CMEonHIV.com is dedicated to providing online CME presentations (slides with voiceover) on HIV/AIDS for healthcare professionals given by local and international experts to keep you up-to-date on the ongoing developments in the field.
New Agents and Therapeutic Drug Monitoring
The most widely used medications to combat HIV infection mainly belong to three classes: protease inhibitors, nucleoside reverse transcriptase inhibitors, and non-nucleoside reverse transcriptase inhibitors. Despite the positive results obtained by using these medications, drug resistance remains a serious problem. Resistance weakens the medications’ effects and the viral load goes back up. The research on new agents and treatment strategies is continually in progress, as we are seeing advances in vaccine development (cf Topic “Immunotherapy and Vaccination”) and new drug classes: viral integrase inhibitors, entry inhibitors, attachment inhibitors, fusion inhibitors (T-20) and others. Therapeutic drug monitoring of antiretrovirals is mostly concerned with PIs, since plasma drug concentrations correlate with virologic response in patients. This allows an optimal dose to be reached.
"HIV Entry Inhibitors - New Hope" Dr. Cécile Tremblay (biography) English - 2008-07-21 - 30 minutes
Summary : Dr. Tremblay introduces her talk on HIV entry inhibitors by presenting some background information on the AIDS epidemic, including the history of pharmacological developments against HIV as well as some statistics pertaining to the current prevalence of AIDS. She then proceeds to explain the mechanism of HIV entry into human cells, when and why tropism assays should be used, and what current data say about the use of entry inhibitors.
HIV entry into CD4 cells is composed of three phases. First, the gp120 subunit of the envelope glycoprotein of HIV-1 must bind to the CD4 receptor on the cell surface. Gp120 then exposes, following a conformational change, a binding site for the co-receptor CCR5. Further conformational change ensues, allowing gp41 to bind
to gp120 and fold onto itself, which is the final step in allowing fusion of the membrane and penetration of the virus into the human cell. Each of these three binding sites is a potential target for pharmaceutical intervention.
The latest developments in this field involve inhibition of CCR5 receptors. However, there is a different receptor that can fulfill the role of CCR5: CXCR4. In the early acute infection, the majority of infecting viruses do not possess CXCR4, but as more time elapses since seroconversion, the patient harbours more and more viruses that can use either receptor, up to about 50% of the virus population. This renders CCR5 inhibitors less useful in preventing virus entry into cells. Tropism assays can be performed in order to predict the response to CCR5 inhibitors in a given patient.
Dr. Tremblay reviews several trials evaluating CCR5 inhibitors, using maraviroc. The MERIT trial considered the efficacy of maraviroc in treatment-naive patients, whereas in MOTIVATE studies 1 and 2 the attention was focused on treatment-experienced patients. Both these studies suggested that virologic suppression could be achieved. Further trials permitted the evaluation of the
possibility of resistance to CCR5 inhibitors, their associated adverse effects, as well as the efficacy of a yet unapproved inhibitor, vicriviroc.
Learning objectives : The mechanism of HIV entry into cells.
The usefulness of the tropism assay.
The clinical data supporting the use of entry inhibitors.
"Managing Complex Drug Interactions: Challenges in the Real World" Dr. Alice Tseng (biography) English - 2006-03-30 - 56 minutes
Summary : As the number of available HIV drugs increases, so does the potential for serious drug interactions. Interactions may result in reduced drug concentrations/effectiveness, and/or increased side effects.
One such interaction outlined in this presentation is the effect of gastric modifying agents on the bioavailability of atazanavir. Although still debatable, some studies have shown that as the gastric PH increases, there is a significant decline in the bioavailability of atazanavir. Dr. Tseng cautions the substantial variability in studies attempting to delineate the clinical significance of this particular drug interaction. Some studies fail to note the use of other antiretroviral agents such as tenofovir which may have an effect. As well, patient histories vary considerably, as does the types of gastric modifiers administered. Dr. Tseng outlines these and a few other parameters, such as pharmacogenomics, that should be taken into consideration when clinically assessing the effect of gastric modifiers on the bioavailability of atazanavir.
In some cases, individuals may be intolerant to ritonavir, therefore necessitating alternative PI regimens which do not require boosting. However, it is important to recognize that combining PIs may also have considerable interaction. In the instance of atazanavir, its bioavailability is reduced significantly when in combination with tenofovir. Since a boosted regimen may not always be a feasible option, Dr. Tseng evaluates the effects of a timely administration of these PIs or an increased dosage of atazanavir. Furthermore, she presents alternative PI combinations describing their benefits and drawbacks.
Other known PI interactions involve tipranavir and have been shown in 2 studies (Harris et al., Peytavin et al.). In these studies, tipranavir significantly reduced concentrations of lopinavir and fosamprenavir, respectively. Interestingly, tipranavir concentrations were affected when taken in combination with enfuvirtide, a fusion inhibitor.
Dr. Tseng concludes by reviewing possible interactions of new agents: CCR5 antagonists, integrase inhibitors, darunivir (a PI), and entravirine (an NNRTI).
Learning objectives : After viewing this presentation, participants will be able to discuss the management of common drug interactions shown with:
- Atazanavir and gastric-acid modifiers;
- Dual PI combinations;
- New antiretroviral agents.
"Therapeutic Drug Monitoring of Antiretrovirals - Lessons from the Netherlands and applications in Canada" Nancy Sheehan (biography) English - 2004-12-01 - 57 minutes
Summary : Ms.Sheehan discusses the need for therapeutic drug monitoring (TDM) in antiretroviral therapy (ARV) in Canada. ARVs have a narrow therapeutic window, as well as varying pharmacodynamic profiles among patients. TDM therefore becomes increasingly valuable to detect patients with drug concentrations outside therapeutic ranges who can in turn benefit from dose modifications.
3 key studies of ARV TDM are presented herein. The ATHENA study and a study by Fletchner et al. showed clear advantages of TDM in viral load reduction and toxicity. Conversely, a third study called PharmAdapt showed no advantage of TDM. Ms. Sheehan addresses various controversies regarding TDM ARV.
The pharmacodynamic and pharmacokinetic parameters that are used in ARV TDM interpretations are detailed here. These include minimal/maximal concentration, area under the curve (AUC), inhibitory quotient (IQ), virtual IQ, normalized IQ, genotypic IQ, and concentration ratio (CR).
