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The goal of antiretroviral therapy is to suppress viral replication to the lowest levels possible, for as long as possible. Within 4 to 6 months of initiating therapy, plasma viral load should decrease to below the level of quantification (usually 400 to 500 copies/mL), and remain there indefinitely. Antiretroviral drug failure therefore occurs in any patient.
Using plasma viral load as a measure of drug efficacy published data from the early clinical trials reported response rates of approximately 70%-90%.
The most appropriate salvage regimen must be selected after a review of the currently available data and the latest information on pathogenesis, resistance, compliance and a thorough understanding.
Defining Failure
The definition of drug failure remains controversial. If the goal of therapy is to achieve complete viral suppression, then it naturally follows that drag failure occurs when this goal is not achieved.
Risk Factors for Virologic Failure
Managing HIV infection requires long-term planning. Determining which patients are likely to fail before treatment is initiated or modified may allow clinicians.
The Role of Viral Reservoirs The majority of HIV resides in tissue, particularly lymph nodes, tonsils and gut associated lymphoid tissue. In general, decay rates in lymphoid tissues closely parallel decay.
Target Cell Availability and Virologic Failure: Predator/Prey Model A model has been proposed that may provide an alternative mechanism for virologic failure. The life cycle of HIV involves a continuous cycle.
Early Viral Load Response as a Predictor of Subsequent Failure
The initial virologic response to therapy appears to predict the long-term response. In ACTG 320, the viral load 4 weeks after initiating ZDV, 3TC and indinavir was the strongest independent predictor of virologic suppression at weeks 24 and 40 [Demeter 2006]. The slope of viral decay over the first few weeks of therapy.
Salvage Therapy after Failure of a Protease Inhibitor: Results from Observational and Controlled Clinical Studies
US Department of Health and Human Service Guidelines offer general recommendations regarding salvage therapy (see Tables 2 and 3). Informative clinical trial data.
ACTG 333 (Saquinavir to indinavir) Saquinavir-hard gel capsule (Invirase) was the first protease inhibitor approved in the US, and was commonly prescribed before more effective drugs became widely available. Therefore, the treatment of the saquinavir experienced patient is a common clinical question. Saquinavir therapy selects for the Lg0M and G48V mutations (the latter mutation may be more common with the soft-gel formulation of saquinavir) [14]. Each alone is associated with a modest increase in phenotypic resistance to saquinavir. In vitro, either mutation confers limited to other protease inhibitors, suggesting that sequential therapy with a second protease inhibitor may be effective in patients previously treated with saquinavir.
In AIDS Clinical Trials Group 333, 72 patients with prior saquinavir-hard gel capsule experience were randomized to receive: (1) continued saquinavir-hard gel capsule, (2) saquinavir-soft gel capsule or (3) indinavir. Nucleoside reverse transcriptase inhibitors were not modified at the time of the switch. In subjects switching to indinavir.
Treatment of the nelfinavir experienced patient Nelfinavir is a popular first line protease inhibitor, partially because in vitro data suggests that nelfinavir does not select for high level cross-resistance to other protease inhibitors.
Treatment of the indinavir or ritonavir experienced patient: Observational studies Indinavir and ritonavir select for similar mutation patterns. Typically, several mutations are seen before high level phenotypic resistance emerges. An initial mutation occurs in the active site of the protease enzyme (ie, the V82A mutation).
Indinavir Failure: Role of Ritonavir plus High-dose Saquinavir
Current drug doses were developed for the treatment of wild-type virus. In the face of drag resistance, the concentration of drag required to inhibit viral replication increases.
Multi-Drug Rescue Therapy
Recognizing the limits of currently available therapies, several groups have pursed very aggressive strategies involving complex regimens. Investigators in Frankfurt, Germany initiated 6 or more drugs in heavily pretreated patients.
Salvage Therapy: Role of Experimental Agents
Most drugs in the advanced stages of clinical development are highly effective against wild-type virus.
Abacavir (Ziagen): Abacavir is a guanosine analogue that is highly effective against wild-type strains. In vitro, resistance to abacavir requires multiple passages and is typically associated with mutations at positions 65, 74, 115 and 184. The in vivo resistance pattern has not been fully described. Abacavir retains significant failed their first combination regimen.
Adefovir dipvoxil (Preveon): Adefovir dipivoxil is a nucleotide analogue with modest anti-HIV activity (approximately 0.5 log decline in viral load has been seen in most studies with adefovir dipivoxil).
bisPOC PMPA Like adefovir, PMPA is a nucleotide analogue. To enhance oral bioavailability, a prodrug has been developed (bisPOC PMPA). In vitro, high-level phenotypic resistance to PMPA was difficult to generate.
Amprenavir (Agenerase): Amprenavir is a protease inhibitor similar in structure to the first generation compounds. In vitro, amprenavir resistance is associated with a unique mutation (at position 50).
ABT 378 ABT 378 is a protease inhibitor now emerging phase II/III evaluation.
Tiprenaivir (pNU-140690): Tiprenavir is a truly novel protease inhibitor.