Resistance Studies From the 10th Conference on Retroviruses
During the 10th Conference on Retroviruses and Opportunistic Infections (CROI), held in Boston during mid-February 2003, some significant advances and important information were presented, especially in the area of resistance. The following, parts of which were initially published at www.medscape.com, is a brief review of the information and studies presented in this constantly evolving area of HIV medicine.
The prevalence of antiretroviral resistance in primary HIV infection (PHI) has always been of intense interest to researchers and clinicians because it may have a significant impact on a patient's chance for successful treatment with HAART. Earlier studies, primarily done in large urban areas of North America, have found relatively high rates of resistance, ranging from 10.7% to 27.6%. A study presented by Chuck Hicks of Duke University at CROI looked at the rate of antiretroviral resistance in PHI in a less urban area.
This study evaluated 31 patients from 2 states in the southeastern United States, North Carolina and Georgia, who were infected with HIV between 1998 and 2002. The patients all had genotypic and phenotypic resistance testing performed within a median of 26 days after onset of their PHI symptoms. As would be expected, at the time of resistance testing, the patients' mean viral load was relatively high, 5.54 log10 copies/mL.
Phenotypes were interpreted using the Virco cutoffs, while genotypes were interpreted with the Stanford database algorithm. The patients were found to have genotypic and phenotypic resistance of 6.5% and 7.4%, respectively, for nucleoside analogues (NAs); 3.2% and 11.1%, for nonnucleoside reverse transcriptase inhibitors (NNRTIs); and 0% and 7.4%, for protease inhibitors (PIs). Of note, only 1 patient had greater than 10-fold reduced susceptibility to any antiretroviral agent, and only 1 patient had both genotypic and phenotypic resistance.
When the genotypic and phenotypic resistance detected were combined, 6 of the 31 patients were shown to have resistance to 1 or more of the antiretroviral agents in the standard HAART regimen (stavudine, didanosine, and nevirapine with or without hydroxyurea) used to treat 30 of the patients before the resistance test results were available. Despite this resistance, 5 of these 6 patients were able to achieve a viral load below 50 copies/ mL, and the only patient who was not able to do so had virus that was resistant to both stavudine and didanosine at baseline and that later became resistant to nevirapine, just as would be expected in a patient effectively treated with monotherapy.
This study raises a number of important issues regarding resistance testing of newly infected patients, but the primary issue remains whether testing is helpful to clinicians trying to determine appropriate treatment. In this study, higher rates of resistance were found with phenotypes than with the genotypes, especially with regard to the NNRTIs and PIs, and it is unclear whether this was a result of inaccurate cutoffs used in the phenotypes, an inaccurate or incomplete algorithm used to interpret the genotypes, or the different sensitivities of detection of mutations in the phenotypic and genotypic assays. The response of the patients to antiretroviral therapy (ART) indicates that inaccurate cutoffs may be to blame, but there are not enough data available to state this with a high degree of confidence. The bottom line seems to be that these assays may be helpful in finding resistance mutations in patients with PHI, but the significance of these mutations remains in doubt.
In 2 other studies presented at CROI, NEAT and SOLO, which will be discussed at length below, baseline genotypes were obtained in antiretroviral-naive patients, and rates of resistance were surprisingly low. In NEAT, fewer than 1% of patients had significant reverse transcriptase (RT) resistance or PI resistance mutations at baseline. In SOLO, 5 (3%) of 191 patients had significant RT mutations, while 2 (1%) of 196 had significant protease mutations. The data for nonnucleoside reverse transcriptase mutations were not presented, but these rates for RT and PI resistance are significantly lower than those reported in some studies and may reflect the international nature of these trials, that is, that they were performed in areas without a high prevalence of earlier antiretroviral use, and the fact that the patients enrolled were chronically, not newly, infected with HIV.
During the 10th Conference on Retroviruses and Opportunistic Infections (CROI), held in Boston during mid-February 2003, some significant advances and important information were presented, especially in the area of resistance. The following, parts of which were initially published at www.medscape.com, is a brief review of the information and studies presented in this constantly evolving area of HIV medicine.
The prevalence of antiretroviral resistance in primary HIV infection (PHI) has always been of intense interest to researchers and clinicians because it may have a significant impact on a patient's chance for successful treatment with HAART. Earlier studies, primarily done in large urban areas of North America, have found relatively high rates of resistance, ranging from 10.7% to 27.6%. A study presented by Chuck Hicks of Duke University at CROI looked at the rate of antiretroviral resistance in PHI in a less urban area.
This study evaluated 31 patients from 2 states in the southeastern United States, North Carolina and Georgia, who were infected with HIV between 1998 and 2002. The patients all had genotypic and phenotypic resistance testing performed within a median of 26 days after onset of their PHI symptoms. As would be expected, at the time of resistance testing, the patients' mean viral load was relatively high, 5.54 log10 copies/mL.
Phenotypes were interpreted using the Virco cutoffs, while genotypes were interpreted with the Stanford database algorithm. The patients were found to have genotypic and phenotypic resistance of 6.5% and 7.4%, respectively, for nucleoside analogues (NAs); 3.2% and 11.1%, for nonnucleoside reverse transcriptase inhibitors (NNRTIs); and 0% and 7.4%, for protease inhibitors (PIs). Of note, only 1 patient had greater than 10-fold reduced susceptibility to any antiretroviral agent, and only 1 patient had both genotypic and phenotypic resistance.
When the genotypic and phenotypic resistance detected were combined, 6 of the 31 patients were shown to have resistance to 1 or more of the antiretroviral agents in the standard HAART regimen (stavudine, didanosine, and nevirapine with or without hydroxyurea) used to treat 30 of the patients before the resistance test results were available. Despite this resistance, 5 of these 6 patients were able to achieve a viral load below 50 copies/ mL, and the only patient who was not able to do so had virus that was resistant to both stavudine and didanosine at baseline and that later became resistant to nevirapine, just as would be expected in a patient effectively treated with monotherapy.
This study raises a number of important issues regarding resistance testing of newly infected patients, but the primary issue remains whether testing is helpful to clinicians trying to determine appropriate treatment. In this study, higher rates of resistance were found with phenotypes than with the genotypes, especially with regard to the NNRTIs and PIs, and it is unclear whether this was a result of inaccurate cutoffs used in the phenotypes, an inaccurate or incomplete algorithm used to interpret the genotypes, or the different sensitivities of detection of mutations in the phenotypic and genotypic assays. The response of the patients to antiretroviral therapy (ART) indicates that inaccurate cutoffs may be to blame, but there are not enough data available to state this with a high degree of confidence. The bottom line seems to be that these assays may be helpful in finding resistance mutations in patients with PHI, but the significance of these mutations remains in doubt.
In 2 other studies presented at CROI, NEAT and SOLO, which will be discussed at length below, baseline genotypes were obtained in antiretroviral-naive patients, and rates of resistance were surprisingly low. In NEAT, fewer than 1% of patients had significant reverse transcriptase (RT) resistance or PI resistance mutations at baseline. In SOLO, 5 (3%) of 191 patients had significant RT mutations, while 2 (1%) of 196 had significant protease mutations. The data for nonnucleoside reverse transcriptase mutations were not presented, but these rates for RT and PI resistance are significantly lower than those reported in some studies and may reflect the international nature of these trials, that is, that they were performed in areas without a high prevalence of earlier antiretroviral use, and the fact that the patients enrolled were chronically, not newly, infected with HIV.
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