Ms. Sheehan reviews her experience in the TDM program in Nijmegen, Netherlands, where they analysed PI’s and NNRTI’s. She presents 3 case studies and discusses the TDM indications and the various analytical methods used for interpretation.
Finally, Ms. Sheehan concludes by providing several suggestions for the development of a TDM program in Canada.
Learning objectives : After viewing this presentation the participants will be able to discuss:
- The advantages of ARV TDM;
- The advantages and disadvantages of parameters used in TDM interpretation;
- The analytical methods involved in the interpretation of TDM, used in Netherland;
- The future of ARV TDM in Canada.
Summary : Let us take a look at the philosophy behind treatment simplification, both from a physician and patient point of view. Physicians went from feeling hopeless with only mono- or dual- therapies in the 1990s, to excited upon the availability of many new treatment options, which were initially hoped to cure the disease. Eventually, though, an awareness grew that patients must live with their therapies for the rest of their lives, which fostered concern for the patient’s quality of life. According to patient reports, much of the drawbacks of ARV therapy can be overcome by simplifying the dosing schedule or reducing the pill burden. Switching therapy is one way to improve virologic outcome and tolerability, and ours is a long-term study, testing switching from a PI to either ABC or EFV, which shows significantly improved overall outcomes over 104 weeks (Maggiolo F et al.CID. In press).
Learning objectives : The participant will view the data of a long-term study of 104 weeks, testing the switch from PI to ABC or EFV (Maggiolo F et al.CID. In press):
1) Replacing the PI in patients with long-standing HIV RNA suppression, with EFV or ABC is generally better tolerated than continuing the PI.
2) This strategy maintains an optimal virological suppression.
3) Subjects pre-treated with dual ARV have a higher chance of virological failure if switched to ABC.
4) The lipid profile of patients on HAART may benefit from switching to a PI-sparing regimen, especially if based on ABC.
Summary : A fundamental turning point in the fight against HIV-1 Infection has been not only the development of antiviral drugs able to target different components of HIV-1 but more importantly, the understanding that multiple therapeutic strategies are necessary to control effectively HIV-1 replication. In fact, mono or bi-therapy approaches have minimal or no impact in controlling HIV-1 replication and disease. The development of triple combination therapies has led to effective control of virus replication and has had a dramatic impact on the progression of HIV-1 disease with a major reduction in morbidity and mortality. However, even though anti-retroviral therapy remains a fundamental component of the global therapeutic strategy against HIV-1 infection, the potential contribution of antiretroviral to the correction of the immunologic abnormalities is extremely limited. Antiretroviral therapy is capable of restoring CD4 T cell counts from a quantitative standpoint in patients with chronic infection but seems to have little impact on the restoration of an effective HIV-1-specific immune response. Therefore, the additional current challenge is to develop strategies that may correct the immunologic defects. The strategies of immune-based interventions that have received particular attention are those aimed at augmenting HIV-1 Specific immunity after immunization with virus subunits (virus proteins) and/or virus vector expressing different HIV-1 Proteins. These immunization strategies are also known as therapeutic vaccine and their main objective, at least in patients with chronic infection, has to be the development of de novo immune responses. Since the type of immune response already present is not able to control HIV-1 replication and all the evidences indicate that this immune response is extremely vigorous, at least with regard to the CD8 T cells, it is unlikely that a quantitative increment of the potency will confer a protective capacity to the immune response. In particular it is fundamental to stimulate HIV-1-specific CD4 helper T cell responses that are absent and/or severely impaired in patients with chronic infection. The restoration of CD4 helper T cells, e.g. therefore of the virus-specific CD4 T cells that function as precursors for the other populations of memory T cells, likely may insure the continuous replenishment of the population of memory CD4 T cells with effector function and the complete maturation of virus-specific memory CD8 T cells by the optimal secretion of factors such as IL-2 and IL-15.
In addition to these conventional strategies of immune-based interventions, it may be interesting to develop strategies that may selectively target other immunologic abnormalities such as the massive immune activation that is extremely deleterious since it further amplifies the immune dysfunction and at the same time supports optimal virus production. Therefore, it is possible that suppression of immune activation in certain phases of HIV-1 infection may result in both virologic and immunologic beneficial effects.
In conclusion, there is a major need for the development of a multi-strategic approach to potentially achieve effective control of HIV-1 infection. Immune-based interventions can be complementary to anti-retroviral therapy that remains the primary treatment intervention in order to achieve effective suppression of virus replication.
"Simplification of Treatment" Dr. Mona Loutfy (biography) English - 2003-03-29 - 46 minutes
Summary : Adherence to antiretroviral therapy is one of the most important factors influencing the effectiveness of HIV treatment. Higher adherence rates, even more than 95%, have been uniformly shown to lead to increased rates of virologic and immunologic success. The reasons for non-adherence with antiretroviral therapy are complex and vary from patient to patient. Regimen characteristics such as frequency of dosing , pill burden, number of different drugs, size of pills, food, water and refrigeration requirements, short- and long-term side effects, and ability to incorporate the treatment regimen into a daily routine have all been shown to significantly influence patient adherence and outcomes.
Since adherence is so important to achieving treatment success, various approaches to maximize adherence including antiretroviral amplifications have been proposed and studied. Since initial efforts to simplify regimens have shown some improvements in outcomes, the goal has become the development of ultra-simple, well-tolerated, low-pill-burden antiretroviral regimens. In fact, the Department of Health and Human Services has recognized this need for simplification and has indicated in their new guidelines that, “ To the extent possible, HAART regimens should be simplified by reducing the number of pills and the frequency of therapy, and by minimizing drug interactions and side effects.”
