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.
Topic
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.
"HBV-HIV Overview" David Wong (biography) English - 2009-10-20 - 46 minutes
(28 slides)
Summary : Hepatitis B is common in HIV-positive patients, due to the shared routes of transmission. In this presentation, Dr. Wong from the Toronto Western Hospital Liver Centre, discusses the diagnosis, assessment of the activity and severity of disease, and the management of hepatitis B.
Screening for HBV should include the 3 tests for HBsAg, anti-HBs and anti-HBc which in combination give a lot of information, says Dr. Wong. After diagnosis of hepatitis B, it is of interest to assess the activity of the disease by observing HBV DNA levels and liver enzymes; and to assess the severity of disease (how much liver fibrosis and whether there is cirrhosis) for which different tests can be used.
For management of hepatitis B in the presence of HIV infection, it recommended to start antiviral treatment at a higher CD4 count. Dr. Wong talks about the antivirals that can be used in combination to suppress HBV and HIV, monitoring of treatment, and the need to watch for hepatocellular carcinoma.
Learning objectives : After viewing this presentation the participant will be able to discuss:
- Diagnosis of hepatitis B
- Assessment of the activity and severity of disease
- Management of HBV-HIV co-infection with antiviral therapy
Conference
"Principles and Trends in Management of HIV Disease: Problems of Drug Resistance in Viruses of Different Subtypes" Prof. Mark Wainberg (biography) English - 2009-03-11 - 43 minutes
(32 slides)
Summary : Some differences are known to exist among the HIV subtypes in terms of development of drug resistance. For example, V106M is known to occur in clade C, and V106A in clade B.
In some populations however, the phenotypes may differ. In a recent paper by Marconi et al., V106M was the second most common NNRTI mutation after K103N in subtype C patients in South Africa, whereas V106A/M mutations were rarely seen in subtype B isolates.
Similarly, drug resistance mutations aren’t necessarily exclusive to certain drugs. There is evidence for example, showing that K65R is not tenofovir-specific. K65R will be a more important mutation in subtype C than in subtype B viruses, says Prof. Wainberg, and this may affect prevention research strategies and treatment options over time, in areas where subtype C viruses are predominant.
Prof .Wainberg discusses more about prevention research and prophylaxis, and the need for HIV genotyping to be performed prior to prescription of ARVs and prior to switching to a second-line regimen.
Learning objectives : After viewing this presentation the participant will be able to discuss:
- How the emergence of resistance in different subtypes of HIV can vary
- Implications for treatment and prevention strategies
"CD4 Rebound with Newer Compared to Older ARVs" Prof. Mark Wainberg (biography) English - 2009-02-04 - 34 minutes
(25 slides)
Summary : Not only are the viral load reductions important following antiretroviral treatment, but also the CD4 rebounds, says Prof. Wainberg. Recent studies in CCR5 inhibitors and protease inhibitors show different magnitudes of CD4 rebound with treatment, which don’t seem to correlate with the amount of viral load decrease.
From the CCR5 inhibitor class, maraviroc was studied in the MOTIVATE and MERIT trials in second-line and first-line regimens respectively. The MOTIVATE trials led to the approval of maraviroc as part of second-line treatment, and showed a strong CD4 rebound after treatment. The MERIT trial showed less viral load reduction compared to efavirenz in first-line treatment; however the MERITES (for MERIT “Enhanced Sensitivity”) study then retrospectively screened out patients with CXCR4 tropic or dual mixed tropic viruses, using the enhanced sensitivity “Trofile” assay. In the remaining patients with CCR5 tropic virus, maraviroc then appeared to achieve equivalence with efavirenz. In MERIT and MERITES again the high CD4 rebound was seen with maraviroc.
Other studies such as ARTEMIS and CASTLE indicate better CD4 rebounds with ritonavir-boosted lopinavir compared to boosted darunavir or boosted atazanavir in ARV-naïve HIV-1 infected patients. The results seen with maraviroc however are above average for CD4 rebounds. Although the viral load reductions don’t match the magnitude of the CD4 rebounds, Prof. Wainberg talks about why viral load determinations after treatment with CCR5 antagonists may not reflect the clinical reality.
Learning objectives : After viewing this presentation the participant will be able to discuss:
- Viral load reductions vs. CD4 rebounds with different ARVs
- Selection of patients for treatment with CCR5 antagonists
Conference
"Management of HCV-HIV Coinfection" Dr. Christine Hughes (biography) English - 2008-09-22 - 35 minutes
(38 slides)
Summary : Hepatitis C and HIV have very similar modes of transmission. The high number of HCV/HIV coinfections, therefore, is not surprising. Dr. Hughes addresses key issues in dealing with coinfected patients. First, should hepatitis C be treated in HIV-infected patients? Though the effect of HCV on HIV remains ambiguous, HIV affects HCV in several ways, such as by increasing the speed of fibrosis progression and causing an increased risk of cirrhosis and decompensated liver disease. Thus, it is important to treat HCV in coinfected patients.
Next, Dr. Hughes takes a look at coinfection treatment trials in order to determine which factors influence sustained virologic response. Data shows genotype to be important, as patients with HCV genotype 2 or 3 had a higher treatment response than patients in the genotype 1 group, of which patients with a lower viral load had a better response than those with high viral load (1). Adherence has also been demonstrated to have a significant impact on treatment outcome, as data from the PRESCO trial (2) shows. This study, which Dr. Hughes compares to an earlier treatment trial, also provides data on the effects of treatment dose and duration.
The question of treatment duration brings Dr. Hughes to talk about the role of early virological response (EVR) and rapid virological response (RVR). These were found to be useful in predicting sustained virological response (STR) and were used in the establishment of guidelines for optimal duration of hepatitis C treatment in HCV/HIV coinfected patients, taking into account HCV genotype.
Dr. Hughes also addresses treatment issues in coinfected patients. The hepatotoxicity of antiretroviral drugs can be due to several mechanisms, such as direct toxicity, hypersensitivity, mitochondrial toxicity, or immune reconstitution. It is more common in patients presenting certain predisposing factors, pertaining to age, sex, and lifestyle. However, Dr. Hughes reminds us that HAART decreases overall and liver-related mortality in HCV/HIV coinfected patients, and so it should not be avoided. Drug interactions are another important concern, and Dr. Hughes explains why didanosine, zidovudine, and stavudine should be avoided in certain patients. She also suggests ways to prevent the following adverse events, seen in HCV/HIV coinfected patients: influenza-like syndrome, depression, anemia and neutropenia, mitochondrial toxicity and liver decompensation, and teratogenicity.
