February 13, 2003
Lanier and colleagues presented data on the use of various antiretroviral (ARV) agents prescribed and the presence of HIV-1 ARV-associated resistance mutations from samples collected from 1999 through the first half of 2002. Several published studies have recently described the increase in ARV-resistant virus transmitted during acute HIV infection, and the increase in ARV-resistant virus from people who are currently taking and failing their regimen. Thus, ARV resistance has emerged as a significant problem in the treatment strategies of HIV-infected people.
Resistance can be assessed by directly examining the genetic sequence of plasma associated HIV-1 reverse transcriptase (RT) and protease (Pr) genes for mutations that change the amino acids of these proteins. This is referred to as genotyping the virus. Mutations are usually referred to by their position number, followed by a letter, which indicates the amino acid change that confers resistance for a particular drug (i.e., 184V is the RT gene mutation which confers resistance to 3TC (lamivudine, Epivir)). Some mutations are specific for a given ARV drug, like 184V above, while others when present, result in ARV resistance to multiple drugs in a class (i.e., RT 103N, which confers resistance to all non-nucleoside reverse transcriptase inhibitors (NNRTI) like nevirapine (NVP, Viramune) and efavirenz (EFV, Sustiva)).
The authors examined two independent databases to assess trends of genotypic resistance mutations and usage of ARV agents (LabCorp and Isis databases respectively). Thus, there was not a direct correlation between development of resistance and ARV use. Almost 38,000 genotypic resistance test results from routine clinical samples submitted to LabCorp were included in this analysis. We were not given the number of patients that were prescribed ARVs or the number of prescriptions for each ARV during the evaluation period. Resistance mutations were grouped by class of ARV and expressed as a percentage of the genotypes examined.
For nucleoside reverse transcriptase inhibitors (NRTI) and NNRTIs, 184V and 103N were the most common mutations (40 percent and 30 percent respectively) and remained constant over the four years. 3TC use remained constant, whereas EFV and NVP use decreased slightly over the observation period.
Thymidine analogue mutations (TAMs, 41L, 67N, 70R, 201W, 215Y and 219E/Q) associated with resistance to AZT (zidovudine, Retrovir) and d4T (stavudine, Zerit) decreased significantly over the four-year period, despite a relatively constant use of these two drugs. Increases in the 115F (0.59-1.42 percent) and 65R (0.64-1.69 percent) mutations, although small, are probably related to the significant increase in abacavir (ABC, Ziagen) and tenofovir (TDF, Viread) use respectively. Overall, prescribing for most protease inhibitors (PI), except lopinavir (LPV+RTV, Kaletra), declined over the observation period. This is reflected in the overall reduction of some of the primary PI-associated mutations (46I/L, 82A, 84V and 90M).
The data presented here has some obvious limitations. Since this data was obtained from two separate sources, there is no true linkage in this report between ARV use and resistance test information. We also do not know the number of repeat tests per patient and across time. In addition, we were not provided with information about ARV history, current regimen or clinical outcome of patients. We do not know whether the trend of performing resistance tests in patients who have never been exposed to ARVs (whose tests would be expected to show no resistance) has increased over time.
Nevertheless, this indirect measurement demonstrates both a reduction and an increase of many of the primary ARV mutations, which appears to be correlated with the declining or increasing use of those ARV agents. Whether this inference truly reflects a reduction in ARV resistance in the U.S. over time will require further studies with linkage between resistance testing and ARV utilization.
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