There are presently several different strategies for antiretroviral treatment simplification. These strategies include once-daily dosing, combining several medications into one pill to reduce pill burden, increasing the drug dose per pill to reduce pill burden, switching to new drugs or classes to reduce side effects and temporary short or long treatment interruptions. There are several antiretroviral agents that are approved for once-daily use and many more being investigated. The agents, which are approved for once-daily use, include tenofovir DF, didanosine tablets and enteric-coated (EC) and efavirenz. The agents, which have been or are being tested for once-daily dosing, include stavudine XR, lamivudine, abacavir, emtricitabine, nevirapine, atazanavir, saquinavir/ritonavir, amprenavir/ritonavir, pro-amprenavir and lopinavir/ritonavir. Many other agents are in phase I and II studies. Two drugs have combined antiretroviral agents into one pill, Combivir and Trizivir and have greatly contributed to simplification. Several new drugs are being released to increase the drug dose per pill to reduce pill burden including a 600-mg efavirenz preparation and pro-amprenavir, which is a precursor of amprenavir and significantly reduces the pill burden. There have been many switch studies to assess the effects of switching to a more tolerable regimen. Finally, many clinicians are stopping therapy in patients with a relatively high CD4 counts and plan to restart therapy at a later date in order to reduce toxicity.
Although simplified antiretroviral regimens have many advantages, there are still several potential drawbacks. One of the most serious problems is the potential for sub-optimal blood drug levels with less frequent dosing. The negative impact of missing a drug dose is greater in a once-daily regimen than in a multiple-dose daily regimen. Missing a dose of medication in a multiple-dose schedule leaves patients unprotected for only several hours while once-daily regimen may leave patients unprotected for an extended period. This can lead to insufficient viral inhibition and emergence of drug-resistant strains of HIV-1. Another problem with simplification is the potential for lack of potency of some simplified regimens. The issues are likely to be less important with combinations such as tenofovir DF, 3TC and efavirenz, which has been shown to be highly potent.
The importance of treatment simplification to the management of HIV cannot be overestimated and this area will continue to be at the forefront of HIV research. Particularly since antiretroviral simplification is not only likely to improve virologic response and durability but also quality of life. Further research is needed in this area to determine the efficacy, safety, potency and durability of simplified strategies.
Learning objectives : The participant will learn the important reasons for treatment simplification, i.e,
- Improved adherence and QOL
- Patients’ preference
- Maintenance of viral suppression
Also, an in-depth review of simplification strategies is covered:
- Once daily
- Reduced pill burden
Bibliographic references : Treatment-related factors and highly active antiretroviral therapy adherence.
Trotta MP, Ammassari A, Melzi S, Zaccarelli M, Ladisa N, Sighinolfi L, Mura MS, d'Arminio Monforte A, Antinori A; AdICoNA Study Group.
Istituto Nazionale per le Malattie Infettive, L. Spallanzani IRCCS, Roma, Italy.
Adherence to highly active antiretroviral therapy (HAART) plays a critical role in the effectiveness of HIV treatment. Nevertheless, the complexity of regimens and frequent side effects make HAART extraordinarily difficult to take, and many HIV-infected persons fail to adhere. The current study offers an overview of the relationship between adherence and antiretroviral treatment-related variables. As for other chronic diseases, medication regimen complexity also has an impact on adherence in the management of HIV infection. In particular, the authors discuss the effect of pill burden, dosing frequency, dietary instructions, number and type of different medications prescribed, short- and long-term side effects, convenience, and ability to incorporate the treatment regimen into a daily routine. Medication side effects are common in HAART-treated persons and are associated with concurrent and future nonadherence. Simplification of regimens, adjustment of the drug schedule to the patient's specific lifestyle, and anticipation and self-management of side effects are treatment-based strategies to optimize HAART adherence and ensure the most effective, convenient, safe, and well-tolerated antiretroviral treatment.
J Acquir Immune Defic Syndr 2002 Dec 15;31 Suppl 3:S128-31
"Treatment Interruptions in HIV Infection" Carlos Zala (biography) English - 2003-03-29 - 31 minutes
Summary : Treatment interruptions are used in acute infection, chronic infection and salvage therapy. In acute infection it is used to enhance immune control of viral replication and in salvage therapy to re-populate with WT virus. Here we will focus on treatment interruption in chronic infection, which is done to limit toxicity and cost. The goal of STI in chronic infection is to reduce therapeutic burden in terms of toxicity, QOL, spread of resistant HIV, and cost, without promoting resistance, reducing treatment options or promoting spread of HIV. A problem with STI in this case is that it may select for resistant mutants, and also in the viral rebound phase the patient becomes an efficient transmitter of HIV infection. As indicated by the results of the Staccato Trial, where the one week on – one week off arm of the study was closed due to high rates of virologic failure, we can deduce that it’s probably not possible to maintain an undetectable viral load and a CD4 response with intermittent therapy. An alternative approach would be to allow viral load rebound, while focusing on viral load set point. The goal would be to reduce overall drug exposure while maintaining protection against clinical progression. The Swiss Spanish Intermittent Therapy Trial (SSIT) showed this approach to be effective in about 20% of patients. Another, more convenient approach would be to ignore the viral load rebound and focus on CD4 maintenance. This was tested in the trial designed by Dr Vella, which was presented at the 10th CROI meeting, where the CD4 counts correlated nicely with the viral load but had problems with accumulation of resistant mutations in all 3 drug classes. The BC Centre for Excellence data also shows that the probability of remaining on STI decreases over time. So STI remains an attractive hypothesis, but more research is needed and until then it may be a valuable tool in selected clinical settings.
Learning objectives : The participant will gain an understanding of the status of STI use in chronic HIV infection, in terms of potential benefits and current problems.
- The goal of STI in chronic infection is to reduce therapeutic burden in terms of toxicity, QOL, spread of resistant HIV, and cost, without promoting resistance, reducing treatment options or promoting spread of HIV.
- Problems with STI in this case are the selection of resistant mutants and the efficacy of transmission at times of viral load rebound.
- The Swiss Spanish Intermittent Therapy Trial (SSIT) tested STI focusing on viral load set point, where it was successful in about 20% of patients.
- STI focusing on CD4 maintenance showed long term success, but increased selection of mutations in all 3 drug classes (Vella S, 10th CROI).
- The BC Centre for Excellence data shows that the probability of remaining on STI treatment decreases over time.
- STI is still an attractive hypothesis but needs more research and may be useful in selected clinical settings.
Bibliographic references : http://jvi.asm.org/cgi/content/full/76/14/7000?view=full&pmid=12072500
J Virol 2002 Jul;76(14):7000-9
Origin of human immunodeficiency virus type 1 quasispecies emerging after antiretroviral treatment interruption in patients with therapeutic failure.
