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.
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Antiretroviral Therapy
The rapidly evolving advances in research allow us to better understand the pathogenesis of HIV, and to optimise clinical and therapeutic approaches to treat patients infected with HIV.
"Nucleoside Analogue Spring 2008 Update - Part 1" Dr. Jaime Hernandez (biography) English - 2008-04-25 - 26 minutes
(45 slides)
Summary : Dr. Hernandez compares the results of three clinical studies conducted by different research teams in order to determine whether the risk of myocardial infarction is increased in patients receiving treatment with HAART.
Dr. Hernandez first presents the results of an observational study from the Data Collection on Adverse Events of Anti-HIV Drugs (DAD), which are based on assessment of a cohort of 33,347 patients between 1999 and 2006, most of whom are European. This study found an association between the recent use of ABC and ddI and an increased risk of myocardial infarction.
Next, Dr. Hernandez takes a look at the literature and reviews a publication from the Veteran's Affair group in the United States, which consists of a retrospective study conducted on 41,213 patients between 1993 and 2003, and presents data sets that, compared to those obtained in the DAD study, are of older patients and contain more patients of black race. This publication concluded that there is no evidence of increased risk of cardiovascular events associated with long-term use of HAART.
Because the DAD's findings were unexpected and no explanation was provided for the results, Dr. Hernandez next takes a look at possible biologic mechanisms of Abacavir, but finds no causative factors either through the review of preclinical toxicology data or of clinical data with patients.
Finally, Dr. Hernandez reviews his group's past clinical trials, which involve a total of 14,680 patients between 1995 and 2007 and finds that he is unable to replicate the findings of the DAD.
Thus, Dr. Hernandez concludes that there is currently not enough information to indicate an association between HAART medication and an increased risk of myocardial infarction.
"Nucleoside Analogue Spring 2008 Update - Part 2" Dr. Jaime Hernandez (biography) English - 2008-04-25 - 18 minutes
(25 slides)
Summary : Dr. Hernandez discusses the results of the ATCG5202 study in which patients with a high viral load were unblinded due to concerns of the Data Safety and Monitoring Boards (DSMB) that Kivexa was demonstrating lower efficacy in comparison with Truvada. This was a phase IV, randomized, double-blind study lasting 96 weeks.
Dr. Hernandez compares these results with that of the HEAT study, which was also a phase IV, randomized, double-blind study of the same length. The main difference between this study and that of ATCG5202 is the definition of virologic failure, which is evaluated by HEAT after 24 weeks rather than 16. This study demonstrated no difference between Kivexa and Truvada in terms of adverse effects, virologic failure, and viral load, and the CD4 cell increase was found to be greater in the group treated with Kivexa.
Dr. Hernandez also presents results from CNA30024, a phase III, randomized, double-blind, multicenter study that demonstrated similar results, regardless of the patients' viral load, from Zidovudine and Abacavir, both of which were combined with 3CT and Efavirenz. This study also compared the time it took for patients to reach a viral load below 400 copies/mL, and found no difference in the results obtained from groups of patients treated with Kivexa compared to those treated with Combivir.
As Dr. Hernandez summarizes the results from different clinical trials, he concludes that the findings from the ACTG5205 are inconsistent with the above stated results as well as with what is seen in clinical practice. Furthermore, Kivexa is still listed as the recommended agent by the Department of Health and Human Services (DHHS) as well as by the International AIDS Society-USA.
"Abacavir HSR: Clinical and Laboratory Experience with HLA-B*5701 Screening" Dr. Simon Mallal (biography) English - 2006-05-26 - 35 minutes
(32 slides)
Summary : Over the years, several studies have confirmed the association of HLA-B*5701 with abacavir hypersensitivity. Numerous factors that led to this speculation include susceptibility in the Caucasian population, familial predisposition, independence of HIV severity, etc. A study by Mallal et al. (2002) ascertained this association in a western Australian cohort where 14 of 18 patients with HSR had HLA-B*5701 establishing a positive predictive value of 74% and a robust negative predictive value of 98%. This has been further exemplified in newer studies.
As abacavir enters the cell, it promptly gets metabolized. Studies demonstrate, through microscopy, a co-localization of the metabolite with class I molecules which eventually cluster at the immunological synapse setting the stage for the hypersensitivity response. Drugs that inhibit abacavir metabolism abrogated this response. This abrogation combined with other in vitro observations has inextricably linked the ABC HSR response to the HLA-B*5701 allele.
This strong association bolstered the need for precise detection assays for the HLA-B*5701 allele. In this presentation, Dr. Mallal reviews DNA based high resolution HLA-B*5701 typing and other rapid assays. Furthermore, he supports the benefits of such assays by presenting data on the screening experience in a western Australian study. Since the introduction of genetic screening, the proportion of ABC-naïve patients discontinuing ABC within 6 weeks precipitously declined. Dr. Mallal also reports on the Brighton experience with genetic screening and its effect on the rate of HSR.