Learning objectives : After viewing this presentation the participant will be able to discuss:
-The epidemiology of HIV and hepatitis C infections
-The impact of coinfection on morbidity and mortality
-Factors predictive of obtaining a sustained virologic response in HCV-HIV coinfected patients
-Treatment issues in coinfected patients including drug interactions and hepatotoxicity of antiretroviral therapy
"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 - 5 minutes
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.
- Nuc-sparing regimens (Abstracts 36 and 39): Preliminary studies suggest these may have benefits and are efficacious yet further controlled studies are required to determine long-term durability of viral suppression and less mitochondrial toxicity.
- Switching ARV regimens (Abstract LB5): Better outcomes (viral loads less than 400) in those patients who were in the alternating (between d4T, ddI, EFV or ZDV, 3TC, NFV) arm.
- Salvage therapy (Abstracts 114, 117, 118): An algorithmic approach was introduced by Dr Schlomo Staszewski (Abstract 114). Unboosted ATV was not as efficacious as LPV/r in failing patients (Abstract 117), and ATV/r was comparable to LPV/r in bringing the viral load to <50 at 24 weeks.
- Entry inhibitor T-20 (Abstract 116): The TORO trials showed that the use of T-20 may be maximized in the case of salvage therapy or treatment failure.
- STI use at treatment failure (Abstract 119): No difference in outcomes found between STI and non-STI groups based on baseline CD4+ count or drug susceptibility.
- New agents (Abstracts LB15, LB16): SPD754 is a nucleoside analog that has activity against isolates with most of the common reverse transcriptase mutations (Abstract LB15). TMC114 is a PI with activity against PI-resistant strains (Abstract LB16).
Bibliographic references : BIKS STUDY(LOPINAVIR|RITONAVIR-EFAVIRENZ COMBINATION): COMPLETE 24-WEEK RESULTS V.Ferré, C.Allavena, I.Poizot-Martin, G.Beck-Wirth, I.Cohen Codar, P.Perré, F.Raffi, and the BIKS study group
Monday, July 14th, 2003 – Session 9OA – Abstract 36
EMTRICITABINE, DIDANOSINE AND EFAVIRENZ ONCE-DAILY (OD) VERSUS CONTINUED PI-BASED HAART (C) IN HIV-INFECTED ADULTS WITH UNDETECTABLE PLASMA HIV-RNA: 48-WEEK RESULTS OF A PROSPECTIVE RANDOMIZED MULTICENTER TRIAL (ALIZE-ANRS 99)
J.M.Molina, F.Ferchal, V.Journot, P.Yéni, W.Rozenbaum, C.Rancinan, L.Morand-Joubert, S.Fournier, P.Morlat, B.Dupont, J.F.Delfraissy, P.Dellamonica, I.Poizot-Martin, E.Rosenthal, G.Chêne, the Alize study group
Monday, July 14th, 2003 – Session 9OA – Abstract 37
A RANDOMIZED, DOUBLE-BLIND, MULTICENTER COMPARISON OF EMTRICITABINE QD TO STAVUDINE BID IN TREATMENT-NAÏVE HIV-INFECTED PATIENTS
F.Raffi, M.Saag, P.Cahn, M.Wolff, D.Pearce, J.M. Molina, J.Hinkle, A.Shaw, E.Mondou, J.B.Quinn, F.Rousseau for the FTC301 Study Team
Monday, July 14th, 2003 – Session 9OA – Abstract 38
COMPARISON OF PI-BOOSTED INDINAVIR WITH EFAVIRENZ+|-STAVUDINE REGIMENS IN EASIER (EUROPEAN AND SOUTH AMERICAN STUDY OF INDINAVIR, EFAVIRENZ, AND RITONAVIR) M.Stek Jr, B.Hirschel, J.Benetucci, G.Reboredo, A.Streinu Cercel, J.Begovac, K.Brinkman, D.Banhegyi, M.Shivaprakash, J.Menten for the EASIER study team
Monday, July 14th, 2003 – Session 9OA – Abstract 39
ACTG 5095: A COMPARATIVE STUDY OF 3 PROTEASE INHIBITOR-SPARING ANTIRETROVIRAL REGIMENS FOR THE INITIAL TREATMENT OF HIV INFECTION.R.M.Gulick, H.J.Ribaudo, C.M.Shikuma, S.Lustgarten, W.A.Meyer, K.Klingman, K.E.Squires, S.Snyder, D.R.Kuritzkes
Monday, July 14th, 2003 – Session 9OA – Abstract 41
INDUCTION OF ANTIRETROVIRAL-NAÏVE HIV-INFECTED SUBJECTS WITH TRIZIVIR (TZV) AND SUSTIVA (efv) FOR 48 WEEKS (ESS40013) M.Markowitz, J.Lang, E.DeJesus, C.Hill-Zabala, E.R.Lanier, Q.Liao, K.Pappa, M.Shaefer
Monday, July 14th, 2003 – Session 9OA – Abstract 42
EARLY VIROLOGIC FAILURE IN A PILOT STUDY EVALUATING THE EFFICACY OF ABACAVIR, LAMIVUDINE AND TENOFOVIR IN THE TREATMENT NAÏVE HIV-INFECTED PATIENTS C.Farthing, H.Khanlou, V.Yeh
Monday, July 14th, 2003 – Session 9OA – Abstract 43
NOVEL STRATEGIES FOR SALVAGE THERAPY
Schlomo Staszewski
Tuesday, July 15th, 2003 – Session 23 – Abstract 114
ANALYSIS OF VIROLOGICAL RESPONSE OF ENFUVIRTIDE IN TORO: IMPLICATIONS FOR PATIENT MANAGEMENT J.Montaner, R.DeMasi, J.Delehanty, J.Chung, Z.Gafoor, M.Salgo, on behalf of the TORO 1 and TORO 2 study group
Tuesday, July 15th, 2003 – Session 23FO – Abstract 116
ANTIVIRAL EFFICACY, METABOLIC CHANGES AND SAFETY OF ATAZANAVIR (ATV) VERSUS LOPINAVIR|RITONAVIR (LPV/RTV) IN COMBINATION WITH 2 NRTIs IN PATIENTS WHO HAVE EXPERIENCED VIROLOGIC FAILURE WITH PRIOR PI-CONTAINING REGIMEN(S): 24-WEEK RESULTS FROM BMS AI424-043 L.Nieto-Cisneros, C.Zala, W.J.Fessel, J.Gonzalez-Garcia, C.Cohen, R.McGovern, E.Adler, C.McLaren
Tuesday, July 15th, 2003 – Session 23FO – Abstract 117
EFFICACY AND SAFETY OF ATAZANAVIR (ATV) WITH RITONAVIR (RTV) OR SAQUINAVIR (SQV)VERSUS LOPINAVIR|RITONAVIR (LPV|RTV) IN COMBINATION WITH TENOFOVIR (TFV) AND ONE NRTI IN PATIENTS WHO HAVE EXPERIENCED VIROLOGIC FAILURE TO MULTIPLE HAART REGIMENS: 16-WEEK RESULTS FROM BMS AI424-045 R.Badaro, E.DeJesus, A.Lazzarin, J.Jemsek, B.Clotet, A.Rightmire, A.Thiry, R.Wilber
