THERAPEUTIC DRUG MANAGEMENT OF HIV-INFECTED PATIENTS WITH COMORBIDITIES

Today, antiretroviral therapy is potent, convenient and usually well tolerated, capable of reducing human immunodeficiency virus (HIV) blood concentration to undetectable values within a few weeks from treatment initiation and of inducing a robust and sustained CD4 T-cell gain. Despite these unquestioned successes, the problem is far from being solved: even in countries with full access to ntiretroviral treatment, life expectancy of people under ARV therapy remains lower with respect to that of uninfected people. Furthermore, large populations of HIV infected individuals who are not diagnosed remain untreated or enter treatment at a very late stage of diseases. Undiagnosed and untreated population represents an infected reservoir that increases HIV transmission. Patient with HIV/Acquired Immunodeficiency Syndrome (AIDS) disease face many problems when commencing antiretroviral therapy also called as highly active ntiretroviral therapy (HAART). In addition to understanding their HIV disease, they are prescribed with combination antiretroviral therapy and have a higher risk of developing adverse drug reactions. Consequently, patients feel that HIV treatment is a burden and turn non-adherent to HAART. One important tool for better patient compliance towards HAART is optimizing therapy for minimal side effects by therapeutic drug monitoring. In the present PhD research work entitled “Traditional and novel therapeutic approaches for the personalized therapy in HIV patients co-infected with opportunistic infections and other co-morbidities” we studied the role of therapeutic drug monitoring in HAART therapy for personalized patient care. The experimental section of the thesis is broadly categories as follows • HPLC UV assay method development for ARV drugs quantification • LC-MS/MS assay method development for ARV drugs quantification • Pharmacokinetics of ARV drugs dosing at conventional doses • Association between antiretroviral pharmacokinetics and drug-related metabolic disorders • Pharmacokinetic interaction between raltegravir and anti HCV drugs in an HIV-HCV liver transplant recipientIn conclusion we developed and validated HPLC-UV and LC-MS/MS methods which are accurate, reproducible and able to simultaneously quantify nineteen antiretroviral agents in plasma by a single assay. Good extraction efficiency and low limit of quantification make these methods suitable for use in clinical trials and for TDM. This method has been successfully applied for our routine TDM and PK studies in HIV-infected patients. When applied these methods for routine therapeutic drug monitoring of antiretroviral drugs we were able to document that a significant proportion of patients treated with some of the antiretrovirals at marketed doses had plasma concentrations exceeding the upper therapeutic threshold. Such selected patients, who might have the highest risk of experiencing drug-related complications, may benefit from therapeutic drug monitoring -driven adjustments in antiretroviral doses with potential advantages in terms of costs and toxicity. In case of atazanavir, a protease inhibitor, we documented that significant proportion of patients treated with conventional atazanavir dosages had plasma concentrations exceeding the upper therapeutic threshold. A likely possibility is an inherited deficit in atazanavir clearance and/or atazanavir metabolism; in particular, atazanavir is a dedicated CYP3A substrate, which includes 3A4 and 3A5, two polymorphic genes. The administration of unboosted atazanavir to healthy subjects carrying the defective CYP3A5*3 resulted in significantly higher ATV concentrations compared with values measured in patients expressing CYP3A5 . Assuming that over 90% of patients in our study were Caucasians with a high prevalence of carriers of CYP3A5*3, it is likely that the observed overexposure to atazanavir concentrations is the result of excessively high dose of ritonavir- boosted atazanavir or of needless boosting with ritonavir. This is a first important conclusion of our study that raises concerns on the need of full dose of ritonavir-boosted atazanavir in caucasian patients and opens new questions about the atazanavir dosages that should considered correct (or in label and off label in Europe). We found the positive correlation of atazanavir concentration with hyperbilirubinemia and lipid dystrophy. We confirmed that the overexposure to ATV is associated with increased risk of nephrolitiasis. We also found that such patients have the highest risk of experiencing atazanavir -related complications and may benefit from therapeutic drug monitoring -driven adjustments in atazanavir dosage with potential advantages in terms of costs and toxicity. At the end when we monitored raltegravir concentration in HIV infected patient co-infected with hepatitis C virus we observed a threefold increase in exposure of raltegravir concentration. HIV-HCV co-infected liver transplant recipients was simultaneously taking ombitasvir, dasabuvir and paritaprevir/ritonavir (3D regimen) for recurrent Hepatitis C virus infection. Such suspected interaction, which might be clinically relevant in selected patients, is easily manageable through therapeutic drug monitoring of raltegravir concentrations, eventually improving the safety of this drug.