There is still a need to investigate the clinical accuracy and cost effectiveness of genetic screening. A pharmacogenetic validation study known as PREDICT-1 is currently underway to demonstrate a reduction in clinical HSR and patch test confirmed HSR in diverse settings and ethnic groups.
Learning objectives : After viewing this presentation, participants will be able to discuss:
- The relationship of HLA-B*5701 to abacavir HSR;
- Immunopathogenesis of HSR;
- The Western Australian experience;
- The current status of HLA-B*5701 testing in various Canadian regions.
Bibliographic references : B. K. ParkCorresponding Author Contact Information, E-mail The Corresponding Author, D. J. Naisbitt, S. F. Gordon, N. R. Kitteringham and M. Pirmohamed Metabolic activation in drug allergies Toxicology. 2001; 158:11-23
William Symonds PharmDa, Corresponding Author Contact Information, E-mail The Corresponding Author, Amy Cutrell MSa, Mark Edwards MSa, Helen Steel MDb, Bill Spreen PharmDa, Gwendolyn Powell MDa, Sue McGuirk PhDb and Seth Hetherington MD Risk factor analysis of hypersensitivity reactions to abacavir Clin Ther. 2002; 24:565-73
H Peyrieere, J Nicolas, M Siffert, P Demoly, D Hillaire-Buys, and J Reynes. Hypersensitivity related to abacavir in two members of a family. Ann Pharmacother. 2001; 35:1291-1292.
DrSeth Hetherington MDa, Corresponding Author Contact Information, E-mail The Corresponding Author, Arlene R Hughes PhDb, Michael Mosteller PhDb, Denise Shortino MSc, Katherine L Baker BSa, William Spreen PharmDa, Eric Lai PhDb, Kirstie Davies BSb, Abigail Handley BSb, David J Dow MRCPathb, Mary E Fling PhDb, Michael Stocum MSb, Clive Bowman MScb, Linda M Thurmond PhDd and Allen D Roses MD Genetic variations in HLA-B region and hypersensitivity reactions to abacavir Lancet. 2002; 359:1121-2
"Lifelong treatment of HIV: Challenges and promises" Dr. Jürgen Rockstroh (biography) English - 2006-01-20 - 44 minutes
(48 slides)
Summary : Dr. Rockstroh discusses the challenges in HIV treatment beginning firstly by addressing the noticeable differences in antiretroviral accessibility in low to middle income countries. Sub Saharan Africa remains to be the most affected with the least accessibility to antiretrovirals.
The question of when and how to initiate antiretroviral therapy (ART) is still a debatable one. The International AIDS society has brought forth several recommendations in the last decade, all of which have had their promises and pitfalls. With the extensive list of HIV drugs available, various treatment options are available. Throughout this presentation, Dr. Rockstroh examines many different ART regimens and their toxicities.
It is well know that complications arise from HAART. These include hepatic toxicity, adherence issues, lipodystrophy, gastrointestinal complications, cardiovascular disease, and resistance emergence. Mitochondrial DNA depletion contributing to lipodystrophy was found to vary among NRTI based regimens but is highest with thymidine analogue regimens such as d4T. Fortunately, the MITOX and RAVE studies demonstrate a degree of reversibility of lipoatrophy when switched to abacavir or tenofovir. Dr. Rockstroh introduces an interesting technique to measure lipoatrophy known as surface laser imaging.
Other adverse events include the well defined hypersensitivity reaction (HSR) induced by abacavir which has been linked to a specific HLA allele; the HLA-B*5701. HSR occurs early on in treatment and is independent of dosage, be it a once daily or twice daily regimen. Prospective genetic screening for HLA-B*5701 show promising outcomes in avoiding HSRs in these predisposed individuals.
Cardiovascular disease is another complication of HIV infections and is speculated to be attributed to inflammation which induces alterations in lipid metabolism. It was made apparent by the ABCDE study that HAART regimens show beneficial effects on lipid profiles. It is important to recognize that this varied depending on the backbone regimen administered thus providing a means of controlling for adverse cardiovascular events.
Furthermore, Dr. Rockstroh discusses the current issues surrounding drug resistance and the effectiveness of genotyping prior to initiating ART. Other important matters to consider when choosing ART are pharmacokinetic profiles of drugs, and potential drug/drug interactions. Finally, Dr. Rockstroh concludes by addressing the challenges of Hepatitis C co-infections and the effects of HAART on liver disease progression.
Learning objectives : After viewing this presentation, participants will be able to discuss:
- The epidemiology and accessibility of ART;
- When and how to initiate ART;
- Prevention and management of short and long term toxicities;
- The importance of drug resistance, interactions and pharmacokinetic profiles when choosing an appropriate ART regimen;
- Hepatitis C co-infections.