Tuesday, July 15th, 2003 – Session 23FO – Abstract 118
FAILURE OF STRUCTURED TREATMENT INTERRUPTION (STI) TO CONFER BENEFIT IN THE SETTING OF TREATMENT FAILURE: CPCRA 064 RESULTS BY BASELINE CD4 COUNT AND PHENOTYPIC SENSITIVITY SCORE (PSS) SUBGROUPS J.Lawrence, K.Huppler Hullsiek, D.Mayers, D.Abrams, R.Reisler, L.Crane, B.Schmetter, T.Dionne, J.Saldanha, M.Jones, J.Baxter, the CPCRA 064 Study Team for the Terry Beirn Community Programs for Clinical Research on AIDSTuesday, July 15th, 2003 – Session 23FO – Abstract 119
ALTERNATION OF ANTIRETROVIRAL DRUG REGIMENS FOR HIV INFECTION: A RANDOMIZED, CONTROLLED TRIAL J.Martinez-Picado, E.Negredo, L.Ruiz, A.Shintani, C.R.Fumaz, C.Zala, P.Domingo, J.Vilaro, J.M.Llibre, P.Viciana, K.Hertogs, C.Boucher, R.T.D’Aquila, B.Clotet and the SWATCH Study Team
Wednesday, July 16th, 2003 – Session 45LB – Abstract LB5
ANTI HIV-1 ACTIVITY OF SPD754 A NEW NRTI: RESULTS OF A 10 DAY MONOTHERAPY STUDY IN TREATMENT NAÎVE HIV PATIENTS P.Cahn, J.Lange, I.Cassetti, J.Sawyer, C.Zala, M.Rolon, R.Bologna, L.Shiveley
Wednesday, July 16th, 2003 – Session 46LB – Abstract LB15
ANTIRETROVIRAL ACTIVITY, SAFETY AND PHARMACOKINETICS OF TMC114, A NEXT-GENERATION HIV-1 PROTEASE INHIBITOR (PI), IN MULTIPLE PI-EXPERIENCED PATIENTS K.Arasteh, N.Clumeck, A.Pozniak, H.Jaeger, M.De Pauw, H.Muller, M.Peeters, R.Hoetelmans, S.De Meyer, W.Parys, R.van der Geest
Wednesday, July 16th, 2003 – Session 46LB – Abstract LB
Conference
"2nd IAS Conference on HIV Pathogenesis and Treatment: A commentary with Dr. Harold Dion" Dr. Harold Dion (biography) English - 2003-07-16 - 13 minutes
(10 slides)
Summary : Dr Dion makes here some generalized comments on the 2nd IAS Conference that took place in Paris from July 13-17. Former President of South Africa Nelson Mandela made a strong case in advocating for HIV treatment in Africa, and the rest of the conference featured high quality talks on advances in HIV treatment.
The transmission rate of resistant virus in primary HIV infection is quite high, and resistance testing guidelines are due to be modified accordingly. One of the newer molecules, tenofovir is promising in its apparent ability to reduce the impact of M184V and K65R mutations.
An interesting debate ensued on whether ART has an effect on cardiovascular disease. As the average age of patients taking ART is only 38 years, an emphasis was placed on risk assessment for CVD by checking for factors such as smoking, family history, being overweight etcetera, and then modifying lifestyle and/or prescribing lipid-lowering agents to decrease risk. If those measures failed it was advised to then change the treatment for one having a better lipid profile.
With regard to using STI in chronic infection it was determined that more studies are needed to establish its suitability and how to use it. A number of phase III vaccines will be tested in the coming year. These vaccines will target viral replication but not necessarily prevent transmission.
Entry inhibitors such as T-20 and T-1249 were discussed. T-20 seems to work well in patients who have a CD4+ count of above 100, a viral load of <100,000 and having 2 or 3 recently active drugs in their regimen. T-1249, which also binds gp41 but on a different site, was proposed as an alternative to T-20 when that no longer worked.
With regard to Hepatitis B and C treatment, it was said that to treat these as soon as possible would be better, to avoid the rapid progression of cirrhosis and hepatocellular carcinoma, especially in HIV patients.
Learning objectives : The participant will receive an update on selected highlights from the 2nd IAS Conference in July 2003:
- Due to the high transmission rates of resistant virus, resistance testing guidelines are due to be modified.
- Tenofovir seems to reduce the impact of M184V and K65R mutations.
- Risk assessment and lifestyle modification should be the first line of recourse in patients on ART at risk for CVD.
- Several phase III vaccines are being tested in the coming year, which target viral replication.
- T-20 works well in patients who have a CD4+ count of above 100, a viral load of <100,000 and having 2 or 3 recently active drugs in their regimen.
- T-1249 is an alternative to T-20 when that no longer works.
Hep B and Hep C should be treated as soon as possible to avoid rapid progression of cirrhosis and hepatocellular carcinoma, especially in HIV patients.
Bibliographic references : MECHANISMS OF HIV DRUG RESISTANCE F. Clavel
Monday July 14th, 2003 – Session 3FO – Abstract 5
USE AND CLINICAL IMPACTS OF DRUG RESISTANCE TESTING IN HIV INFECTION D. Kuritzkes
Monday July 14th, 2003 – Session 3FO – Abstract 6
COMBINING TENOFOVIR TO OTHER NRTIs: IMPACT ON RESISTANCE
AND VIRAL FITNESS AT THE MOLECULAR LEVEL
B. Canard1, J. Deval1, K.L. White2, M.D. Miller2, J. Courcambeck3, B. Selmi1, J. Boretto1 1CNRS, Marseille, France, 2Gilead, Foster City, USA,
3Genosciences, Marseille, France
Monday July 14th, 2003 - Session 2PL - Abstract 7
SHOULD WE MODIFY ANTIRETROVIRAL TREATMENT BASED ON CARDIOVASCULAR RISK?
