- Email: [email protected]
SP18-2 Current and future issues in HIV treatment
S20
Keynote sessions and Symposia / International Journal of Antimicrobial Agents 42S2 (2013) S1–S40
should do from now in order to use antimicrobial PK–PD for our best practice. SP17-3 PK/PD principles: pharmacological aspects A. Novelli *. Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Italy E-mail address : andrea.novelli@unifi.it In recent years, the rules for selection of antimicrobial agents have been undergoing critical revision in terms of optimum dosing for control of infectious diseases, with the goal of potentiating treatment efficacy and reducing the risk of selecting multidrug resistant pathogens. The most important criterion for rational choice of an antimicrobial agent is defined by its pharmacodynamic (PD) characteristics, and thus its antimicrobial activity which can be summarized as the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC). The second criterion for selecting an antibiotic is due to its pharmacokinetic (PK) characteristics, since it has been demonstrated that antibiotic concentrations at the infection site influence the intensity and duration of the effect, and together with the PD parameters, provide a general inter-relationship and contribute to defining the potential clinical efficacy of a drug. Pharmacodynamics have been upgraded in the last 15 years with in vitro and animal models which have helped to identify fairly precise correlations with therapeutic efficacy of antibiotics. Moreover, the principles that link concentrations of antibiotics within body system in humans and their effects have been outlined in order to determine the optimal dosing interval. From a pharmacodynamic point of view the antibiotics have been recently divided into two major groups: Those with a time-dependent killing activity, such as beta-lactams, glycopeptides, linezolid and tigecycline and those with a concentration-dependent killing activity, such as aminoglycosides, fluoroquinolones, colistin and daptomycin. Antimicrobial drugs with a concentration-dependent activity should be administered as a single daily dose to maximize the peak serum concentration/MIC ratio, while for example beta-lactams, having a time-dependent efficacy, need to be given with short dosing intervals or even by continuous or prolonged infusion to maintain plasma levels exceeding the MIC for a sufficiently long period. There are extensive data showing that the administration of antimicrobials according to pharmacokinetic/pharmacodynamic parameters improves the possibility of a positive clinical outcome, particularly in severely ill patients. Simulations using PK/PD data can help predict the probability of achieving the ideal target exposure for a given dose. Evidence from Monte Carlo simulations, coupled with data from animal models and clinical studies, has led to the development of strategies for improved efficacy. Evidence is growing that when pharmacokinetic/pharmacodynamic parameters are used to target not only clinical cure but also eradication, the spread of resistance will also be contained. Symposium 18. Current and future issues in HIV treatment SP18-1 Comparing evidence and scope behind different guidelines S. Vella *. Istituto Superiore di Sanit` a, Rome, Italy E-mail address : [email protected] The first structured guidelines on antiretroviral treatment for HIV infection were produced in 1996. Focusing on the need for triple drug combination, early treatment and use of HIV-RNA monitoring, they changed the natural history of a disease which was then turned from an inevitably fatal one into a chronic manageable infection. Since then, evolution of the HIV guidelines has been influenced by the advances in HIV pathogenesis and by the development of safer and better tolerated drugs and regimens. During the session, the most advanced guidelines – including the new WHO ones – will be presented and discussed, with specific focus on questions like “when to start antiretroviral therapy” and “what regimens can be used to start”.