Bibliographic references : Charles C. J. Carpenter; Margaret A. Fischl; Scott M. Hammer; Martin S. Hirsch; Donna M. Jacobsen; David A. Katzenstein; Julio S. G. Montaner; Douglas D. Richman; Michael S. Saag; Robert T. Schooley; Melanie A. Thompson; Stefano Vella; Patrick G. Yeni; Paul A. Volberding. Antiretroviral Therapy for HIV Infection in 1998: Updated Recommendations of the International AIDS Society–USA Panel. Journal of the American Medical Association, July 1998. 280(1), 78-86.
Patrick G. Yeni; Scott M. Hammer; Charles C. J. Carpenter; David A. Cooper; Margaret A. Fischl; Jose M. Gatell; Brian G. Gazzard; Martin S. Hirsch; Donna M. Jacobsen; David A. Katzenstein; Julio S. G. Montaner; Douglas D. Richman; Michael S. Saag; Mauro Schechter; Robert T. Schooley; Melanie A. Thompson; Stefano Vella; Paul A. Volberding. Antiretroviral Treatment for Adult HIV Infection in 2002: Updated Recommendations of the International AIDS Society-USA Panel. Journal of the American Medical Association, July 2002. 288(2), 222-235.
Patrick G. Yeni; Scott M. Hammer; Martin S. Hirsch; Michael S. Saag; Mauro Schechter; Charles C. J. Carpenter; Margaret A. Fischl; Jose M. Gatell; Brian G. Gazzard; Donna M. Jacobsen; David A. Katzenstein; Julio S. G. Montaner; Douglas D. Richman; Robert T. Schooley; Melanie A. Thompson; Stefano Vella; Paul A. Volberding. Treatment for Adult HIV Infection: 2004 Recommendations of the International AIDS Society-USA Panel. Journal of the American Medical Association, July 2004. 292(2), 251-265.
"Predicting the Future: The role of resistance in selecting a first-line backbone" Dr. Vincent Calvez (biography) English - 2005-11-19 - 24 minutes
(23 slides)
Summary : The importance of the initial regimen to the overall treatment paradigm has supplied much of the impetus towards greater treatment convenience in recent years. The resultant changes in regimen composition have greatly influenced the extent and type of resistance observed at first – line virological failure. The emergence of resistance to non-nucleoside reverse transcriptase inhibitors at first virological failure is common and mutational patterns similar across selecting agents, and virological failure on any retonavir-boosted protease inhibitor (PI) seldom appears to result in protease mutations in viruses that were not previously exposed to PIs.
Given this, the diversity of resistance patterns at first virological failure is driven predominantly by the nucleoside analogues used in the backbone, and the increasing popularity of convenient fixed dose combinations (FDCs) of two nucleoside has further simplified the patter seen. There are 3 current dual nucleoside FDCs: zidovudine/lamivudine (ZDV/3TC) and the more recent once daily combinations of tenofovir/emtricitabine (TDF/FTC) and abacavir/lamivudine (ABC/3TC). All have a deoxycytidine analogue in common (3TC or FTC) that generates M184V as the most common NRTI mutation associated with virological failure. M184V generates high level resistance to both 3TC and FTC but has little impact on the other components of the various FDCs.
Mutations to the non-deoxycytidine analogue FDC components are less common at first-line failure than M184V, and generally only found in combination with it. ZDV has the most complex and variable pattern, being an accumulation whose phenotypic effect on susceptibility to other NRTI drugs depends on the number of mutations present. The K65R mutation along with M184V will be observed in a proportion of failures on TDF with either 3TC or FTC. K65R has relatively low level phenotypic effects on a range of NRTIs, whose clinical impact is still not entirely certain. However, in combination with M184V it significantly reduces susceptibility to subsequent abacavir at a level likely to abrogate response.
Abacavir generates L74V as the second most common mutation after M184V in the minority of failures on ABC/3TC regimens. Like K65R, L74V have typically low level phenotypic effects of uncertain clinical relevance. However, L74V with M184V promotes a substantial improvement in susceptibility to tenofovir. Interestingly, although abacavir can also select for K65R, data from first-line ABC/3TC failures show very uncommon and low level emergence of K65R in viral samples displaying L74V.
Conference
"Safeguarding the Future: Pharmacogenomics and the short and long term tolerability of abacavir/lamivudine" Dr. Simon Mallal (biography) English - 2005-11-19 - 39 minutes
(27 slides)
Summary : The combination of abacavir and lamivudine as a nucleoside backbone combines a favorable long-term safety and tolerability profile with limited short-term side effects, apart from abacavir hypersensitivity reactions (HSR). HSR is a well-characterized phenomenon typically occurring in some 4% to 8% of individuals in clinical studies, though lower and higher incidences have been observed, with a mean incidence across studies of around 5%. HSR occurs early, with a median time to onset of less than 2 weeks and with more than 90% of cases occurring within the first 6 weeks of abacavir exposure.