Pro speaker: Marc van der Valk
Con speaker: Sam Bozette
Monday July 14th, 2003 – Session 18CO – Abstract 101
ANALYSIS OF VIROLOGICAL RESPONSE OF ENFUVIRTIDE IN
TORO: IMPLICATIONS FOR PATIENT MANAGEMENT
J. Montaner1, R. DeMasi2, J. Delehanty2, J. Chung3,
Z. Gafoor2, M. Salgo3, on behalf of the TORO 1 and TORO 2
study groups
1University of British Columbia, Vancouver, Canada,
2Trimeris, NC, USA, 3Roche, NJ, USA
Tuesday July 15th, 2003 – Session 23 FO – Abstract 116
FAILURE OF STRUCTURED TREATMENT INTERRUPTION (STI)
TO CONFER BENEFIT IN THE SETTING OF TREATMENT FAILURE:
CPCRA 064 RESULTS BY BASELINE CD4 COUNT AND PHENOTYPIC
SENSITIVITY SCORE (PSS) SUBGROUPS
J. Lawrence1, K. Huppler Hullsiek2, D. Mayers3, D. Abrams1, R. Reisler4, L. Crane5, B. Schmetter6, T. Dionne7, J. Saldanha8, M. Jones1, J. Baxter9, the CPCRA 064 Study
Team for the Terry Beirn Community Programs for Clinical Research on AIDS
1Univ. of California, San Francisco, CA, USA, 2Univ. of
Minnesota, Minneapolis, MN, USA, 3Henry Ford Hospital,
Detroit, MI, USA, 4Univ. of Maryland, Baltimore, MD, USA,
5Wayne State Univ., Detroit, MI, USA, 6Social and Scientific
Systems, Inc., Silver Spring, MD, USA, 7VA Medical Center,
Washington, DC, USA, 8Denver Public Health Department,
Denver, CO, USA, 9Cooper Hospital/RWJ Medical School,
Camden, NJ, USA
Tuesday July 15th, 2003 – Session 23FO – Abstract 119
ATTENUATION OF SIVMAC239 AND SHIV89.6P INFECTIONS BY
REPLICATION-DEFECTIVE ADENOVIRUS VACCINES
J.W. Shiver1, D.R. Casimiro1, X. Liang1, W.A. Schleif1,
F. Wang1, Z. Zhang1, A. Bett1, M. Davies1, L.G. Tussey1,
J.H. Condra1, T. Fu1, L. Handt1, A.B. McDermott2,
D.I. Watkins2, E.A. Emini1
1Merck Res. Labs., West Point, PA, USA, 2Univ. Wisconsin,
Madison, WI, USA
Tuesday July 15th, 2003 – Session 33OA – Abstract 178
MEASLES VACCINE AS A POTENTIAL VECTOR FOR AIDS VACCINATION
F. Tangy1, C. Combredet1, V. Labrousse1, C. Lorin1, L. Mollet1,
M. Brahic1, B. Hurtrel2
1Unité des Virus Lents, 2Physiopathologie des Infections
Lentivirales, URA-CNRS 1930, Pasteur Institute, Paris,
France
Tuesday July 15th, 2003 – Session 33OA – Abstract 179
EFFICACY OF DNA AND FOWLPOXVIRUS PRIME/BOOST VACCINES
FOR HIV-1 AND SHIV
S.J. Kent1, C.J. Dale1, R. De Rose1, I. Stratov1, S. Chea1,
D.F.J. Purcell1, I.A. Ramshaw2, S. Thomson2, D.B. Boyle3,
B. Coupar3, A.J. Ramsay4, R. Ffrench5, M. Law5, S. Emery5,
D.A. Cooper5, for the Australian HIV Vaccine Design and
Development Team
1University of Melbourne, Melbourne, Australia, 2Australian
National University, Canberra, Australia, 3CSIRO animal health,
Geelong, Australia, 4University of Newcastle, Newcastle,
Australia, 5University of New South Wales, Sydney, Australia
Tuesday July 15th, 2003 – Session 33OA – Abstract 180
Th1 PLASMID CYTOKINE ENHANCEMENT OF RNA OPTIMIZED
PLASMID DNA VACCINE POTENCY IN NON HUMAN PRIMATES
SUGGESTS ATTAINMENT OF A CRITICAL MILESTONE IN DNA
VACCINE AND IMMUNE THERAPY DEVELOPMENT
D.B. Weiner1, J. Boyer1, M. Kutzler1, R.R. MacGregor1,
T. Robinson1, A. Choo1, M. Chattergoon1, K. Muthumani1,
S. Calarota1, M. Otero1, M. Lewis4 ,N. Letvin5,
E.B. Schadeck2, M. Sidhu2, M.A. Egan2, G. Pavlakis3,
Z. Israel2, J. Eldridge2
1University of Pennsylvania, Philadelphia PA, USA,
2Department of Viral Vaccines Immunology, Wyeth Research,
Pearl River, NY, USA, 3National Cancer Inst., Frederick MD,
4SRI, Virginia, 5Harvard Medical School, Boston, USA
Tuesday July 15th, 2003 – Session 33OA – Abstract 181
HIV-1 VACCINES THAT INCLUDE NOVEL ENVELOPE STRUCTURES
INDUCE BROAD AND POTENT ANTI-VIRAL IMMUNE RESPONSES
S.W. Barnett1, I. Srivastava1, L. Stamatatos2, J. Zur Megede1,
G. Otten1, D. Montefiori3, S. Engelbrecht4, E. Janse van
Rensburg4, D. O’Hagan1, J. Polo1, J. Ulmer1, J. Donnelly1
1Chiron Corporation, Emeryville, CA, United States, 2Seattle
Biomedical Research Institute, Seattle, WA, United States,
3Duke University, Durham, NC, United States, 4University of
Stellenbosch, Tygerberg, South Africa
Tuesday July 15th, 2003 – Session 33OA – Abstract 182
LENTIVIRAL VECTORS AS POTENTIAL TOOLS FOR DENDRITIC
CELL-MEDIATED THERAPEUTIC VACCINATION AGAINST AIDS
C. Iglesias1, L. Mollet2, K. Courbeyrette1, F. Tangy2,
P. Langlade-Demoyen3, F. Lemonnier3, P. Charneau1
1Groupe de Virologie Moleculaire et Vectorologie, 2Unité de
Virus Lents, 3Unité d’Immunité Cellulaire Antivirale, Institut
Pasteur, Paris, France
Tuesday July 15th, 2003 – Session 33OA – Abstract 183
MODELING IMMUNE INTERVENTION STRATEGIES FOR HIV-1
INFECTION OF HUMANS IN THE MACAQUE MODEL
G. Franchini
Basic Research Laboratory, NCI, NIH, Bethesda,
Maryland, USA
Tuesday July 15th, 2003 – Session 33OA – Abstract 184
HIV-RECOMBINANT CANARYPOX VACCINE BOOSTS AND BROADENS
HIV-SPECIFIC CD4 AND CD8 T-CELLS IN THE VACCITER
ANRS094 THERAPEUTIC IMMUNISATION CLINICAL TRIAL
G. Carcelain1, R. Tubiana2, M. Legarff1, C. Dalban3,
C. Rabian4, V. Calvez5, R. Elhabib6, C. Katlama2, B. Autran1,
the Vacciter study group
1Cell Immunology Inserm U543, 2Infectious Diseases,
3Inserm EMI 0214, Pitie-Salpetriere University Hospital,
Paris, 4Immunology Saint-Louis University Hospital, 5Virology,
6Aventis Pasteur, Marcy l’Etoile, France
Tuesday July 15th, 2003 – Session 33OA – Abstract 185
DOES HCV CO-INFECTION INCREASE THE INCIDENCE OF
NONALCOHOLIC CIRRHOSIS AND HEPATOCELLULAR CARCINOMA?
