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

The manifesto of pharmacoenosis: Merging hiv pharmacology into pathocoenosis and syndemics in developing countries

Pathocoenosis and syndemics theories have emerged in the last decades meeting the frequent need of better understanding interconnections and reciprocal influences that coexistent communicable and non-communicable diseases play in a specific population. Nevertheless, the attention to pharmacokinetic and pharmacodynamics interactions of co-administered drugs for co-present diseases is to date limitedly paid to alert against detrimental pharmacological combos. Low and middle-income countries are plagued by the highest burden of HIV, tuberculosis, malaria, and helminthiasis, and they are experiencing an alarming rise in non-communicable disorders. In these settings, co-infections and comorbidities are common, but no tailored prescribing nor clinical trials are used to assess and exploit existing opportunities for the simultaneous and potentially synergistic treatment of intertwined diseases. Pharmacoenosis is the set of interactions that take place within a host as well as within a population due to the compresence of two or more diseases and their respective treatments. This framework should pilot integrated health programmes and routine clinical practice to face drug–drug interaction issues, avoiding negative co-administrations but also exploiting potential favourable ones to make the best out of the worst situations; still, to date, guiding data on the latter possibility is limited. Therefore, in this narrative review, we have briefly described both detrimental and favourable physiopathological interactions between HIV and other common co-occurring pathologies (malaria, tuberculosis, helminths, and cardiovascular disorders), and we have presented examples of advantageous potential pharmacological interactions among the drugs prescribed for these diseases from a pharmacokinetics, pharmacodynamics, and pharmacogenetics standpoint

Low plasmatic concentration of intensified antiretroviral therapy in a pregnant woman: a case report

Identifying the most appropriate antiretroviral regimen for pregnant women with Human Immunodeficiency Virus (HIV-1) infection can be challenging, mainly due to pregnancy-related physiological alterations which can significantly reduce maternal drug plasma concentration. We would like to report our experience as it consists of an unusual case of low plasmatic concentration of antiretroviral drugs despite regimen intensification in a HIV-positive pregnant woman. It also underlines the need for accurate monitoring and treatment adjustment in pregnant women with Human Immunodeficiency Virus (HIV)

Innovation and Standards in Clinical Practice: The Case of HIV Treatments

The goal of this study was to analyze the emergence of treatment standards associated with the adoption of anti-HIV drug innovations in the empirical setting of Italian clinical practice. Due to the rapid pace of technological change and the initial uncertainty concerning capabilities and indications of new treatments, the emergence of standard patterns of care turned out to be far from predictable and straightforward. Health providers' links to an international medicine and their internal coordination mechanisms were found to be associated with clinical decisions. Effectiveness and health costs of diverging treatment strategies were also compared.Medical innovation, Treatment standard, Clinical guidelines, HIV/AIDS, Sequence analysis

Risk of Cardiovascular Events in People with HIV (PWH) Treated with Integrase Strand-Transfer Inhibitors: The Debate Is Not Over; Results of the SCOLTA Study.

Cardiovascular disease (CVD) is common in people with HIV (PWH), and has great impact in terms of morbidity and mortality. Several intertwined mechanisms are believed to play a role in determining the increased risk of CVD, including the effect of certain antiretrovirals; among these, the role of integrase strand-transfer inhibitors (INSTIs) is yet to be fully elucidated. We conducted a multicenter, observational study comprising 4984 PWH evaluating the antiretroviral therapy (ART)-related nature of CVD in real life settings, both in naïve vs. treatment-experienced people. A comparison was conducted between INSTIs vs. either protease inhibitors (PIs) or non-nucleoside reverse transcriptase inhibitors (NNRTIs) considering demographic, baseline clinical characteristics, incidence of CVD in both 2-year and complete follow-up periods. Among 2357 PWH exposed to INSTIs, 24 people experienced CVD; the corresponding figure was 12 cases out of 2599 PWH exposed to other ART classes. At univariate and multivariate analysis, a tendency towards an increased risk of CVD was observed in the 2-year follow-up period in PWH exposed to INSTIs in the absence, however, of statistical significance. These findings leave open the hypothesis that INSTIs may play a role, albeit minimal, in determining an increased risk of CVD in PWH