Accurate symptomatic diagnosis of HSR can be confounded by the variability of its clinical presentation, and by the overlap between common symptoms of HSR and clinical manifestations of immune restoration disease, other incurrent illnesses or drug side effects. Diagnostic precision of suspected HSR is materially assisted by the immunologically mediated nature of most if not all cases. Immunophenotyping by skin patch testing is a promising research approach to help differentiate true HSR from a confounded diagnosis, and has been shown to provide a positive signal for many months after an initial HSR event. Of particular interest, however, are data showing a strong genetic link with predisposition to immunologically-mediated abacavir hypersensitivity. The MHC class 1 allele HLA-B*5701 is strongly linked to patch test-positive cases of HSR, particularly in Caucasian populations, and may represent a potential means of prospective screening for propensity towards abacavir hypersensitivity. However, before routine HLA screening can be recommended, its utility will require careful and robust evaluation in diverse populations. Furthermore, it is well to consider that even a validated screening procedure will not necessarily eliminate abacavir HSR from the clinic, nor prevent the need for clinical vigilance. Clinical diagnosis must remain the basis of clinical decision making with respect to HSR.
For the majority of individuals who do not experience an abacavir HSR, data indicate very few short or long-term complications on abacavir/lamivudine. Neither drug displays obvious signature toxicities (other than HSR) and neither appears significantly linked to long-term issues such as cumulative mitochondrial toxicity or lipoatrophy. The extensive long-term safety and tolerability data on abacavir/lamivudine, and the fact that hypersensitivity to abacavir in a minority of individuals is the only significant short-term issue of note, make this combination a promising one for long-term administration.
Conference
"First Line Therapy: A Virological Perspective" Anna Maria Geretti (biography) English - 2005-06-06 - 60 minutes
(45 slides)
Summary : Factors such as adherence, toxicity, drug interactions, cost and resistance pathways are important to consider when choosing a first line therapy. In the case of double nucleoside backbone regimens, the standard and therefore largest set of data available is for the co-formulated ZVD/3TC regimen. However, ZVD/3TC seems to be inferior to ABC/3TC and TDF/3TC in terms of potency and toxicity. Of these 3 co-formulations, ABC/3TC appears to be the most promising combination with the exception of the acute hypersensitivity reactions associated with ABC (AHS).
As ABC dosage was shown to have a limited effect on the extent of the AHS, Dr Geretti reviews previous studies aimed to identify genetic factors that can predict the occurrence of AHS. She reviews studies by Mallal et al (2002), Hetherington et al. (2002) and Martin et al. (2002), who have screened for markers such as HLA-B*5701 and Hsp70hom’C’ to determine their predictive ability of AHS. However, in a diverse multiethnic population, screening for these genetic markers is not only lengthy but may also be inaccurate.
The question that Dr. Geretti brings to our attention is the importance of DNA screening for resistance mutations in ethnically diverse groups to determine the ideal first line antiretroviral therapy. Dr. Geretti examines in detail the genotypic baseline resistance and resistance at failure in several drug combinations.
Learning objectives : After viewing this presentation, participants will be able to discuss:
- Comparison of co-formulated double nucleoside backbone regimens;
- Abacavir hypersensitivity reaction (AHS);
- Genetic markers associated with AHS;
- Baseline resistance mutations;
- Resistance mutations associated with specific drug combinations.
Bibliographic references : Phillips, Elizabeth J a; Wong, Gavin A b; Kaul, Rupert c; Shahabi, Kamnoosh c; Nolan, David A e; Knowles, Sandra R d; Martin, Annalise M e; Mallal, Simon A e; Shear, Neil H dClinical and immunogenetic correlates of abacavir hypersensitivity.AIDS. 19(9):979-981, June 10, 2005.
Seth Hetherington, Arlene R Hughes, Michael Mosteller, Denise Shortino, Katherine L Baker, William Spreen, Eric Lai, Kirstie Davies, Abigail Handley, David J Dow et al.Genetic variations in HLA-B region and hypersensitivity reactions to abacavir The Lancet, Volume 359, Issue 9312, 30 March 2002, Pages 1121-1122
Summary : Boosted protease inhibitor (PI) regimens are now in wide use and their benefits are well known. Dr. Marta Boffito explains the rationale for and possible mechanisms of action of so-called double-boosted PI regimens.
Although perhaps not initially evident, as PI’s all have the same target, there is the possibility of a benefit in a host with multiple strains of HIV that may be differentially sensitive to a given PI. However, not all double-boosted PI regimens were created equal!