A COHORT STUDY OF HIV-INFECTED US VETERANS, 1992-2001
T.P. Giordano1-2, J.R. Kramer3, J. Souchek1-2,
P.A. Richardson2, H.B. El-Serag1-2
1Houston Veterans Affairs Medical Center, 2Baylor College of
Medicine, 3University of Texas Houston School of Public
Health, Houston, Texas, USA
Wednesday July 16th, 2003 – Session 41FO – Abstract 213
ENFUVIRTIDE TORO STUDIES: 48 WEEK RESULTS CONFIRM 24 WEEK FINDINGS Katlama et al
Wednesday July 16th, 2003 – Late Breakers – Oral LB2
Conference
"Antiretroviral Therapy Issues in HIV-Infected Women" Dr. Sharon Walmsley (biography) English - 2003-03-30 - 34 minutes
Summary : There are little published data on the short and long term effects of antiretroviral therapy in women. Clinical trials have generally enrolled fewer than 20% women and have been underpowered to look at gender specific differences in efficacy and side-effects of drug therapy. In addition, post-marketing surveillance of antiretroviral drugs has been limited and not gender specific. Observational cohorts (e.g. SWISS, ICONA, BC Center for Excellence) have proved invaluable for addressing issues of efficacy and tolerability of antiretroviral agents outside the clinical trial setting. Information derived from these cohorts is frequently used by physicians to inform treatment decisions. Unfortunately, existing cohorts are primarily composed of gay and bisexual men. Consequently it has become necessary to extrapolate findings from men to guide treatment options for women.
There are several potential reasons gender may influence the response to antiretroviral drugs including differences in body mass, hormonal status, and drug metabolism. In fact, there is evidence that women are at increased risk for certain side effects, for example, rash with nevirapine and gastrointestinal side effects with ritonavir. There also may be differences in the manifestations of drug related effects, such as breast enlargement, that particularly impact women's self-esteem. For women taking antiretrovirals, such adverse events may affect their ability to adhere to therapy. Furthermore, simply the perception that women are at greater risk for toxicity could contribute to delays (either by women or their health care providers) in the initiation of therapy, depriving women of meaningful immune reconstitution that could prevent serious outcomes of HIV infection.
Conference
"Initial Therapy" Dr. Jose Gatell (biography) English - 2003-03-29 - 50 minutes
Summary : Like a marathon run, antiretroviral therapy is a business for life. In fact, is a life long therapy because HIV-1 eradication at present is not an achievable objective and supervised or structured therapy interruptions (STI`s) or immune based therapies still remain in the domain of clinical research. Not all athlestes are equally fitted to participate in marathons and only a few of them can expect to have some chances of winning. The same is true for antiretroviral regimens. Some unfair across studies comparisons have lead to the easy and superficial conclusion that the response rate, if ever, exceeds 50% at 24-48 weeks using an intent to treat analysis (in general missing = failure). Yet, while the greater response rate with a sustained durability up to 3-6 years even using the most stringent intent to treat analysis (non-completers = failure) and some of them with a fairly acceptable tolerance. Just to mention a few examples regimens already available like ZDV + 3TC + Efavirenz Kaletra or Tenofivir + 3TC + Efavirenz fulfill these requirements and atazanavir containing regimens may be a future option implying a smaller proportion of patients with metabolic abnormalities requiring lipid lowering agents.
Several years ago we have learnt that even small and transient perturbations in the replicative capacity of HIV-1 can dramatically influence the natural history of the disease. Moreover, a sustained suppression of the viral replication quickly translated into an immunological reconstitution a delay in the disease progression and ultimately in a much prolonged survival. Recommendations about when and how to initiate antiretroviral therapy have dramatically shifted to more conservative positions during the past 1-2 years switching from the principle of hitting “early and hard” to hitting “not too late and wisely”. The major driving forces for these changes have been 1) the realization of the high incidence of metabolic disturbances and clinical lipodystrophy and their potential consequences on mid and long term cardiovascular events and other mid and long term events, 2) the complexity, inconveniences and restrictions associated with some of the most useful and widely used antiretroviral regimens, and 3) the ability to achieve an apparent sufficient degree of self reconstitution of the immune system even when antiretroviral therapy is initiated when the CD4+ cell count drops below 200 cells per microliter or even lower and being the adherence to prescribed therapy and the levels of physician experience strongest markers of clinical pregression or death. Conversely, apart from common sense there a number of biological, virological and immunological reasons to initiate antiretroviral therapy in much earlier stages of HIV-1 disease providing a potent, durable, convenient and save antiretroviral regimen is available.