Kijak GH, Simon V, Balfe P, Vanderhoeven J, Pampuro SE, Zala C, Ochoa C, Cahn P, Markowitz M, Salomon H
J Virol 2003 Mar;77(5):3229-37
Genetic characterization of rebounding human immunodeficiency virus type 1 in plasma during multiple interruptions of highly active antiretroviral therapy.
Dybul M, Daucher M, Jensen MA, Hallahan CW, Chun TW, Belson M, Hidalgo B, Nickle DC, Yoder C, Metcalf JA, Davey RT, Ehler L, Kress-Rock D, Nies-Kraske E, Liu S, Mullins JI, Fauci AS
"New Agents" Dr. Joep Lange (biography) English - 2003-03-29 - 43 minutes
Summary : Resistance testing has become routine in HIV management, especially for patients who have undergone multiple rounds of drugs. Genotyping is done much more frequently than phenotyping, as there are reasonably priced commercial testing kits available on the market. The caveat of all resistance testing remains though, the interpretation. The rules of interpretation were very simple in the beginning, for example 184V/I equals 3TC resistance, 215Y/F equals AZT resistance and so on. Now however, the mutations for these drug resistances need to be deduced by computer programs because of their complex combinations. These rules/ algorithms have been found, however to be erroneous in predicting phenotype. In the past couple of years, systematic approaches have been developed to predict phenotypes based on complex mutational patterns. The “Virtual Phenotype” is one example, which requires a substantial genotype-phenotype database, and relies on analysis of pre-defined mutational clusters. The “Neural Networks” technique is another one, which is trained with large data sets, learning to connect complex data and identify patterns by being “fed” many examples. The networks can be used to relate resistance mutations to phenotype or clinical response. The HIV Resistance- Response Database Initiative (RDI) has been designed to “..improve the clinical management of HIV infection by developing and making freely accessible a large clinical database and bioinformatic techniques that define with increased precision and reliability the relationships between drug resistance and virologic response to treatment.” The RDI approach involves collecting genotype, clinical and outcome data from large numbers of patients, and using a large number of data analysis methodologies to relate resistance to clinical response. Neural Networks models have been incorporated here, to allow the system to predict viral load change, viral load trajectory (whether the VL goes up, stays the same or goes down), virologic failure, and most interestingly, to predict a patient’s response to various combination drug therapies based on his/ her genotype. The new RDI approach is thus looked upon to improve the accuracy of predicting outcome from genotype.
Learning objectives : The participant will be introduced to the systematic approaches now being used to predict phenotype and clinical response from a patient’s genotype, focusing on the Neural Networks and RDI techniques.
Bibliographic references : HIV resistance to antiretroviral drugs: mechanisms, genotypic and phenotypic resistance testing in clinical practice.
Blaise P, Clevenbergh P, Vaira D, Moutschen M, Dellamonica P.
CHU Liege, Belgium.
HIV resistance to antiretroviral agents is a major contributory cause of treatment failure. The dynamics of HIV replication, together with patient-, physician-, and drug-related factors, lead to emergence of HIV resistant strains in most of the patients. Phenotypic assays look for an increase in the antiretroviral drug (ARV) concentration that inhibits 50% of the growth of the tested HIV strain (IC50), comparatively with a reference strain cultivated in parallel. Genotypic tests detect resistance mutations in the reverse transcriptase and protease genes by comparing the gene sequences of a resistant virus to those of a wild-type strain that has previously been described. The efficacy of each ARV class and each individual ARV is threatened by specific mutations and resistance mechanisms. In retrospective studies of genotypic or phenotypic resistance testing, baseline resistance tests results were correlated with virological outcomes. There is some evidence from prospective studies that resistance testing may have some benefits when used to choose salvage regimens. However, problems in the areas of test interpretation, patient compliance, availability of active drugs, and technical test performance limit the usefulness of resistance testing in clinical practice. This article reviews the mechanisms underlying HIV resistance, the principles of phenotypic and genotypic tests, and the use of these tests in clinical practice.
Acta Clin Belg 2002 Jul-Aug;57(4):191-201
"An overview of switch maintenance therapy" Pr. Christine Katlama (biography) English - 2002-11-17 - 35 minutes
"Sequencing Antiretroviral Therapy: What are the Data?" Dr. Sharon Walmsley (biography) English - 2002-04-26 - 60 minutes
Learning objectives : Part 1: sequencing for resistance
To examine the reasons why sequencing antiretroviral therapy is necessary.
Factors in selecting one HAART therapy among many comparable ones.
Discussion of different kinds of mutations, eg NAMS, TAMS, M184V, cross-class etc.
Possible sequencing strategies.
Part 2: sequencing for simplification
Simplification involves lower drug dosing frequency, pill burden, food/ fasting requirements.
Sequencing for toxicity: switch an agent in the same/other class with no toxicity. Mitochondrial toxicity (inhibition of mitochondrial DNA polymerase).
Discussion of the risk of hyperlactemia. Study results of lactic acidosis.
Studies of the risk of lipodystrophy associated with various drugs.
"Emerging Data from Switch Studies" Dr. Daniel Podzamczer (biography) English - 2002-04-20 - 18 minutes
Summary : Due to the important limitations of current protease inhibitors (PI)-containing regimens, the strategy of " simplification " therapy i.e. switching from a PI-based regimen to one containing a non-nucleoside reserve transcriptase inhibitor (NNRTI) (nevirapine or efavirenz) or abacavir is being widely used, particularly in Europe. The theoretical advantages of this strategy include: to offer a more comfortable and simpler regimen, without food restrictions, to avoid metabolic complications and possibly lipodystrophy, and to improve adherence and quality of life. It is not easy to evaluate data emerging from current studies because many of them are not randomized; have relatively small sample sizes; and/or a short follow-up.
Abacavir has been shown to maintain virological suppression in most cases, with an improvement in some metabolic parameters (reduction in cholesterol and triglyceride plasma levels). However, the failure rate increases in patients who were previously treated with sub-optimal nucleoside analogue regimens. By contrast, nevirapine and efavirenz seem to maintain virological control even in these patients. While metabolic improvements have been clearly demonstrated in patients who have switched to nevirapine (reduction in total cholesterol and triglyceride plasma levels and elevation of HLD cholesterol plasma levels). The metabolic results have been more variable in efavirenz-treated patients.