Dr. Boffito reviews her own group’s pharmacokinetic work and that of other investigators on double-boosted PI regimens in order to determine the most effective PI combinations. Limitations of paired-PI regimens, such as an increased risk for drug-drug interactions and an increased pill burden, are also addressed.
Dr. Boffito concludes her talk with a brief discussion of the interactions between PI’s and antacid medications.
Learning objectives : After viewing this presentation, participants will be able to discuss:
- The definition of single- and double-boosted protease inhibitor (PI) regimens
- The rationale for double-boosted PI regimens
- The pharmacokinetics of different double-boosted PI regimens
- The limitations of double-boosted PI regimens, including adverse effects
- The interaction between PI’s and antacid medications
"Clinical NRTI Update: Support for your Backbone Options" Graeme Moyle (biography) English - 2005-04-26 - 61 minutes
(42 slides)
(24 slides)
Summary : Zidovudine has been the common drug of choice in an antiretroviral backbone regimen. This presentation delivers extensive evidence to support alternative backbone options in antiretroviral therapy. Particularly, Prof. Moyle compares the efficacy of abacavir and tenofovir to zidovudine or stavudine looking specifically at viral load, CD4 recovery, drug interactions, resistance profiles, and adverse effects. To support these comparisons, Prof. Moyle discusses key studies in detail. These include the ABCDE, GS903, 934, CNA30024, ESS30008, and the RAVE study.
In addition to efficacy, other important aspects to consider in a backbone are the drug interactions and adverse effects. Prof Moyle reviews in detail the adverse effects observed in the ABCDE, 903, MITOX, and RAVE study. Among the effects reported are lipodystrophy, metabolism, hypersensitivity, bone mass density, and renal dysfunction.
Finally, resistance profiles and their consequences need to be considered in a regimen. Phenotypic susceptibility to resistance mutations and the alternative treatment options to circumvent this susceptibility are outlined in this presentation.
Overall, Prof. Moyle provides a thorough and evidence-based presentation supporting abacavir and/or tenofovir as alternative backbone options in treatment naïve patients.
Learning objectives : After viewing this presentation, participants will be able to discuss:
- Efficacy of abacavir and tenofovir in an antiretroviral drug regimen;
- Drug interactions, adverse effects, and resistance profiles of these backbone options.
Summary : In this presentation, Dr. Rockstroh begins by reviewing the present treatment regimens available and employed in Germany. He discusses the tendency for patients to discontinue initial HAART regimens and the rationale behind it, looking specifically at various toxicities.
A therapeutic drug monitoring program by Back et al. in Liverpool showed that when boosting protease inhibitors (PI) with ritonavir, patients exhibited higher drug levels and improved virological response rates. Dr. Rockstroh discusses the ideal scenario which favours a boosted PI therapy.
Dr. Rockstroh focuses on boosted fosamprenavir looking particularly at pharmacokinetic (pk) - profile, resistance barriers, pregnancy, safety profile, pk-interactions, and the APV30005 study. The APV30005 study, a rollover study of APV30002, was designed to address the long term efficacy, safety and tolerability of fosamprenavir over 120 weeks. Dr. Rockstroh reviews the results of this study in detail.
Finally, Dr. Rockstroh presents a case study of a 40 year old man with HIV and the various treatment regimens initiated since his diagnosis in 1993. He addresses the reasons for switching treatment therapies looking specifically at CD4 counts, viral load, toxicities and genotypic resistance profiles.
Learning objectives : After viewing this presentation, the participant will be able to discuss:
- The present treatment strategies employed in Germany;
- The efficacy and ideal scenario for the use of boosted PI’s;
- The use of boosted fosamprenavir;
- A case report of a 40 year old patient and the various treatments initiated over 12 years.
Bibliographic references : Saye H. Khoo, Patrick G. Hoggard, Ian Williams, E. Rhiannon Meaden, Philippa Newton, Edmund G. Wilkins, Alan Smith, John F. Tjia, Judy Lloyd, Kevin Jones, Nick Beeching, Peter Carey, Barry Peters, and David J. BackIntracellular Accumulation of Human Immunodeficiency Virus Protease Inhibitors Antimicrobial Agents and Chemotherapy, October 2002, p. 3228-3235, Vol. 46, No. 10
Patrick G. Yeni; Scott M. Hammer; Martin S. Hirsch; Michael S. Saag; Mauro Schechter; Charles C. J. Carpenter; Margaret A. Fischl; Jose M. Gatell; Brian G. Gazzard; Donna M. Jacobsen; David A. Katzenstein; Julio S. G. Montaner; Douglas D. Richman; Robert T. Schooley; Melanie A. Thompson; Stefano Vella; Paul A. VolberdingTreatment for Adult HIV Infection: 2004 Recommendations of the International AIDS Society-USA PanelJAMA. 2004;292:251-265.