The paradigm about composition of initial antiretroviral regimens shifted about 2-3 years ago from PI containing regimens to PI sparing regimens (namely 2NRTI + 1NNRI) and most recently even to 3NRTI (less effective regimens). Particularly the 2NN study has shown non-inferiority of a nevirapine containing triple therapy as compared with efivirenz. Long term potential for toxicity (mainly metabolic disturbances and lipodystrophy) may be lower with some of these newer regimens. Moreover, it is already possible to contrust simple and potent regimens able to be administered once per day, eventually directly supervised. With such regimens we may try to better target hard to reach population like IVDU or those with lower socioeconomical status.
Conference
"Interactions among HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors" Dr. Keith Gallicano (biography) English - 2003-03-29 - 30 minutes
Summary : Drugs interactions occurring among protease inhibitors (PI) and non-nucleoside reverse transcriptase inhibitos (NNRTI) are complex, time-dependent and multi-directional. Co-administration of dual PI with NNRTI or triple PI without NNRTI have necessitated management strategies to ensure a balance between maximizing efficacy, tolerance and convenience and minimizing toxicity. All HIV PI are metabolized by and inhibit cytochrome P450 (CYP) 3A4. Ritonavir, lopinavit, nelfinavir and amprenavir also simultaneously induce this enzyme leading to time-dependant interactions that vary in magnitude of effect. In addition, ritonavir and nelfinavir induce a host of other CYP isoforms. The NNRTI delavirdine potently inhibits CYP3A4, whereas nevirapine and efavirenz are inducers of CYP3A4. Antiretroviral regimens that include low-dose ritonavir (100mg BID) have been successfully implemented to elevate plasma exposure of other PI, improve tolerability, and maintain suppression of HIV replication. However, this dose does not appear to offset inductive effects by NNRTI, leading to potentially sub-optimal levels. Ritonavir 200 mg BID or 400 mg BID can be used with efavirenz or nevirapine to prevent decreases in amprenavir or saquinavir levels but 200 mg QD may not be effective. The use of low-dose delavirdine (100 or 200 mg BID) to boost PI exposure may be an alternative to low-dose ritonavir as a PI booster, but the potential inductive effect of PI such as amprenavir and nelfinavir on delavirdine needs to be considered. Regimens of delavirdine (600 mg BID) and amprenavir (600 mg BID) show a strong bi-directional interaction whereby amprenavir reduces delavirdine exposure by 30% to 50% and delavirdine increases amprenavir exposure by about 4-fold. Several triple regimens that include ritonavir/lopinavir (400/100 mg BID) and another PI are currently being investigated, particularly for treating PI-experienced HIV-infected patients or those requiring salvage therapy. Combining nelfinavir or amprenavir with ritonavir/lopinavir significantly reduces both ritonavir and lopinavir plasma exposures. In addition, adding lopinavir/ritonavir to amprenavir/ritonavir regimens lowers amprenavir levels by about 50%. No significant negative interactions between ritonavir/lopinavir and either saquinavir or indinavir have been reported. This presentation reviews clinically important beneficial and detrimental interactions in HIV therapy that occur among PI and NNRTI agents.
"Post 10th Conference on Retroviruses and Opportunistic Infections" Dr. Marina Klein (biography) English - 2003-03-11 - 42 minutes
(44 slides)
Summary : Dr Marina B. Klein presents here the salient features of selected topics from the 10th CROI which took place in Boston in February 2003. New epidemiological data reflect the importance of initiation of antiretroviral therapy (ARV) when the CD4 cell count is still above 350 (Poster 910) even with durable virologic control (Poster 570), to get the most favourable outcomes in terms of clinical manifestations and mortality. An update follows on the treatments for Hepatitis C and HIV/HCV coinfection : comparisons of peg-IFNa2b/Ribavirin versus IFNa/Ribavirin (abstracts 841, 842) and associated toxicities (abstract 843); and mitochondrial toxicity with RBV/ddI compared to RBV with other NRTIs (Poster 763). We now also have some preliminary data on the success rate of liver transplantation in HIV and/or HCV coinfected patients (Abstract 155). New studies on ''old drugs'' show comparisons between nevirapine and efavirenz with a backbone therapy of d4T/3TC (2NN Study) talking about treatment success, virologic failure, change in treatment, disease progression and adverse events (oral session 176). The Gilead-903 Trial shows new data on tenofovir in treatment naïve patients, substituting d4T for tenofovir in a triple combination regimen, with a backbone of efavirenz and 3TC (Poster 564b). The presentation closes with a review of new targets, strategies and drugs, touching on RNA interference, fusion inhibitors and the TORO Phase III Trials (abstract 568), pegylated interferon alpha 2b, STIs (HIV NAT Study, abstract 64), Ritonavir boosted Tipranavir - a non-peptidic PI (abstract 179), and finally some preliminary data on new therapeutic vaccines (MVA-BN-Nef, ALVAC-HIV 1433(canary pox vaccine), ALVAC-HIV 1433+Lipo-6T combined with IL-2).
Learning objectives : - Review new epidemiological data on HIV/AIDS
- Hepatitis C and HIV/HCV coinfection
- New studies on " old " drugs: nevirapine, efavirenz, d4T and 3TC (2NN Study), and D4T, tenofovirDF, 3TC, EFV(Gilead 903 Study)
New targets, strategies and treatments: RNAi, Fusion inhibitors (T-20, T-1249), the TORO (T-20 vs Optimized Regimen Only) Phase III Trials, peg-IFNa2b, , STIs (HIV NAT Trial), TPVr, and therapeutic vaccines (MVA-BN-Nef, ALVAC-HIV 1433(canary pox vaccine), ALVAC-HIV 1433+Lipo-6T combined with IL-2)
Bibliographic references : Double-stranded nef RNA interferes with human immunodeficiency virus type 1 replication.
Yamamoto T, Omoto S, Mizuguchi M, Mizukami H, Okuyama H, Okada N, Saksena NK, Brisibe EA, Otake K, Fuji YR.
Division of Nutritional Sciences, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Aichi 467-8603, Japan.