SP18-2 Current and future issues in HIV treatment P.E. Sax *. Division of Infectious Diseases, Brigham and Women’s Hospital and Harvard Medical School, USA E-mail address : [email protected] HIV treatment guidelines now advocate antiretroviral therapy for essentially all individuals with HIV infection. This treatment both preserves immune function and prevents transmission of the virus to others. Since a significant proportion of people with HIV are asymptomatic (in particular those with relatively preserved CD4 cell counts), use of treatment strategies that are effective, safe, and well tolerated is a high priority. In addition, regimens that are convenient are necessary to sustain adherence over the long term. There is an accumulating body of evidence in support of HIV regimens that include all the components of the treatment into a single pill to be taken once daily. In observational studies, use of these single-tablet regimens (STRs) has been associated with higher levels of compliance, virologic suppression, patient satisfaction, and reduced risk of hospitalization compared with regimens that consist of multiple pills. These benefits persist even after adjusting for baseline characteristics that may contribute to these favorable outcomes. In addition, prospective clinical trials of STRs have demonstrated high levels of virologic suppression and low rates of treatment discontinuation, results comparable to widely used initial antiretroviral regimens. There are three currently available STRs; all contain the two NRTIs tenofovir and emtricitabine. The first available STR also included the NNRTI efavirenz. More recently, two additional STRs have become available. One contains the NNRTI rilpivirine and the other the integrase inhibitor elvitegravir with the pharmacokinetic booster cobicistat. These newer regimens offer a differentiated adverse-event profile from tenofovir/emtricitabine/ efavirenz, increasing the STRs options among both treatment naive and virologically suppressed patients. Future promising treatment options include the investigational integrase inhibitor dolutegravir and the NRTI tenofovir alafenamide. There are plans to combine these antiretrovirals into other novel STRs. Case reports of two patients with apparent HIV eradication have stimulated extensive and exciting research into how HIV can be cured; such strategies will need to be safe, effective, and reasonably affordable to improve on our current successful antiretroviral treatment options. SP18-3 Treatment of HIV/HCV co-infection in the DAA era J.K. Rockstroh *. Department of Medicine I, University of Bonn, Germany E-mail address : [email protected] With the development of effective therapies against HIV, chronic HCV infection has become a major cause of morbidity and mortality among patients harboring both infections. Therefore, fibrosis stage assessment and consideration of HCV treatment options is of utmost importance in this particular patient group. Over the last years, treatment with pegylated interferon (IFN) plus ribavirin (RBV) has been recommended for co-infected patients who are at the greatest risk for liver disease progression;however, despite acceptable response rates for HCV genotype 2 and 3 patients, the effectiveness of HCV treatment in the widespread genotype 1 and 4 patients has been disappointing. The high prevalence of relative and absolute contraindications to HCV treatment in HIV/HCV coinfected patients has been a further barrier for HCV treatment initiation. Therefore, the development of direct acting antivirals for treatment of HCV has been eagerly awaited to hopefully improve HCV treatment outcome in coinfected individuals. Indeed, the advent of the first hepatitis C protease inhibitors (PI) boceprevir and telaprevir for HCV genotype 1 patients in 2011 has started to change the gold standard of treating hepatitis C allowing for substantially improved on-treatment viral suppression under triple HCV-PI/pegylated interferon/ribavirin therapy. Indeed first pilot trials suggest that up to 70% of HCV treatment-naïve HIV/HCV coinfected patients may achieve sustained virlogical responses 24 weeks after stopping HCV therapy. More recent data also suggests that HIV/HCV coinfecetd patients
Keynote sessions and Symposia / International Journal of Antimicrobial Agents 42S2 (2013) S1–S40
should do from now in order to use antimicrobial PK–PD for our best practice. SP17-3 PK/PD principles: pharmacological aspects A. Novelli *. Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Italy E-mail address : andrea.novelli@unifi.it In recent years, the rules for selection of antimicrobial agents have been undergoing critical revision in terms of optimum dosing for control of infectious diseases, with the goal of potentiating treatment efficacy and reducing the risk of selecting multidrug resistant pathogens. The most important criterion for rational choice of an antimicrobial agent is defined by its pharmacodynamic (PD) characteristics, and thus its antimicrobial activity which can be summarized as the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC). The second criterion for selecting an antibiotic is due to its pharmacokinetic (PK) characteristics, since it has been demonstrated that antibiotic concentrations at the infection site influence the intensity and duration of the effect, and together with the PD parameters, provide a general inter-relationship and contribute to defining the potential clinical efficacy of a drug. Pharmacodynamics have been upgraded in the last 15 years with in vitro and animal models which have helped to identify fairly precise correlations with therapeutic efficacy of antibiotics. Moreover, the principles that link concentrations of antibiotics within body system in humans and their effects have been outlined in order to determine the optimal dosing interval. From a pharmacodynamic point of view the antibiotics have been recently divided into two major groups: Those with a time-dependent killing activity, such as beta-lactams, glycopeptides, linezolid and tigecycline and those with a concentration-dependent killing activity, such as aminoglycosides, fluoroquinolones, colistin and daptomycin. Antimicrobial drugs with a concentration-dependent activity should be administered as a single daily dose to maximize the peak serum concentration/MIC ratio, while for example beta-lactams, having a time-dependent efficacy, need to be given with short dosing intervals or even by continuous or prolonged infusion to maintain plasma levels exceeding the MIC for a sufficiently long period. There are extensive data showing that the administration of antimicrobials according to pharmacokinetic/pharmacodynamic parameters improves the possibility of a positive clinical outcome, particularly in severely ill patients. Simulations using PK/PD data can help predict the probability of achieving the ideal target exposure for a given dose. Evidence from Monte Carlo simulations, coupled with data from animal models and clinical studies, has led to the development of strategies for improved efficacy. Evidence is growing that when pharmacokinetic/pharmacodynamic parameters are used to target not only clinical cure but also eradication, the spread of resistance will also be contained. Symposium 18. Current and future issues in HIV treatment SP18-1 Comparing evidence and scope behind different guidelines S. Vella *. Istituto Superiore di Sanit` a, Rome, Italy E-mail address : [email protected] The first structured guidelines on antiretroviral treatment for HIV infection were produced in 1996. Focusing on the need for triple drug combination, early treatment and use of HIV-RNA monitoring, they changed the natural history of a disease which was then turned from an inevitably fatal one into a chronic manageable infection. Since then, evolution of the HIV guidelines has been influenced by the advances in HIV pathogenesis and by the development of safer and better tolerated drugs and regimens. During the session, the most advanced guidelines – including the new WHO ones – will be presented and discussed, with specific focus on questions like “when to start antiretroviral therapy” and “what regimens can be used to start”.
