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.
Salvage therapy concerns the treatment administered after failure of a potent antiretroviral therapy. The salvage therapy is chosen based on the resistance profile and toxicity of previous treatments. (Cf topic: Treatment related complications)
"Management of ART-Experienced and Salvage Patients" Dr. Chris Fraser (biography) English - 2003-11-10 - 14 minutes
Summary : In this presentation Dr Fraser will discuss the evolution of HIV drug resistance in relation to replicative capacity and viremia based on a clinical cohort study (Deeks et al); and give a review of cohort studies on treatment interruption in ART-experienced patients (GigaHAART, CPCRA 064, REVERSE), and an introduction to Boosted Double PI Therapy (CRIXILOP Study).
Learning objectives : The participant will learn new information presented at the 9th EACS on the following topics:
-HIV drug resistance in relation to replicative capacity and viremia (Deeks et al)
-Cohort studies of treatment interruption in ART-Experienced patients (GigaHAART, CPCRA 064, REVERSE)
-Boosted double PI therapy (CRIXILOP Study)
"Second Line Therapy" Dr. Frank J. Palella (biography) English - 2003-03-29 - 41 minutes
Summary : The optimal selection of antiretroviral agents for inclusion in second line therapy and beyond must include consideration of several important factors. These include :
- reasons for discontinuation of first line HAART therapy (ie. efficacy versus tolerability)
- - viral susceptibility data (genotype, phenotype, virtual phenotype, replication capacity)
- underlying/preexisting patient diagnoses or comorbid conditions
- known history of drug toxicity
- patient preference
- likelihood of medication adherence
- drugs option remaining for inclusion in a second line (or beyond) regimen
- whether or not complete viral suppression is a realistic option
- fear of development of metabolic complications
feasibility and advisability of an interruption in therapy
Learning objectives : The participant will learn that it is important to use the following guidelines in optimizing second line HAART therapy:
- Use at least 2 or 3 active agents as determined by genotype or phenotype
- Switch treatment as early on in the course of virologic failure as possible to minimize additional resistance, and to increase the chance of successful salvage
- Simplify regimens when possible to enhance adherence and tolerability
- Communicate effectively with patients
Bibliographic references : Factors associated with the successful modification of antiretroviral therapy. HIV Outpatient Study Investigators.
Weidle PJ, Lichtenstein KA, Moorman AC, Von Bargen JC, Greenberg KS, Palella FJ Jr, Holmberg SD.
Epidemiology Branch, Division of HIV/AIDS Prevention Surveillance and Epidemiology, National Center for HIV, STD, and TB Prevention, Centers for Disease Control, Atlanta, GA 30333, USA. firstname.lastname@example.org
OBJECTIVES: To assess the characteristics of medication regimen modification and the influence of a commercial genotypic resistance assay on the short-term (3-12 weeks) viral load response (> or = 0.5 log reduction) in HIV-1-infected patients extensively treated with antiretroviral therapy (ART). METHODS: A nested cohort study was performed in two clinics from the HIV Outpatient Study of 96 persons with a HIV-1 viral load of 10(4) log copies/ml or greater taking at least two antiretroviral medications. RESULTS: Successful modification was associated with adding at least two new medications [relative risk (RR), 1.5; 95% confidence interval (CI), 1.1-2.2], adding a drug from a previously unused class of agents (RR, 2.0; CI, 1.4-2.9), the initiation of a non-nucleoside reverse transcriptase inhibitor (NNRTI) (RR, 1.7; CI, 1.2-2.4), but not substituting a protease inhibitor or the use of a commercial genotypic resistance assay. CONCLUSION: Incorporating a drug from a previously unused class or changing at least two new medications, but, within the confines of this study, not using a commercial genotypic resistance assay, was associated with the successful modification of ART as measured by a reduction in viral load.
AIDS 2000 Mar 31;14(5):491-7
"Management Following Multiple Failures" Dr. Julio Montaner (biography) English - 2003-03-29 - 45 minutes
Summary : There is a lack of objective data on the topic of salvage therapy, unfortunately, and so much of what we discuss here today is opinion-based. Clinical (ART cohort) studies show a virological failure rate of over 25% of patients within the first 6 months of therapy, which is unacceptably high. The advent of routine testing is therefore welcome at this time, and with appropriate genotyping and susceptibility testing, doctors should better be able to choose therapies. The use of the Virtual Virus method is superior to baseline testing, in terms of predicting the kinds of mutations the patient may be harbouring. With regard to therapeutic drug monitoring (TDM), the virtual inhibitory quotient, which relates the IC50 of the virus to the Ctrough of the medication, is a very good method of finding an optimal regimen, through drug boosting, synergies or addition of other compounds. Dealing with treatment failure is a special challenge, which has the possibility to be overcome by multidrug rescue therapy (MDRT), or perhaps with newer agents. New data presented at the CROI 2003 conference are favourable for STIs, as seen in the GIGA-HAART study. The issue of whether to use STIs remains, though a debate, and is not generally recommended, but can be used depending on the clinical circumstances.