The NEFA trial is the first study to compare the three PI-sparing options in patients with undetectable plasma viral loads while taking PI-containing regimens. This Spanish multicenter, randomized, open trial studied 460 patients. No differences in the overall efficacy rates were found between the treatment arms in the intent-to-treat (ITT) analysis performed at 12 months. Although there was a higher virological failure rate in the abacavir arm (10.7% vs. 5.1% (NVP) vs. 3.2% (EFV), p=0.019), better tolerance of abacavir led to a lower proportion of patients discontinuing therapy due to adverse effects in this arm, compared to nevirapine- or efavirenz- treated patients (6.0% vs. 16.7% and 16.6%, respectively, p=0.006). Of note, approximately 50% of this cohort had previously received mono/dual nucleoside analogue therapy: 20.2% of these patients failed in the abacavir arm vs. 6.4% (nevirapine arm) and 4.4% (efavirenz arm).
Preliminary six-month data from a metabolic substudy showed metabolic improvements in the overall cohort, especially in patients without lipodystrophy. Nevirapine use was associated with a better performance in terms of the proportion of patients with changes in HDL cholesterol and triglyceride plasma levels, as well as in the proportion of patients wih changes in HDL cholesterol and triglyceride plasma levels, as well as in the proportion of patients with any improvements in lipid alterations.
In summary, reported data from PI switch studies suggest that, while virological suppression may be maintained and metabolic alterations improved by the three PI-sparing regimens, there may be some differences between them, both in terms of efficacy as well as in metabolic benefits, Longer follow-up is needed to ascertain if these differences are maintained over time.
Learning objectives : To compare the virological response when switching from protease inhibitors (PI) to either nevirapine, efavirenz or abacavir in HIV-infected adults having suppressed viral load while on two NRTIs and at least one PI.
"Therapeutic Drug Monitoring: Program in British Columbia" Chris Alexander (biography) English - 2002-04-15 - 30 minutes
Summary : The use of potent combination antiretroviral therapies has achieved a dramatic reduction in the morbidity and mortality associated with HIV-1 infection. However, up to 20% of therapy naïve patients fail to achieve virologic success in their 1st year on triple therapies with 20% more failing in the 2nd year. Variability in the response to antiretroviral agents has been attributed to virologic, immunologic, pharmacokinetic and behavioural differences between patients. The first two issues have been addressed with drug resistance testing and monitoring of patient CD4 cell counts as a standard of care. However, pharmacokinetic and behavioural problems are not routinely addressed by any objective measure. At the B.C. Centre for Excellence in HIV/AIDS we are exploring the utility of therapeutic drug monitoring (TDM) of protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) as a tool for managing these issues.
While antiretroviral regimens are designed to maintain concentrations within the therapeutic window, the pharmacokinetic characteristics can vary significantly between individuals. Metabolic differences, disease state and drug-drug interactions are just a few of the factors that can lead to sub-therapeutic or toxic levels of antiretrovirals. Current efforts at the Centre are focused primarily on examining the drug-drug interactions involved in multiple drug rescue therapy (MDRT) regimens including 2 or more PIs and/or NNRTIs.
Kaletra is currently an important component of salvage therapies administered in B.C. The active constituent lopinavir (LPV) is a potent protease inhibitor that has been formulated with small doses of ritonavir (RTV) to take advantage of the well-known boosting properties of the latter compound. The pharmacokinetic interactions of Kaletra with other individual PIs or NNRTIs have been generally well characterised; however, little is known about the co-administration of 2 or more of these drugs. The NNRTIs nevirapine (NVP) and efavirenz (EFV) decrease plasma levels of LPV and increased LPV/RTV doses are recommended to overcome this interaction. The PI amprenavir (APV) also lowers plasma levels of LPV/RTV while saquinavir (SQV) has no effect. The interactions of NVP or EFV on the pharmacokinetics of co-administered LPV/RTV and SQV-SGC or LPV/RTV and APV will be discussed.
Current protocols at the Centre call for full pharmacokinetic profiles involving multiple blood draws taken over the entire dosing period (usually 12 hours). These assessments, considered to be the most informative, yield important variables of drug disposition including peak and trough concentrations (Cmin and Cmax respectively) and areas under the curve (AUC). However, such a costly invasive procedure is not a practical approach to monitoring the HIV-infected population at large and has been limited to individuals on MDRT regimens.
In an attempt to reach a larger population, we are currently attempting to determine if PI and/or NNRTI concentrations in plasma samples collected for viral load testing are predictive of outcomes. This approach is unorthodox in that the timing of the drug administration relative to the blood collection is not known. However, we hypothesise that the concentrations of drugs should fall within a predictable range and measurement of drug levels outside these limits might reflect pharmacokinetic and/or adherence problems. With this approach, we hope to design a relatively inexpensive, non-invasive (in that it requires no addition blood collection) screening procedure to identify patients that may be at risk of drug failure or toxicity. Early results suggest that a single plasma drug level measurement taken a median five weeks after initiating therapy was a predictor of long-term outcomes including death. Results from these preliminary studies will be discussed.
"Future Treatment Perspectives" Dr. Stephano Vella (biography) English - 2002-04-15 - 36 minutes
Summary : Future treatment advances need to be addressed both from a short term and a mid-long term perspective.
1. Short Term Perspectives
1.1. Reconsidering the best time to initiate therapy
With "eradication" not in the horizon, the goal of therapy has been redirected towards a less ambitious goal: the long-term management of a chronic infection. As of today, consensus has been reached that treatment should be initiated only when risk of progression becomes relevant (e.g. CD4+ approaching 300 / mm3). However, we shouldn't lose sight of remarkable progress made in controlling HIV disease progression in the developed world. Very probably, when simple, potent, durable, non-toxic regimens become the norm, pendulum will swing again toward more aggressive (early) approach. In the meantime, we need to consider that delaying therapy may not be the only option. Alternatives may be dependent on the discovery of "new" predictors of progression and of genetic correlates of drug metabolism and toxicity, on toxicity prophylaxis and treatment, and on the use of intermittent therapy to reduce toxicity.