Risk of Cardiovascular Events in People with HIV (PWH) Treated with Integrase Strand-Transfer Inhibitors: The Debate Is Not Over; Results of the SCOLTA Study

Cardiovascular disease (CVD) is common in people with HIV (PWH), and has great impact in terms of morbidity and mortality. Several intertwined mechanisms are believed to play a role in determining the increased risk of CVD, including the effect of certain antiretrovirals; among these, the role of integrase strand-transfer inhibitors (INSTIs) is yet to be fully elucidated. We conducted a multicenter, observational study comprising 4984 PWH evaluating the antiretroviral therapy (ART)-related nature of CVD in real life settings, both in naïve vs. treatment-experienced people. A comparison was conducted between INSTIs vs. either protease inhibitors (PIs) or non-nucleoside reverse transcriptase inhibitors (NNRTIs) considering demographic, baseline clinical characteristics, incidence of CVD in both 2-year and complete follow-up periods. Among 2357 PWH exposed to INSTIs, 24 people experienced CVD; the corresponding figure was 12 cases out of 2599 PWH exposed to other ART classes. At univariate and multivariate analysis, a tendency towards an increased risk of CVD was observed in the 2-year follow-up period in PWH exposed to INSTIs in the absence, however, of statistical significance. These findings leave open the hypothesis that INSTIs may play a role, albeit minimal, in determining an increased risk of CVD in PWH

Malaria and Hiv in Adults: when the Parasite Runs into the Virus

Malaria and HIV/AIDS are among the principal causes of morbidity and mortality worldwide, particularly in resource-limited settings such as sub-Saharan Africa. Despite the international community’s efforts to reduce incidence and prevalence of these diseases, they remain a global public health problem. Clinical manifestations of malaria may be more severe in HIV infected patients, which have higher risks of severe malaria and malaria related death. Co-infected pregnant women, children and international travelers from non-malaria endemic countries are at higher risk of clinical complications. However, there is a paucity and conflicting data regarding malaria and HIV co-infection, particularly on how HIV infection can modify the response to antimalarial drugs and about drug-interactions between antiretroviral agents and artemisinin-based combined regimens. Moreover, consulting HIV-infected international travelers and physicians specialized in HIV care and travel medicine should prescribe an adequate chemoprophylaxis in patients travelling towards malaria endemic areas and pay attention on interactions between antiretrovirals and antimalarial prophylaxis drugs in order to prevent clinical complications of this co-infection