SP18-2 Current and future issues in HIV treatment P.E. Sax *. Division of Infectious Diseases, Brigham and Women’s Hospital and Harvard Medical School, USA E-mail address : [email protected] HIV treatment guidelines now advocate antiretroviral therapy for essentially all individuals with HIV infection. This treatment both preserves immune function and prevents transmission of the virus to others. Since a significant proportion of people with HIV are asymptomatic (in particular those with relatively preserved CD4 cell counts), use of treatment strategies that are effective, safe, and well tolerated is a high priority. In addition, regimens that are convenient are necessary to sustain adherence over the long term. There is an accumulating body of evidence in support of HIV regimens that include all the components of the treatment into a single pill to be taken once daily. In observational studies, use of these single-tablet regimens (STRs) has been associated with higher levels of compliance, virologic suppression, patient satisfaction, and reduced risk of hospitalization compared with regimens that consist of multiple pills. These benefits persist even after adjusting for baseline characteristics that may contribute to these favorable outcomes. In addition, prospective clinical trials of STRs have demonstrated high levels of virologic suppression and low rates of treatment discontinuation, results comparable to widely used initial antiretroviral regimens. There are three currently available STRs; all contain the two NRTIs tenofovir and emtricitabine. The first available STR also included the NNRTI efavirenz. More recently, two additional STRs have become available. One contains the NNRTI rilpivirine and the other the integrase inhibitor elvitegravir with the pharmacokinetic booster cobicistat. These newer regimens offer a differentiated adverse-event profile from tenofovir/emtricitabine/ efavirenz, increasing the STRs options among both treatment naive and virologically suppressed patients. Future promising treatment options include the investigational integrase inhibitor dolutegravir and the NRTI tenofovir alafenamide. There are plans to combine these antiretrovirals into other novel STRs. Case reports of two patients with apparent HIV eradication have stimulated extensive and exciting research into how HIV can be cured; such strategies will need to be safe, effective, and reasonably affordable to improve on our current successful antiretroviral treatment options. SP18-3 Treatment of HIV/HCV co-infection in the DAA era J.K. Rockstroh *. Department of Medicine I, University of Bonn, Germany E-mail address : [email protected] With the development of effective therapies against HIV, chronic HCV infection has become a major cause of morbidity and mortality among patients harboring both infections. Therefore, fibrosis stage assessment and consideration of HCV treatment options is of utmost importance in this particular patient group. Over the last years, treatment with pegylated interferon (IFN) plus ribavirin (RBV) has been recommended for co-infected patients who are at the greatest risk for liver disease progression;however, despite acceptable response rates for HCV genotype 2 and 3 patients, the effectiveness of HCV treatment in the widespread genotype 1 and 4 patients has been disappointing. The high prevalence of relative and absolute contraindications to HCV treatment in HIV/HCV coinfected patients has been a further barrier for HCV treatment initiation. Therefore, the development of direct acting antivirals for treatment of HCV has been eagerly awaited to hopefully improve HCV treatment outcome in coinfected individuals. Indeed, the advent of the first hepatitis C protease inhibitors (PI) boceprevir and telaprevir for HCV genotype 1 patients in 2011 has started to change the gold standard of treating hepatitis C allowing for substantially improved on-treatment viral suppression under triple HCV-PI/pegylated interferon/ribavirin therapy. Indeed first pilot trials suggest that up to 70% of HCV treatment-naïve HIV/HCV coinfected patients may achieve sustained virlogical responses 24 weeks after stopping HCV therapy. More recent data also suggests that HIV/HCV coinfecetd patients