1.2 Refining the clinical use of resistance testing assays
Data from the eight controlled studies performed so far are somehow conflicting, with only 3 out of eight giving a short-mid term advantage of using resistance testing to guide the selection of second and third line treatment options. Despite numerous justifications for the negative results, its clear that more research is needed, keeping in mind that genotypic tests are more similar in their complexity to an EKG, a biopsy, or MRI than to a typical antimicrobial susceptibility test.
1.3 Management of metabolic toxicities
Although lack of a standard case definition complicates characterization, diagnosis, and tracking, the reality is that morphologic changes have a substantial impact on quality of life and cardiovascular sequelae of dyslipidemia appears minimal short-term but long-term outcome is unknown.
So far, management approaches of fat redistribution syndromes and of metabolic toxicies are largely empirical. Only few of them are based on short term controlled studies: antiretroviral therapy switches, exercise and diet, anabolic steroids, recombinant human growth hormone (rhGH), testosterone, metformin, tiazolidinediones and plastic surgery for fat redistribution syndromes; lifestyle modification (diet, exercise), use of lipid-lowering agents and switching to non-PI regimens for dislypidemic syndromes.
1.4. New drugs of existing classes
New drugs belonging to the existing classes are eagerly awaited to address issues of toxicity, potency, resistance and to improve convenience and tolerability. Indeed, new formulations/dosing schedules of "old" drugs have been recently introduced, while new members of each available class have been or are expected to enter the clinic in the next few months. The following are just a few examples of drugs in advanced stage of clinical investigation:
HIV protease inhibitors
-Tipranavir (TPV), BMS 232,632, mozenavir (DMP-450), Ag 1776, DPC 681, DPC 684, Tibotec compounds
1.5. New Strategies
The major advances are indeed expected to come not from the availability of new drugs, but, as it happened in the recent history of antiretroviral therapy, from the careful evaluation of new treatment strategies such as revisiting induction / maintenance or treatment simplification strategies or the careful testing of Structured (Strategic) Treatment Interruptions (STIs). In fact, many patients now being treated had marginal indications for therapy based on current guidelines and may be able to remain off therapy for a substantial period of time following a period of full viral suppression and CD4+ gain.
Structured or strategic treatment interruption (STI) has raised many practical and theoretical questions. As a way of re-exposing the immune system to HIV antigens after periods of prolonged suppression on successful antiretroviral therapy, STI becomes a form of auto-vaccination. This strategy has worked well in a preliminary study in patients with acute or extremely recent HIV infections. The results in established infection have been less promising. A more recent type of STI, named structured intermittent therapy (SIT), has recently been suggested. Here, therapy is used intermittently, for example on alternate weeks, simply to decrease or delay cumulative drug doses and hence toxicity. However, this must be seen as a research strategy and cannot be recommended apart from controlled trials.
2. Mid-Long Term Perspectives
2.1 New drugs classes
In addition to the new more potent and safe drugs belonging to the existing classes, there is an urgent need to develop antiretroviral drugs directed against new HIV replicative targets. Among these, the more advanced are the HIV entry inhibitors (attachment inhibitors; co-receptor inhibitors; fusion inhibitors) and the HIV integrase inhibitors.
2.2 Immune interventions
The failure rate of drug combinations due to either lack of efficacy or unacceptable toxicity has also necessitated development of long term strategies which optimize efficacy but minimize toxicity and cost: the use of pharmacologic monitoring, resistance testing, and novel drug schedules need more examination. The inability of many patients to derive long term benefit from antiretroviral drugs should also stimulate renewed interest in approaches which augment immune response to determine if such strategies may allow longer preservation of immune competence with an acceptable rate of toxicity. Although effective suppression of HIV-1 replication has been the major focus of the therapeutic research effort in recent years, there has been increasing interest in the concept of manipulating the immune response to the benefit of the host. The combination of HAART and immune-based therapies presently appear as the most appealing approach for achieving a long term, stable containment of HIV replication. These approaches should include attempts to augment or to dampen the immune response generally, and those designed to stimulate relevant HIV-1 specific immune effector mechanisms.
2.3 HIV Eradication
The great hope of eradicating HIV seems to be definitely out of our perspective, because all the pharmacological attempts at eliminating any form of virus from an infected individual so far have failed. In fact, there exist two major types of reservoirs, i.e. sanctuary sites of viral replication poorly accessible to antiretroviral therapies: anatomical reservoirs (CNS, male and female genital tract…) and cellular reservoirs (latently infected, resting memory CD4+ T lymphocytes carrying an integrated copy of viral DNA; persistently infected macrophages; follicular dendritic cells trapping extracellular virions). However, we cannot lose sight of the importance of continuing research on HIV eradication, despite the delusions of the recent past.
Various strategic approaches can be envisaged to clear these reservoirs: eliminating anatomical sanctuaries appears to be a more pharmacological issue, dealing with problems such as bioavailability, penetration into blood-brain barrier, reduced protein binding, etc. On the other hand, attacking cellular reservoirs of HIV is a major and so far unmet challenge, requiring complex and innovative approaches.
"Immune-Based Intervention in HIV Infection" Dr. Giuseppe Pantaleo (biography) English - 2002-04-15 - 37 minutes
Summary : A major feature of primary HIV-1 infection is the massive immune activation. The immune activation may be deleterious for several reasons. Although HIV-1 may replicate in both quiescent and activated CD4+ T cells, proliferating and activated CD4+ T cells support massive HIV-1 replication and production. High levels of virus replication and massive stimulation of the immune system may lead to clonal exhaustion of HIV-specific CD8+ T cells and rapid elimination of virus-specific CD4+ T helper cells.
For these reasons, few studies in the past have tested in HIV-1 infection the therapeutic effects of therapeutic agents such as Cyclosporin A (CsA) that selectively suppresses T cell activation. CsA, a cyclic undecapeptide, is an immunosuppressive agent which has been hypothesized to suppress HIV-1 replication indirectly by limiting T cell activation, and directly by interference with HIV-1 gag polyprotein processing resulting in production of non-infectious particles. CsA suppresses T-cell activation by directly blocking activation of the genes for interleukin (IL)-2, IL-4 and the IL-2 receptor in T cells, thus inhibiting IL-2 dependent T cell proliferation and differentiation. The results from the above clinical studies were quite disappointing since there was no evidence for a beneficial effect. In this regard, it is important to underscore that in these studies CsA was used as monotherapy in patients with chronic infection and at advanced stages of disease. However, administration of CsA in monkeys acutely inoculated with SIV showed a beneficial effect on the kinetics of CD4 depletion. The results obtained in the SIV model of primary infection supported the rationale of careful exploration of the strategy of interference with the heightened state of immune activation in combination with HAART in primary HIV-1 infection.