RNA interference (RNAi) has been reported to be post-transcriptional gene silencing (PTGS) by approximately 500 nucleotide-(nt)-long double-stranded (ds) RNA that specifically targets homologous sequences of messenger RNA. In this report, we describe inhibition of HIV-1 transcription by synthetic dsRNAs constructed with mutated nef genes (nef dsRNAs) derived from long-term non-progressors (LTNPs) using cotransfection of the target gene-expressing plasmid and dsRNA. The effects of nef dsRNAs were examined with luciferase (Luc) reporter which is combined with the HIV-1 (SF2) LTR in persistently HIV-1-infected T cell and macrophage cell lines. At 48 hr, a defective nef dsRNA (556 nt) suppressed Luc activity more potently than did SF2 full-length nef dsRNA (744 nt), suggesting that approximately 500 nt-long nef dsRNA could interfere with the HIV-1 transcription.
Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium. erik.declercq@rega.kuleuven.ac.be
Virtually all the compounds that are currently used or are subject of advanced clinical trials for the treatment of HIV infections, belong to one of the following classes: (i) nucleoside reverse transcriptase inhibitors (NRTIs): i.e., zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, emtricitabine and nucleotide reverse transcriptase inhibitors (NtRTIs) (i.e., tenofovir disoproxil fumarate); (ii) non-nucleoside reverse transcriptase inhibitors (NNRTIs): i.e., nevirapine, delavirdine, efavirenz, emivirine; and (iii) protease inhibitors (PIs): i.e., saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, and lopinavir. In addition to the reverse transcriptase and protease reaction, various other events in the HIV replicative cycle can be considered as potential targets for chemotherapeutic intervention: (i) viral adsorption, through binding to the viral envelope glycoprotein gp120 (polysulfates, polysulfonates, polycarboxylates, polyoxometalates, polynucleotides, and negatively charged albumins); (ii) viral entry, through blockade of the viral coreceptors CXCR4 (i.e., bicyclam (AMD3100) derivatives) and CCR5 (i.e., TAK-779 derivatives); (iii) virus-cell fusion, through binding to the viral envelope glycoprotein gp41 (T-20, T-1249); (iv) viral assembly and disassembly, through NCp7 zinc finger-targeted agents [2,2'-dithiobisbenzamides (DIBAs), azadicarbonamide (ADA)]; (v) proviral DNA integration, through integrase inhibitors such as 4-aryl-2,4-dioxobutanoic acid derivatives; (vi) viral mRNA transcription, through inhibitors of the transcription (transactivation) process (flavopiridol, fluoroquinolones). Also, various new NRTIs, NNRTIs, and PIs have been developed that possess, respectively: (i) improved metabolic characteristics (i.e., phosphoramidate and cyclosaligenyl pronucleotides by-passing the first phosphorylation step of the NRTIs), (ii) increased activity ["second" or "third" generation NNRTIs ( i.e., TMC-125, DPC-083)] against those HIV strains that are resistant to the "first" generation NNRTIs, or (iii), as in the case of PIs, a different, modified peptidic (i.e., azapeptidic (atazanavir)) or non-peptidic scaffold (i.e., cyclic urea (mozenavir), 4-hydroxy-2-pyrone (tipranavir)). Non-peptidic PIs may be expected to inhibit HIV mutant strains that have become resistant to peptidomimetic PIs. Copyright 2002 Wiley Periodicals, Inc.
Med Res Rev 2002 Nov;22(6):531-65
Conference
"Introduction" Pr. François Raffi (biography) English - 2002-11-17 - 9 minutes
(9 slides)
Conference
"Aims of long-term therapy" Dr. Margaret Johnson (biography) English - 2002-11-17 - 29 minutes
(38 slides)
Conference
"Quadruple therapy as induction" Dr. Brian Gazzard (biography) English - 2002-11-17 - 27 minutes
(31 slides)
Conference
"We should spare the NNRTI" Dr. Sharon Walmsley (biography) English - 2002-10-30 - 21 minutes
(45 slides)
Conference
"Counterpoint to "We should use NNRTI in first line"" Dr. Sharon Walmsley (biography) English - 2002-10-30 - 27 minutes
"Emerging issues impacting the health outcomes of HIV infected individuals initiating antiretroviral therapy" Dr. Robert Hogg (biography) English - 2002-04-26 - 17 minutes
(18 slides)
Summary : Highly Active Antiretroviral Therapy (HAART) has been shown to dramatically decrease morbidity and mortality in symptomatic and asymptomatic HIV infected individuals. As a result, these antiretroviral drug regimens have been widely adopted for the treatment oh HIV infection. In the past, recommendations for the initiation of antiretroviral therapy were largely based on both CD4 cell count and plasma HIV RNA levels.
Current observational evidence suggests that rates of disease progression to AIDS or death among those on antiretroviral therapy are a function of baseline CD4 cell counts rather than of HIV RNA levels. The aim of this talk is to briefly characterize patterns of antiretroviral usage, changes in rates of morbidity and mortality and salient prognostic factors associated with diseases progression in the province of British Columbia with evidence from other observational studies from around the world. In addition, the potential impact of these findings on current guidelines and on antiretroviral access in region outside North America, Europe and Oceania will be assessed.
Learning objectives : To learn about survival improvements of patients starting ART, data on the time to start ART, data on antiretroviral class, and issues of antiretroviral access worldwide.
Conference
"Study Case : Case Presentations by Attendees to the Faculty" Dr. Silvia Guillemi (biography) English - 2002-04-15 - 20 minutes
(12 slides)
Summary : Centre for Exellence in HIV/AIDS , St. Paul's Hospital
Moderator: Julio Montaner
Panel Participants: Jose Gatell, Stefano Vella, Giuseppe Pantaleo,
Keith Gallicano, Richard Harrigan, Mark Wainberg, Joep Lange
This Study Case was presented in Whistler (British Columbia) on
April 15th, 2002, Chateau Whistler
Conference
"Study Case : Case Presentations by Attendees to the Faculty" Dr. Carol Murphy (biography) English - 2002-04-15 - 23 minutes
(12 slides)
Summary : Spectrum Health Care Clinic , Vancouver, St. Paul's Hospital
Moderator: Julio Montaner
Panel Participants: Jose Gatell, Stefano Vella, Giuseppe Pantaleo,
Keith Gallicano, Richard Harrigan, Mark Wainberg, Joep Lange
This Study Case was presented in Whistler (British Columbia) on
April 15th, 2002, Chateau Whistler
Conference
"Study Case : Case Presentations by Attendees to the Faculty" Dr. Brian Willoughby (biography) English - 2002-04-15 - 19 minutes
(18 slides)
Summary : Clinical Associate Professor, UBC, Centre for Excellence in HIV/AIDS.