Learning objectives : The participant will get an expert opinion on how to deal with multiple class failure:
- Think carefully before starting therapy
- Identify and correct the reason for failure
- Switch early and avoid cross-resistance
- Consider cumulative drug exposure
- Use resistance – PK liberally
- Aim for full suppression, be ready to compromise
- Role of STI unclear (not recommended)
"Emerging Trends in the Management of Treatment Failure." Dr. Schlomo Staszewski (biography) English - 2002-04-26 - 29 minutes
Summary : The goal of antiretroviral therapy, as defined by current guidelines, is to reduce the plasma viral load (pVL) to below detectable levels. This approach is based on the assumption that detectable pVL of any magnitude reflects viral replication which is a major factor in the emergence of drug resistant virus that has the ability to replicate despite antiretroviral treatment. Viral rebound in the presence of therapy is referred to as virologic failure; it is not necessarily accompanied by a decrease in CD4 cell counts. In many patients, the CD4 cell counts remain stable with virologically ineffective treatment, suggesting that, in these cases, the resistant virus may be less harmful to CD4 cells than wild type virus.
The rationale for suppressing the virus to undetectable levels is to delay and prevent the development of viral drug resistance and cross-resistance. This should facilitate longer periods of successful treatment. Clinical studies have demonstrated that pVLs can be suppressed to below detectable levels of the PCR assay in a considerable proportion of patients taking effective combinations of antiretroviral drugs. In clinical practice, however, 40% to 60% of the treated patients are unable to maintain viral suppression despite treatment.
Important reasons for virologic failure are low drug concentrations and insufficient antiviral activity. Sub-inhibitory drug concentrations allow viral replication to occur in the presence of drug, which results in selection of resistant virus and, eventually, in virologic failure. Low drug concentrations may be due to poor compliance, malabsorption, drug interaction and/or inter-individual fluctuations in plasma concentrations. Insufficient antiviral activity is frequently a consequence of inadequate treatment strategies such as monotherapy or intensification of a failing regimen by adding single drugs.
The management of failing therapies is currently changing due to the availability of resistance testing and therapeutic drug monitoring (TDM) which, in addition to the treatment history, are helpful in evaluating the cause of failure. They can also assist in creating a more targeted approach to changing the drug(s) within the failing regimen. In patients with early virological failure, resistance tests should help to identify inactive drugs while maintaining drugs to which the virus is still suspectible. Inactive protease inhibitors (PIs) or nucleoside analogues (NRTIs) may be replaced by NNTRIs if resistance testing has demonstrated susceptibility to this class of drugs. Ritonavir boosted lopinavir (Kaletra) and amprenavir are frequently effective when the number of protease gene mutations is less than 4-6. Tenofovir or abacavir may be useful in the presence of the M184V mutation as long as the number of TAMs is not greater than four.
Management of patients with multiple treatment failure is much more complicated due to limited treatment options. These patients not only harbor viruses that are resistant to the majority of the available drugs, but also frequently have low CD4 cell count and high pVLs which make them more vulnerable to clinical progression. Several strategies have been applied to this group of patients in order to re-suppress the resistant virus:
1.Mega-HAART regimens, consisting of at least six drugs have been successful in approximately 50% of the treated patients in several cohorts. Due to poor tolerability, these regimens are not suitable for long term treatment. However, switching to simpler regimens once the pVL has been successfully reduced may be an option.
2.Interruption of therapy after multiple failures with subsequent initiation of mega-HAART. In a randomized study conducted by the French ANRS, this strategy was superior to the immediate implementation of mega-HAART after failure. The benefit of the interruption may be due to the shift of the mutated virus to wild type virus during the treatment interruption.
3.Resistance-guided simple salvage regimen consisting of ritonavir boosted double Pis without RTIs in patients with virus resistant to RTIs, but susceptible to PIs. In the Frankfurt HIV Cohort, patients who were pre-treated and experiencing therapy failure of their current regimen due to resistance or systemic toxicity, were switched to a new regimen of lopinavir/r plus saquinavir-SGC after genotype testing showed RTI resistance but PI sensitivity. After a median follow up time of 21weeks, the patients had a median pVL decrease of 3.4 log10 copies/mL and a median increase of 70CD4 cells/mm3. Pharmakinetic profiles were performed after a minimum of 14 days of therapy. A considerable range of inter-individual plasma levels was observed. Low ritonavir plasma levels were effective in boosting both lopinavir/r and saquinavir. Comparaisons between the pharmacokinetics of lopinavir/r/saquinavir and ritonavir/saquinavir indicated that lopinavir/r and saquinavir may be combined without dose adjustments. For patients with PI-sensitive HIV who are not able to take RTIs due to resistance or toxicity, the RTI-sparing, double boosted PI regimen of saquinavir plus lopinavir/r is a potential option. Patients with previous PI-resistant virus may benefit from this strategy after sift to wild type in the gene mutations.
Learning objectives : Early treatment failure usually arises due to non-compliance arising from a complicated drug regimen. New classes of drugs should be used.
Discussion of trans-class cross resistance arising after late stage treatment interruption.
Discussion of Mega HAART, and other salvage therapies, with case study examples.
"Second Line Antiretroviral Therapy" Dr. Joep Lange (biography) English - 2002-04-14 - 41 minutes
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