Recently, another immunosuppressive drug, e.g. mycophenolate mophetil, has been used in pilot studies in HIV-1 infection. In principle, mycophenolate mophetil may inhibit HIV-1 replication by a direct effect, e.g. depletion of the guanosine nucleotide pool (critical substrate for the completion of reverse transcription), and by an indirect effect, e.g. suppression of T cell activation. Mycophenolate mophetil is an inhibitor of inosine monophosphate dehydrogenase, an enzyme critical for effective protein synthesis. The inhibitory activity of mycophenolate mophetil is highly selective on B and T lymphocytes. Evidence will be presented that the rapid shutdown of the immune activation associated to HIV-1 infection may be beneficial for both immunologic and virologic measures.
"Trends in HIV Drug Resistance Testing" Pr. Richard Harrigan (biography) English - 2002-04-14 - 40 minutes
Summary : HIV drug resistance testing using genotyping methods are now well established in clinical practice. However, the large number of potential combination therapies, and the vast number of permutations drug resistance mutations means that there is still relatively little data based evidence linking any particular genotype with clinical outcomes. Furthermore, the confounding effects of incomplete adherence, cross-resistance, and the reversion of mutations upon stopping or changing therapies mean that interpretation of this data will be difficult even with large treatment response databases. I will summarize the contribution of these factors to observed HIV drug resistance in the British Columbia cohort, and suggest a potential alternative analytical approach. Finally, I will summarize trends observed in the HIV drug resistance program in samples from 1996-2001.
"Viral Fitness" Prof. Mark Wainberg (biography) English - 2002-04-14 - 33 minutes
Summary : Viral fitness generally refers to the relative replication competence of a virus under defined circumstances. Since viral fitness is generally assessed in tissue culture systems, its relevance to the clinical situation may be difficult to fully establish. At the same time, inferences about the relative fitness or replication competence of different types of viruses can often be derived from clinical trial data and particularly from determinations of levels of plasma viremia. In tissue culture, the ability of any given strain of HIV to replicate may be somewhat dependent on the types of cells that are used for viral propagation in the first place. Hence, certain cell types may display greater or lesser degrees of receptiveness for given viral strains. In some cases, this may be a reflection of co-receptor utilization by a particular viral subtype and, hence, the determinants of fitness can be varied and can include considerations of co-receptor usage. Drug resistance-conferring mutations have also been shown to impact on viral fitness and many have argued that any individual resistance-conferring mutation must, by definition, be one that impairs fitness since, otherwise, these mutated varieties should appear in the absence of treatment as wild-type. However, this interpretation may be overly simplistic because it fails to take into account how individual mutations may impact on one another to alter viral phenotype. As an example, plasma viremia data suggest that the 184V mutation in reverse transcriptase that confers high-level resistance to lamivudine can impact negatively on viral fitness. At the same time, the simultaneous presence of other mutations in reverse transcriptase may cause a reversion to wild-type replication kinetics and overcome any deficit in this regard.
Viral fitness can be directly assessed in tissue culture systems by several methods. One of these involves a recombinant assay in which viral genomic material is transfected into host cells that are then replicated and assessed for their ability to yield progeny virus in comparison to transfection with constructs that would normally encode a wild-type virus. A different method is the simultaneous replication within a single culture of different types of purified cloned viruses that may be studied at different proportions at the time of infection. Genetic sequencing can subsequently establish which of the viruses added to these cultures was the most fit or robust in terms of ability to grow out to high titer. The clinical validation of fitness as a concept in surrogate monitoring of patients with HIV disease is compelling but has still not been fully validated. The latter will require that assessments of fitness be built into prospective clinical trials that may be randomized to include patients receiving different types of drug regimens or who have different mutational profiles responsible for resistance to various antiviral drugs. It may also be premature to equate diminished fitness, in the context of a virus harboring certain drug resistance mutations, with diminished pathogenesis or virulence. Indeed, it is possible to contemplate that viruses may, on occasion, sacrifice a degree of replication competence without necessarily losing their ability to cause serious disease. Finally, compensatory mutations may emerge over time in the viral genome that result in increased replication efficiency.
"Treatment Interruptions" Dr. Jose Gatell (biography) English - 2002-04-14 - 38 minutes
Summary : In order to achieve a sustained suppression of the HIV-1 replication is necessary a high level of compliance (probably above 90-95% of the prescribed medications) with a combination (usually three or more drugs) of antiretroviral agents. Moreover the clinical benefits of HAART have also been very well documented. Yet, interruptions of antiretroviral therapy have gained wide acceptance and popularity not only among patients and non-governamental organizations but also among treating physicians despite lack of controlled data. Structured, supervised, or strategic treatment interruptions (STIs) have been considered in very different situations: following aggressive therapy of acute HIV syndrome, following suppressive antiretroviral therapy of established infection, to facilitate salvage after therapy has failed. The rationales for interruption of therapy in these three setting are very different.
The goal of STIs following successful treatment of acute HIV-1 infection is to avoid loosing the specific immunological response against HIV-1 and/or further boost host HIV-specific immune responses, with the hope that maintained and boosted responses will suppress virus replication sufficiently to eventually reduce of obviate the need for further antiretroviral treatment at least during transient period of time. Data from preliminary uncontrolled trials from small numbers of acutely infected patients suggest that this may be possible.
Treatment interruptions in the setting of chronic established infection and suppressed viral load are aimed at reducing long-term toxicity and cost by limiting drug exposure. Boosting HIV-specific immune responses occurs less frequently in this setting but have been demonstrated in a limited percentage of patients. Following treatment interruption, a very quick virus rebound is observed, with pre-therapy setpoint reached in a few days or weeks together with a progressive decrease in CD4+ cell counts. A few instances of recurrence of acute HIV syndromes also have been observed following treatment interruptions in chronically infected patients in whom virus was maximally suppressed.