Bluma Brenner, Mark A. Wainberg, Horacio Salomon, Danielle Rouleau, André Dascal, Bonnie Spira, Rafik-Pierre Sekaly, Brian Conway, Jean-Pierre Routy and Investigators of the Quebec Primary Infection StudyResistance to antiretroviral drugs in patients with primary HIV-1 infection Int J of Antimic Agents, Vol 16, Issue 4, Dec 2000, Pages 429-434
Conference
"Maintenance Without Sacrifice - A Way to Optimise HIV Treatment" Dr. Giuseppe Pantaleo (biography) English - 2004-05-25 - 42 minutes
(58 slides)
Summary : In this presentation, Dr. Pantaleo discusses how changes in antiretroviral maintenance therapy can be used to optimize the treatment of HIV.
HIV patients on highly-active anti-retroviral therapy (HAART) may benefit from a simplification in their regimen, says Dr. Pantaleo, with reduced toxicities and side-effects, improved quality of life and patient satisfaction, and, ultimately, improved adherence to treatment. However, a simplified regimen must, nonetheless maintain virologic control.
Dr. Pantaleo examines the results of a number of studies that compare continued protease inhibitor-containing HAART with NRTI triple therapy, as well as with an NNRTI plus NRTI dual therapy. Patient populations include those HIV patients with either low or high pre-HAART viral RNA loads, as well as those who have received either optimal or sub-optimal therapy pre-HAART.
Learning objectives : After viewing this presentation, the participant will be able to discuss the safety and efficacy of:
• Switch maintenance therapy with a triple-NRTI or dual NRTI+NNRTI regimen versus continued therapy with a PI-based regimen
• Switch maintenance therapy in patients with sub-optimal therapy prior to HAART
• Maintenance therapy in patients with a high viral load at baseline
• Abacavir (ABC) substitution in patients with dyslipidemia and/or lipoatrophy on a first-line therapy of stavudine (d4T) plus a PI or NNRTI
"3TC+ABC as a NRTI Backbone" Dr. Edwin DeJesus (biography) English - 2004-05-13 - 37 minutes
(31 slides)
Summary : Despite the emergence of new antiretroviral treatments, 2-nucleoside backbone therapy remains the cornerstone for HIV treatment. Numerous clinical trials have studied lamivudine (3TC) and abacavir (ABC) in combination with NNRTIs, PIs, or NRTIs.
In this presentation Dr. DeJesus presents the results of the CNA30024 and CNA30021 studies which looked at ABC vs. ZDV BID with 3TC and EFV, and ABC QD vs. BID with 3TC and EFV.
The CNA30024 trial showed the non-inferiority of ABC compared to ZDV, with a significantly better CD4+ response in the ABC group. The CNA30021 study showed the non-inferiority of ABC QD compared to BID when combined with 3TC QD and EFV.
"The Role of Abacavir in HAART" Dr. Andrew Carr (biography) English - 2004-03-29 - 70 minutes
(25 slides)
(39 slides)
Summary : In this presentation Dr Carr presents new data on the use of Abacavir in antiretroviral therapy, focusing on topics such as triple nucleoside therapy, once daily dosing, managing metabolic complications, and the resistance profiles of nucleoside analogs.
Possible advantages of triple-nuc therapy include PI/NNRTI sparing, minimal fasting requirements and improved adherence. Once-daily dosing also improves adherence and the CNA 30021 Study showed no difference in response rates, virologic failure or discontinuation due to adverse or other events with ABC OD compared to ABC BID.
The CNA 30024 Study showed the non-inferiority of ABC compared to zidovudine (ZDV) in terms of viral response rates (70%ABC vs 69%ZDV); and a significant increase in CD4+ count from baseline was observed at 48 weeks with ABC compared to ZDV.
Addition of ZDV to ABC reduced the incidence of mutations K65R and L74V (Ait-Khaled M, et al. XI Resistance, 2002: Poster 129).
The presence of HLA-B*5701 and Hsp-70-Hom M493T alleles is required for the development of ABC hypersensitivity (1); Risk factors for ABC hypersensitivity include non-Black/Hispanic race, female gender, CDC clinical stage A/B and use of HSR CRF module (GSK 24 week data).
Switching from d4T/ZDV to ABC improved lipodystrophy with a 39% increase in limb fat over 2 years (Martin et al, AIDS, in press); ABC/3TC backbone was shown to prevent loss of limb fat compared to a backbone with ddI/d4T, with a follow-up of almost 3 years (Shlay et al, 5th Lipo Workshop, 2003).
"11th Conference on Retroviruses and Opportunistic Infections" Dr. Sharon Walmsley (biography) English - 2004-03-17 - 83 minutes
(18 slides)
(25 slides)
Summary : In this presentation Dr Walmsley does a review of the findings from several studies presented at the 11th CROI meeting, relating to the topics of antiretroviral therapy and resistance, management of HIV/HCV coinfection and management of antiretroviral toxicity.
