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Excerpt
Once highly active antiretroviral therapy (HAART) fails to suppress HIV RNA to undetectable levels and resistance emerges, it is difficult to find alternative combinations, as the potential for cross-resistance within all available antiretroviral drug classes is high. Therefore, the introduction of new drugs is recommended by international treatment guidelines [1]. Two new antiretroviral drugs, abacavir (a nucleoside reverse transcriptase inhibitor; NRTI) and efavirenz (a non-nucleoside reverse transcriptase inhibitor; NNRTI), became available in Germany in 1998. These two potent drugs offered the basis for a new salvage regimen for multiply pretreated patients.
For this retrospective analysis, we identified 50 patients with a long antiretroviral pre-treatment history (6.3 ± 1.8 years), who experienced virological failure on HAART and were switched to a combination of abacavir plus efavirenz and NRTI and/or a protease inhibitor (PI). All patients had received at least three different previous NRTI and two PI, 20 had also received NNRTI before (delavirdine, n = 4; nevirapine, n = 16), but all were naive to efavirenz and abacavir. NRTI and/or PI as background therapy had to be different from the drugs the patients had received before, and were chosen on an individual basis (27 single NRTI; seven double NRTI; three single PI; four double PI; six NRTI plus PI; three didanosine plus hydroxyurea). All patients were followed for 48 weeks. Besides the determination of CD4 cell counts and HIV-RNA levels, genotypic resistance testing was performed before switching in all patients who had a plasma sample available and continued therapy for more than 4 weeks (n = 35). After 24 and 48 weeks genotypic analysis was repeated in all patients failing the salvage regimen who had at least one baseline and one follow-up sample available. All treatment discontinuations and adverse events were recorded. Statistical analysis followed an intent-to-treat approach. Comparison with baseline values was performed using the t-test for paired data. Differences between different treatment groups were tested using Fisher's exact test. Multiple logistic regression was used to explore the effects of various baseline characteristics on the probability of virological response.
The baseline CD4 cell count was 229 ± 180/μl (mean ± SD), viral load 4.75 ± 0.83 log copies/ml. Nineteen of the study subjects discontinued treatment during the 48 week follow-up (38%). Nine of these discontinuations were considered to be related to study drugs, which all occured within the first 4 weeks of treatment (rash caused by efavirenz, n = 5; abacavir hypersensitivity, n = 2; rash of unknown aetiology, n = 1; efavirenz neurotoxicity, n = 1). Four treatment discontinuations were caused by virological failure and six had other causes, which were in detail: progression of HIV infection (sepsis); renal insufficiency; stop for the treatment of tuberculosis; didanosine-associated pancreatitis; one patient stopped for his own reasons.
CD4 cell counts increased significantly by 86 cells/μl after 48 weeks (P < 0.05). The viral load decreased by 1.6 log copies/ml (P < 0.05) after the same period. A total of 19% of all patients were below the limit of detection after 48 weeks in the observed data analysis, whereas only 12% were below 80 copies/ml after an intention-to-treat approach.
