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Conference
"Emerging Trends in the Management of Treatment Failure." Dr. Schlomo Staszewski (biography) English - 2002-04-26 - 29 minutes
(35 slides)
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.
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