Treatment interruptions following failed therapy have been proposed as an approach to enhance the reemergence of wild-type virus in the circulating pool, thereby increasing antiretroviral options for subsequent treatment regimens. This approach is associated with considerable risk, including precipitous reductions in CD4+ cell counts eventually leading to development of opportunistic infections. Moreover, archived resistant virus can typically still be detected in peripheral blood lymphocytes once therapy is reinstituted. These approach seems to be justified exclusively in case of unmanageable toxicity to antiretroviral agents.
Finally, treatment discontinuation has also been proposed as a strategy for individuals who on appropriate antiretroviral regimens have achieved CD4+ cell counts above and plasma HIV RNA levels below those currently recommended for instituting therapy. There are no long-term studies assessing the validity of this approach. One report suggests that individuals in whom this is attempted return to the CD4+ cell count and HIV RNA setpoints they had before therapy was instituted at a median time of 24 weeks with more rapid decline in those with a low CD4+ cell count nadir. Thus, until more data are available, the recommendation is that treatment discontinuation should not be recommended. Definitely should not be recommended for individuals who prior to therapy, were symptomatic, had low CD4+ cell counts or high plasma HIV RNA levels or who had been receiving suboptimal therapies in the past.
The best sequencing for drug discontinuation has not been defined, particularly when using regimens containing drugs with widely differing half-lives. In this case stopping simultaneously all drugs may expose the patient to monotherapies eventually leading to selection of mutant strains. Once STI is attempted, patients must be monitored closely for symptoms, CD4+ cell decline, viral rebound, and the emergence of drug resistance virus. No information is available on the optimal time after initiation of aggressive therapy to attempt STI, or if and when to restart treatment once STI has been attempted. Given the paucity of available data and the potential risk, STIs (as differentiated from unplanned treatment interruptions associated with toxicity) cannot be recommended for current clinical practice, and should exclusively be attempted in the context of cohort studies of clinical trials.
"New Antiretroviral Agents" Dr. Joep Lange (biography) English - 2002-04-14 - 40 minutes
Summary : Adherence to highly-active antiretroviral therapy (HAART) is important for successful viral suppression. However, HAART is difficult to take on a long-term basis. Factors that influence adherence include the complexity of the regimen, the number of daily doses, the number of pills, and dietary restrictions. Different formulations and combinations have led to simplified regimens that provide significant advantages in terms of acceptability and adaptability to specialized situations, such as directly observed therapy.
The number of daily doses:
The pharmacokinetics of some NRTIs (ddI, d4T, 3TC) and NNRTI's (efavirenz, nevirapine) make once daily dosing of these agents feasible. Ritonavir boosting, which takes advantage of pharmacokinetic interactions between PIs, has opened the way to simplified twice or even once daily dosing of PIs. Antiviral efficacy has been shown for regimens including indinavir/ritonavir (800/100 mg) bid, Fortovase/ritonavir (1600/100 mg) once-daily, and lopinavir/ritonavir bid. Trials comparing the antiviral efficacy of boosted-PI regimens head-to-head are underway. Combinations of NNRTIs and PIs also take advantage of pharmacokinetic interactions. Newer antiretrovirals, such as tenofovir, a nucleotide-reverse-transcriptase inhibitor, which is dosed once-daily (300 mg), add to therapy simplification.
The number of pills:
Newer formulations have reduced the daily number of pills. Trizivir, a combination pill of AZT, 3TC, and Abacavir, is administered as a single pill twice daily, and has established antiviral efficacy in treatment-naïve patients. Newer formulations of antiretrovirals include enteric-coated ddI which is better tolerated and can be administered once daily.
Dietary restrictions have been lessened by certain pharmacokinetic interactions, such as ritonavir boosting. However, components of once-daily regimens may still need to be taken at separate times during the day if ddI is part of the regimen. Treatment simplification should be part of a comprehensive approach to enhance adherence to antiretroviral therapy. Other aspects of this approach include limiting drug-related toxicity, improving tolerability, and providing ongoing psychosocial support for HIV-infected individuals.
"NEV/EFA/ABA Trial - SWITCHING PROTEASE INHIBITORS TO NEVIRAPINE, EFAVIRENZ OR ABACAVIR: A RANDOMIZED, MULTICENTER, OPEN-LABEL, SIMPLIFICATION TRIAL" Dr. Jose Gatell (biography) English - 2002-04-13 - 27 minutes
Summary : Background: In suppressed patients on 2 NRTI + 1 PI, switching from the PI to NEV, EFA or ABA is a common practice in order to improve convenience and compliance and potentially to prevent/revert side effects. Randomized studies comparing NEV, EFA and ABA have not been reported
Objective: To compare the virological response when switching from protease inhibitors (PI) to either nevirapine, efavirenz or abacavir in HIV-infected adults having suppresed viral load (VL<200 copies/mL) while on two NRTIs and at least one PI. Ref: NEFA Trial
"AZT Pressure Accelerates The Disappearance Of The M184V Mutation" Dr. Matthias Gotte (biography) English - 2001-10-26 - 23 minutes
"Therapeutic drug monitoring in the clinical management of HIV infection" Dr. Joep Lange (biography) English - 2001-04-24 - 45 minutes
"Role of adjuvant therapies and simplification of therapy" Natasha Press (biography) English - 2001-04-24 - 34 minutes
"Resistance Testing" Pr. Richard Harrigan (biography) English - 2001-04-23 - 37 minutes
"Newer agents" Dr. Scott Hammer (biography) English - 2001-04-23 - 63 minutes
"Should Resistance Testing be Used to Guide Treatment of HIV Disease" Dr. Stephano Vella (biography) English - 2000-04-27 - 33 minutes
"Genotypic and Phenotypic Tests for HIV Drug Resistance" Pr. Richard Harrigan (biography) English - 2000-04-27 - 47 minutes
USER ACKNOWLEDGES AND AGREES THAT ALL DECISIONS MADE WITH THE ASSISTANCE OR USE OF THE SOFTWARE AND/OR THE WEBSITE AND/OR BASED ON CONTENT FOUND HEREIN WILL BE EXCLUSIVELY THE RESPONSIBILITY OF THE USER.