Moderator: Julio Montaner
Panel Participants: Jose Gatell, Stefano Vella, Giuseppe Pantaleo,
Keith Gallicano, Richard Harrigan, Mark Wainberg, Joep Lange
This Study Case was presented in Whistler (British Columbia) on
April 15th, 2002, Chateau Whistler
Conference
"Initiating Antiretroviral Therapy (Why, When and How to Initiate Antiretroviral Therapy)" Dr. Jose Gatell (biography) English - 2002-04-14 - 39 minutes
Summary : Like a Marathon run, antiretroviral therapy is a business for life. In fact, is a long life therapy because HIV-1 eradication at present is not an achievable objective and supervised or structured therapy interruptions (STI´s) or immune based therapies still remain in the domain of clinical research. Not all athletes are equally fitted to participate in marathons and only a few of them can expect to have some chances of winning.
The same is true for antiretroviral regimens. Some unfair across studies comparisons have lead to the easy and superficial conclusion that response rate rarely, if ever, exceeds 50% at 24-48 weeks using an intent to treat analysis (in general missing = failure). Yet, while the efficacy of some antiretroviral regimens have never been tested or proved beyond 48 weeks, other regimens have already shown a substantially greater response rate with a sustained durability up to 3-6 years even using the most stringent intent to treat analysis (non completers = failure). Several years ago we have learnt that even small and transient perturbations in the replicative capacity of the HIV-1 can dramatically influence the natural history of the disease.
Moreover, a sustained suppression of the viral replication quickly translated into an immunological reconstitution a delay in the disease progression and ultimately in a much prolonged survival. Recommendations about when and how to initiate antiretroviral therapy have dramatically shifted to more conservative positions during past 1-2 years switching from the principle of hitting ''early and hard'' to hitting ''not too late and wisely''. The major driving forces for these changes have been: 1) the realization of the high incidence of clinical lipodystrophy and other mid and long term side effects, 2) the complexity, inconveniences and restrictions associated with some of the most useful and widely used antiretroviral regimens and, 3) the ability to achieve a sufficient degree of self reconstitution of the immune system even when antiretroviral therapy is initiated in late stages of HIV-1 disease.
No randomized studies have addressed the question of when to start in the era of HAART. However the analysis of several, but not all, cohorts highlights to the fact that the greatest and most evident clinical benefit is obtained when antiretroviral therapy is initiated when the CD4+ cell count drops below 200 cells per microliter or even lower and being the adherence to prescribed therapy the strongest marker of lack of clinical progression or death. Conversely, apart from common sense there are a number of biological, virological and immunological reasons to initiate antiretroviral therapy in much earlier stages of HIV-1 disease providing a potent, durable, convenient and save antiretroviral regimen is available.
The paradigm about composition of initial antiretroviral regimens shifted about 2-3 years ago from PI containing regimens to PI sparing regimens (namely 2NRTI + 1NNRI) and most recently even to 3NRTI. Long term potential for toxicity (mainly metabolic disturbances and lipodystrophy) may be lower with these newer regimens. Moreover, within next months it should be possible to construct simple and potent regimens able to be administered once per day, eventually directly supervised, and with a lower potential for long term toxicity.
Conference
"HAART-Less : Current Evidence and Future Implications" Dr. Robert Hogg (biography) English - 2002-04-14 - 33 minutes
Summary : Highly active antiretroviral therapy has been shown to dramatically decrease morbidity and mortality in symptomatic and asymptomatic HIV infected individuals. As a result, these antiretroviral drug regimens have been widely adopted for the treatment of HIV infection. In the past recommendations for the initiation of antiretroviral therapy were largely based on both CD4 cell count and plasma HIV RNA levels. Current observational evidence suggests that rates of disease progression to AIDS or death among those on antiretroviral therapy are a function of baseline CD4 cell counts rather than HIV RNA levels. The aim of Dr. Hogg's talk is to briefly characterize patterns of disease progression among persons on antiretroviral therapy. The presentation will focus on characterizing patterns of antiretroviral usage, changes in rates of morbidity and mortality and salient prognostic factors associated with disease progression in this province. As well, Dr Hogg will compare current patterns of disease progression in the province of British Columbia with evidence from other observational studies from around the world. In addition, he will explore how these findings may impact on current guidelines and on antiretroviral access in regions outside North America, Europe and Oceania.
Dr. Hogg's work is supported in part by a career investigator award from the Michael Smith Foundation for Health Research and an investigator award from the Canadian Institutes of Health Research.
Conference
"Highlights from the ICAAC’01 and Retrovirus 2002 Meeting" Dr. Sharon Walmsley (biography) English - 2002-03-26 - 50 minutes
(29 slides)
(21 slides)
Conference
"Optimizing the use of Antiretroviral Therapy Safety Profile of ART" Dr. Julio Montaner (biography) English - 2001-10-26 - 49 minutes
(44 slides)
Conference
"Survival Benefit from the Initiation of Antiretroviral Therapy is Compromised by Baseline CD4 + T Cell Counts Below 200 Cells/mm and not Plasma HIV-1 RNA Levels" Dr. Robert Hogg (biography) English - 2001-06-01 - 17 minutes
(15 slides)
Conference
"When and how to start antiretroviral therapy" Dr. Stephano Vella (biography) English - 2001-04-23 - 41 minutes
(27 slides)
(43 slides)
Conference
"Bases for the use of 3TC in clinical practice" Prof. Mark Wainberg (biography) English - 2001-04-23 - 43 minutes
(27 slides)
Conference
"Factors affecting ART effectiveness" Dr. Robert Hogg (biography) English - 2001-04-23 - 33 minutes
(32 slides)
Conference
"Should Advanced Disease be Treated Differently ?" Dr. Richard B. Pollard (biography) English - 2000-09-17 - 35 minutes
(27 slides)
Summary : University of Texas Medical Branch - Galveston, TX
Conference
"Factors Associated with a Durable Response to Antiviral Therapy" Dr. Robert Murphy (biography) English - 2000-04-28 - 60 minutes
(64 slides)
Summary : Northwestern University - Chicago, IL
Conference
"Drug Pharmacokinetics and Antiviral Activity in Semen and Cerebrospinal Fluid in Patients Treated with Amprenavir, Zidovudine and Lamivudine" Dr. Robert Murphy (biography) English - 2000-04-27 - 50 minutes
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