Topics discussed will include the performance of all-NRTI regimens compared to standard HAART, effects of the long half-life of NNRTIs in prolonging the therapeutic effect after stopping the drug, performance of peg-IFN/RBV in the treatment of HIV/HCV coinfected patients, and new information on antiretroviral toxicities such as hepatic steatosis in HCV coinfected patients, lipoatrophy, renal insufficiency and anal dysplasia.
"Antiretroviral Therapy in Naïve Patients" Dr. Sharon Walmsley (biography) English - 2003-12-19 - 11 minutes
(6 slides)
Summary : The QUAD and Time Studies tested various regimens in ARV naïve patients. The QUAD Study tested a 4 drug regimen against a 3 drug regimen: TZV+SQV/R vs CBV+SQV/R. The Time Study looked at (TZV/EFV 48 weeks) vs (TZV/EFV 24 weeks followed by TZV 24 weeks) vs TZV 48 weeks. New data from these studies will be discussed here, as well as data on the time to treatment change from PI to NNRTI or 3RT therapy, and treatment simplification with once daily TDF/DDI/EFV.
Learning objectives : The participant will learn about new data presented at the 9th EACS Meeting on the following topics:
- QUAD Study in ARV naïve patients testing TZVor CBV in combination with boosted SQV.
- Time Study in ARV naïve patients testing (TZV/EFV 48 weeks) vs (TZV/EFV 24 weeks followed by TZV 24 weeks) vs TZV 48 weeks.
- Time to treatment change from PI to NNRTI or 3RT therapy.
- Treatment simplification with once daily TDF/DDI/EFV.
Conference
"An Overview of Switch Maintenance" Pr. Christine Katlama (biography) English - 2003-11-28 - 45 minutes
(43 slides)
Summary : In order to promote long-term tolerability in patients having an undetectable viral load, there are several options, one of which is to switch the treatment to maintenance therapy with another treatment, when it is desired, for example to improve tolerability, metabolic abnormalities or adherence, and/or to simplify the regimen.
This presentation will look at several studies of switching therapy, and compare different regimens on the basis of potency, metabolic profile, tolerability, fat distribution, adherence, patient acceptability and quality of life.
Learning objectives : The participant will learn about the use of Switch-Maintenance therapy.
Conclusions:
-Switch-Maintenance has a definitive role in long-term therapy where the object of treatment is to maintain a virologically suppressive regimen in a context of a minimal toxicity.
-NNRTI and 3 Nuc regimens are simple and convenient therapies...one of the critical issues in long-term compliance.
-3 Nuc regimens may reduce adverse events (including lipid improvements);
-Not all 3 nuc regimens are similar in terms of efficacy. Past ARV history is a key issue to consider before switching patient.
-Long-term tolerance with specific attention to lipodystrophy syndrome should be investigated.
"HIV/AIDS Patient Care" Linda Robinson (biography) English - 2003-11-07 - 79 minutes
(23 slides)
Summary : This presentation will cover highlights from the HIV/AIDS Patient Care Level 1 Certificate Program held by the Ontario Pharmacists' Association and Drug Information and Research Centre from September 12-14, 2003 in Toronto. Pharmacists and healthcare providers face many challenges in the successful management of HIV/AIDS patients, and here we will explore some of these issues.
As adherence is a major parameter affecting the outcome of antiretroviral therapy, appropriate steps must be taken with the patient in order to maintain adherence. This might be easier to achieve in some patients than others, for example marginalized populations such as the homeless, intravenous drug users and sex trade workers, who need to be treated with special considerations.
Drug interactions can affect drug efficacy and toxicity and so it is important to be well informed about them, and to know all the drugs being taken by the patient. Adverse drug reactions such as abacavir hypersensitivity and efavirenz CNS effects are also important to fully understand, including their detection and steps to take afterwards.
Learning objectives : The participant will review highlights of the HIV/AIDS Patient Care Level 1 Certificate Program of the Ontario Pharmacists' Association and Drug Information and Research Centre, which was held from September 12-14, 2003:
- Adherence
- Treatment of Marginalized Populations
- Drug interactions
- Adverse Drug Reactions
"A Summary of Two Talks Given during the ICAAC on the Ziagen Backbone" Dr. Jaime Hernandez (biography) English - 2003-09-24 - 18 minutes
(20 slides)
Summary : In this presentation we will do a review of the use of abacavir (ABC) as part of a nucleoside backbone. Previous studies like CLASS, NEAT and SOLO looked at ABC+3TC as the nucleoside backbone. Two new studies were presented at the ICAAC meeting in Chicago: CNA30024 (ABC vs ZDV with 3TC BID +EFV) and CNA30021 (ABC QD Vs ABC BID with 3TC/EFV QD).
