July 14, 2003
Marcelin and colleagues presented data from a study in which HIV drug-naive patients were given Trizivir (AZT [zidovudine, Retrovir] + 3TC [lamivudine, Epivir] + abacavir [ABV, Ziagen]) and were then examined to determine which type of HIV drug resistance developed after this regimen failed.
Ninety-seven patients were included in this study with a median follow-up time of 14 months. Seven patients also received efavirenz (EFV, Sustiva). Two-thirds were men and the average age was 38 years. One-third of patients came from sub-Saharan Africa. The median CD4 count and viral load were 221 cells/mm3 and 4.88 log/ml (range 2.5-6.1 log/ml) respectively. Nine percent of the patients were coinfected with hepatitis C virus. Blood samples for viral load were obtained periodically for up to 18 months. Treatment failure was defined as two consecutive viral load tests with values greater than 200 copies/mL.
The median reduction in HIV viral load and increase in CD4 count after 18 months was 2.49 log/mL and 288 cells/mm3 respectively. Fourteen patients had at least one viral load reading over 200 copies/mL. Ten patients had virologic failure as evidenced by consecutive detectable viral loads. The median time to viral load rebound was six months (range three-33 months). Twelve of 14 patients had samples from which a resistance test could be obtained. Three of the patients with one viral load "blip" had sequence data, two of which showed wild-type virus and one that demonstrated the M184V mutation, in which the amino acid valine has been substituted for the wild-type methionine at codon number 184 in the reverse transcriptase gene. This codon change confers resistance to 3TC and to FTC (emtricitabine, Emtriva), which was recently approved in the U.S. Of the nine treatment failures, four patients showed wild-type virus with no resistance changes. Of the other five patients who failed treatment, two showed only the M184V change and three had the M184V change as well as additional thymidine analogue mutations (TAMs), which are usually seen with AZT resistance. TAMs can also be seen with d4T (stavudine, Zerit) and abacavir resistance.
This study demonstrated that the majority of patients receiving Trizivir alone maintained undetectable viral loads for 18 months. This particular regimen is easy to take and is relatively well-tolerated. In other clinical trials there have been higher failure rates using this triple nucleoside combination alone, and some experts advise that combination therapy should include at least three drugs in two different classes.
Of those who failed this regimen in this study, most only had the M184V mutation. In other words, they did not develop resistance to all the drugs in the Trizivir combination. If such failure is caught early and resistance testing is performed to reveal such a result, then a modification of the regimen (such as discontinuing the 3TC and continuing to use the other two medications in combination with another drug) is very possible. If, however, additional TAM mutations are present, then the activity of AZT and abacavir would be compromised as well, and the entire regimen would have to be changed. This study also demonstrates the importance of routine viral load monitoring and -- when virologic failure is detected -- of the prompt use of resistance testing information to guide choices for the next regimen.
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