has to subtract 5-15 seconds from the aPTT-results under argatroban and beginning oral anticoagulation. This leads to the conclusion that a prolongation of the aPTT during the transition from argatroban to oral anticoagulation should not lead to an interuption or dose reduction of the argatroban infusion in this period. Generally the dose of argatroban should be fixed to 1-2 µg/kg/min during the transition period. As well as with hirudin, the ecarin clotting time should be, if clinically indicated, preferably used for the monitoring of the direct argatroban effects on coagulation. In this case the aPTT does not deliver exact results, which might be as well needed in high risk patients. This applies to either the use of argatroban alone or its coadministration with oral anticoagulants

Lipometabolic side-effects of three ritonavir-boosted double protease inhibitor regimens without reverse transcriptase inhibitors

Poster presentation: Purpose of the study To compare the lipometabolic profiles of three double-boosted protease inhibitor (PI) regimens at standard dose, containing saquinavir and ritonavir in combination with lopinavir (LOPSAQ), atazanavir (ATSAQ) or fosamprenavir (FOSAQ) in HIV-positive patients, treated without reverse transcriptase inhibitors (RTI). ..

Virological and immunological response to three boosted protease inhibitor regimens

Poster presentation: Purpose of the study To compare the virological, immunological and clinical response to three boosted double protease inhibitor (PI) regimens of saquinavir and ritonavir in combination with lopinavir (LOPSAQ), atazanavir (ATSAQ) or fosamprenavir (FOSAQ) without reverse transcriptase inhibitors (RTI) in HIV-positive patients with limited RTI treatment options. ..

Repositioning HIV protease inhibitors and nucleos(t)ide RNA polymerase inhibitors for the treatment of SARS-CoV-2 infection and COVID-19

AIMS: SARS-CoV-2 is a single-stranded RNA virus which is part of the ß-coronavirus family (like SARS 2002 and MERS 2012). The high prevalence of hospitalization and mortality, in addition to the lack of vaccines and therapeutics, forces scientists and clinicians around the world to evaluate new therapeutic options. One strategy is the repositioning of already known drugs, which were approved drugs for other indications. SUBJECT AND METHOD: SARS-CoV-2 entry inhibitors, RNA polymerase inhibitors, and protease inhibitors seem to be valuable targets of research. At the beginning of the pandemic, the ClinicalTrials.gov webpage listed n=479 clinical trials related to the antiviral treatment of SARS-CoV-2 (01.04.2020, “SARS-CoV-2,” “COVID-19,” “antivirals,” “therapy”), of which n=376 are still accessible online in January 2021 (10.01.2021). Taking into account further studies not listed in the CTG webpage, this narrative review appraises HIV protease inhibitors and nucleos(t)ide RNA polymerase inhibitors as promising candidates for the treatment of COVID-19. RESULTS: opinavir/ritonavir, darunavir/cobicistat, remdesivir, tenofovir-disoproxilfumarate, favipriravir, and sofosbuvir are evaluated in clinical studies worldwide. Study designs show a high variability and results often are contradictory. Remdesivir is the drug, which is deployed in nearly 70% of the reviewed clinical trials, followed by lopinavir/ritonavir, favipiravir, ribavirine, and sofosbuvir. DISCUSSION: This review discusses the pharmacological/clinical background and questions the rationale and study design of clinical trials with already approved HIV protease inhibitors and nucleos(t)ide RNA polymerase inhibitors which are repositioned during the SARS-CoV-2 pandemic worldwide. Proposals are made for future study design and drug repositioning of approved antiretroviral compounds

Cytochrome P450 3A Inhibition by Atazanavir and Ritonavir, but Not Demography or Drug Formulation, Influences Saquinavir Population Pharmacokinetics in Human Immunodeficiency Virus Type 1-Infected Adults▿

Inadequate concentrations of the human immunodeficiency virus (HIV) protease inhibitor saquinavir jeopardize individual therapy success or produce side effects despite treatment according to the current guidelines. We performed a population pharmacokinetic analysis with NONMEM and determined that the steady-state pharmacokinetics of saquinavir in 136 HIV type 1-infected adults was modulated by a decrease in saquinavir CL following coadministration of the cytochrome P450 3A inhibitors ritonavir and atazanavir. In contrast, age, sex, weight, pregnancy, and the pharmaceutical formulation exerted only minor, nonsignificant effects

Decrease of Atazanavir and Lopinavir Plasma Concentrations in a Boosted Double Human Immunodeficiency Virus Protease Inhibitor Salvage Regimen▿

The human immunodeficiency virus protease inhibitor combination of atazanavir (ATV)-lopinavir-ritonavir was reported to exhibit a mutual pharmacoenhancement of plasma lopinavir and ATV concentrations which may be beneficial for salvage patients. We identified 17 patients in our pharmacokinetic database taking this combination and found conflicting results. Plasma concentrations of both ATV and lopinavir were modestly, although not significantly, decreased when the drugs were coadministered. Therefore, patients should be selected carefully for this regimen and frequent clinical and therapeutic drug monitoring is strongly advised

Association of Saquinavir Plasma Concentrations with Side Effects but Not with Antiretroviral Outcome in Patients Infected with Protease Inhibitor-Susceptible Human Immunodeficiency Virus Type 1▿

The objective of this study was to identify parameters among saquinavir pharmacokinetics, patients' demographics or comedications, to be addressed for improved personalized therapy. The presence of human immunodeficiency virus type 1 (HIV-1) RNA at therapy week 48 (principal target parameter), CD4 cell count at week 48, infections and side effects during 48 weeks, indicators of liver toxicity and lipid abnormalities at week 48, and a 12-h saquinavir plasma concentration-versus-time profile were assessed in 56 patients receiving saquinavir-ritonavir (1,000 and 100 mg, respectively) twice daily (44 therapy-naïve and 12 antiretrovirally pretreated patients) for association with saquinavir plasma concentrations, demographics, baseline values of target parameters, and coadministered antiretrovirals. Antiretroviral failure was observed in 8 of the 56 patients in whom HIV-1 RNA was detectable at week 48. This therapeutic failure was not associated with individual saquinavir pharmacokinetics. More likely, therapeutic failure was related to incidences interfering with antiretroviral therapy, causing therapy interruptions or incompliance. Weak associations were, however, seen between high maximum saquinavir plasma concentrations and both CD4 counts of ≥200 cells μl−1 at week 48 (P = 0.014) and constitutional side effects during 48 weeks (P = 0.002). However, patients with high CD4 counts and constitutional side effects were not identical (P = 0.53). Saquinavir therapeutic drug monitoring in patients infected with protease inhibitor-susceptible HIV-1 taking saquinavir-ritonavir (1,000 and 100 mg, respectively) is not demanded for improving the antiretroviral effect. It may be contemplated in cases with constitutional side effects or low CD4 counts with weak immune responses