Investigating the Effectiveness of Antiretroviral Therapy in sub-Saharan Africa

Antiretroviral therapy (ART) has revolutionised outcomes of HIV infection among people living with HIV (PLWH). But despite these great strides, ongoing concerns of drug-drug interactions, widespread use of herbal medication while using ART, safety in pregnancy and breastfeeding are challenges of HIV treatment in PLWH. Potent new ART are not widely used in most low and middle income countries (LMIC) due to insufficient safety data and fear of adverse events. This Thesis aimed at evaluating the pharmacokinetic (PK) safety of DTG in pregnant and breastfeeding women, drug drug interaction of DTG and Artemisinin Combination Therapy (ACT), and evaluate the factors that affect ART in PLWH such as use of herbal medication among PLWH. Therefore the thesis evaluated the following: Chapter 2 reviewed the clinical PK and pharmacogenetic, drug-drug interactions and safety of DTG in diverse populations from different studies, and concluded that DTG has a variable PK influenced by factors such as food, research conditions and population variability. Chapter 4 evaluated the PK of DTG in 3rd trimester of pregnancy and postpartum women and found no clinically significant difference in DTG PK between pregnancy and postpartum period in women. Safety and efficiency of HIV control was also evaluated and concluded that DTG efficiently control viral load within a short period of time even when women present late in pregnancy. xx Chapter 5 evaluated the drug-drug interaction of DTG and ACT, and concluded that DTG can be co-administered with ACT in treatment of malaria among PLWH on DTG. Chapter 6 evaluated the impact of pharmacogenetics and pregnancy on tenofovir and emtricitabine Pharmacokinetics. An estimated 1-2-fold increase in FTC blood concentration was observed in pregnant and postpartum women with ABCC2 12:g.154962860T>C T allele allele compared to women with CT and CC allele. Sample size was small and was recognise as a limitation. Therefore require verification with larger clinical studies and result should be interpreted with caution. Chapter 7 evaluated the widespread use of herbal medicines amongst PLWH and contamination of herbal medicines with ART in Nigeria as a recognised challenge of ART in sub-Saharan Africa. In conclusion, approximately 2-4% of maternal plasma DTG concentration was excreted in BM, and DTG PK changes were not clinically significant in both pregnancy and postpartum period. DTG Ctrough decreased by 37%, when DTG was administered with AL, 42% when administered with AS-AQ and 24% decrease in AUC0-24 when administered with AS-AQ, but were all above the protein adjusted IC90 for the Ctrough and does not warrant dose adjustment. An estimated 41.8% use of herbal medication was recorded amongst 742 PLWH attending HIV clinics. Herbal use preceded HIV therapy in 38.4% while 14.5% were yet to commence ART. A total of 3 (2%) out of 138 herbal samples evaluated, were contaminated with detectable levels of tenofovir and emtricitabine which is a concern, though implication is unknown

Intracellular Quantitation And Pharmacokinetic Modeling Of Nucleoside Analogs In The Female Genital Tract

Human Immunodeficiency Virus (HIV) is one of the leading infectious diseases in the world. In spite of substantial progress in the advancement of antiretroviral therapy for HIV treatment, new infections outpace the number of infected persons initiating ART. Therefore, the prevention of HIV remains a crucial health issue. Pre-Exposure Prophylaxis, (PrEP), which involves using one or more antiretroviral agents to reduce the risk of HIV infection prior to potential exposure, has shown effectiveness at reducing HIV transmission in study volunteers with different sexual orientation around the world. The clinical pharmacology of antiretroviral drugs, specifically tenofovir (TFV) and emtricitabine (FTC), in relation to their ability to prevent HIV transmission is still being evaluated. The objective of this dissertation was to develop pharmacokinetic models of TFV and FTC in the plasma and eventually peripheral blood mononuclear cells (PBMCs) and the female genital tract (FGT), which can be used to simulate the appropriate dosing interval needed to achieve optimal drug concentrations for PrEP in each compartment. The development of liquid chromatography/ mass spectrometry (LC/MS/MS) methods resulted in successful quantification of TFV and FTC in plasma, PBMCs, cervical fluid, and endothelial cells of the FGT from 30 HIV-seropositive (HIV+) women. Also, utilizing the LC/MS/MS methods developed, in vitro TFV and FTC uptake in non-monocyctic genital tract cells was determined and compared in the presence and absence of hormonal contraceptives. The major results demonstrated 1) CD4+ and squamous epithelia cells exhibited significantly increased uptake relative to control for both antiretrovirals; 2) individually, synthetic estrogen and progesterone significantly altered uptake across all cell lines except squamous epithelium cells for TFV and CD4+ cells for FTC; and 3) CD8+ and dendritic cells demonstrated decreased uptake of TFV and FTC when dosed one hour prior to being dosed with combined hormonal contraceptives. Development of predictive pharmacokinetic models of TFV and FTC concentration-time profiles in the plasma was achieved using population pharmacokinetic analysis software. Collectively, the results expand upon current knowledge of antiretroviral penetration into the FGT for the use of evaluating PrEP agents and help guide PrEP research on ideal dosing for prevention and transmission of HIV