Dr Edwin de Jesus presented the 48-week data from CNA30024, which showed similar virologic responses in the ABC and ZDV arms, and ABC showed a significantly greater median change in CD4+ from baseline (Oral presentation H-446).
The second study, CNA30021, also known as ZODIAC (Ziagen Once Daily in Anti-retroviral Combination therapy) was presented as a late breaker (H-1722b) by Dr Brian Gazzard. CBV-TP, the active moiety of ABC was shown to have a half life of more than 20 hours, thus making it suitable for once-daily dosing (ICAAC 2003 poster A-1797). From the CNA30021 study it was found that ABC/3TC/EFV is a viable once daily treatment option. Also, ABC QD is non-inferior to ABC BID when used with 3TC once daily plus EFV. ABC QD and BID had similar resistance and Adverse Event profiles, as well as incidence and presentation of HSR (ABC hypersensitivity).
Learning objectives : The participant will learn about the results of 2 new studies presented at the ICAAC 2003 meeting in Chicago, looking at abacavir (ABC) in the nucleoside backbone of the antiretroviral regimen:
Study CNA30024, presented by Dr Edwin de Jesus (Oral presentation H-446)
Conclusions:
- Virologic response ¡Ü 50 c/ml through Wk 48* confirms the non-inferiority of ABC/3TC/EFV compared to ZDV/3TC/EFV.
- CD4+ cell count response was significantly better in the ABC treatment group.
- No new or unusual safety concerns with the ABC treatment group.
- A triple drug regimen containing ABC, 3TC and EFV is associated with a potent and durable antiretroviral response.
*Using ITT Exposed, TLOVR Algorithm.
Study CNA30021 was presented as a late breaker (H-1722b) by Dr Brian Gazzard.
Conclusions:
- ABC/3TC/EFV is a viable once daily treatment option.
- ABC QD is non-inferior to ABC twice daily when used in combination with 3TC once daily plus EFV.
- ABC BID and QD had similar resistance profiles; most frequent mutation was single M184V/I
- The Adverse Event profile of ABC QD is similar to ABC BID.
- The incidence and presentation of HSR was similar when ABC was administered once daily or twice daily.
Bibliographic references : ICAAC 2003 Oral presentation H-446. DeJesus E et al. Abacavir BID Vs. Zidovudine BID in Combination with Lamivudine and Efavirenz in ART Naïve Subjects CNA30024: 48-Week Final Results.
ICAAC 2003 Late Breaker presentation H-1722b. Gazzard B.G. et al. Abacavir (ABC) Once Daily (OAD) Plus Lamivudine (3TC) OAD in Combination with Efavirenz (EFV) OAD is Well-Tolerated and Effective in the Treatment of Antiretroviral Therapy (ART) Naïve Adults with HIV-1 Infection (ZODIAC Study: CNA30021)
Conference
"2nd IAS Conference on HIV Pathogenesis and Treatment" Dr. Anita Rachlis (biography) English - 2003-07-28 - 14 minutes
(10 slides)
Summary : Dr Rachlis presents here some highlights from the 2nd IAS Meeting in Paris, focusing on antiretroviral therapy. Several presentations were made looking at treatment simplification and alternative treatment strategies. The ACTG 5095 study will continue to look at the combined arms (TZV/CBV + EFV) to see whether TZV or CBV is superior. Emtricitabine is a once daily alternative for treatment naïve as well as PI-suppressed patients. The once-daily ABC, 3TC, TDF regimen leads to virologic failure with both M184V and K65R mutations. The SWATCH Study showed favourable outcomes in patients who alternated treatment regimens. In salvage therapy, ATV/r was found to be comparable to LPV/r in bringing the viral load<50 in 24 weeks. Also, promising new drugs are coming out such as SPD754, a nucleoside analog that has activity against isolates with most of the common RT mutations, and TMC114, a PI with activity against PI-resistant strains. These and other findings from the 2nd IAS will be discussed in this presentation.
Learning objectives : The participant will learn about some new data on antiretroviral therapy presented at the 2nd IAS Meeting in Paris:
- PI-sparing regimens (Abstract 41): The updated results from the ACTG 5095 study comparing 3 PI-sparing regimens for initial HIV therapy showed that at 48 weeks the viral load <200 was 89% for the combination arms (TZV/CBV + EFV) and 74% for the Trizivir only arm. Viral load <50 was 74% for the combined arms and 61% for the Trizivir only arm. The study will continue to compare the combined arms to determine whether TZV or CBV is superior.
- Simplified regimens: Emtricitabine seems a good once daily alternative for patients previously suppressed on PIs (Abstract 37), and also for treatment naïve patients (Abstract 38).
- Triple-nuc regimens (Abstract 34): A pilot study showed that once-daily ABC with 3TC and TDF leads to virologic failure with both M184V and K65R mutations.
