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Emergence of drug-resistant HIV-1 variants in patients undergoing structured treatment interruptions
 
 
  AIDS 2002; 16(17):2342-2344
 
We report the emergence of drug-resistant viral mutations in chronically HIV-infected individuals undergoing structured treatment interruptions (STI). The protease mutation M46L and the reverse transcriptase mutations K101E and K103N were detected at the end of the second or third STI. We conclude that the repeated abrupt termination and resumption of certain antiretroviral drug regimens during STI therapy may lead to the development of drug resistance in chronically HIV-infected individuals.
 
We recently reported that HIV-1-specific CD8 T-cell immunity was significantly augmented in chronically infected individuals undergoing structured treatment interruptions (STI) compared with patients undergoing continuous antiretroviral therapy. However, there was no corresponding reduction in rebound viral load in STI individuals during periods off drug. In five out of eight STI patients, the viral load was suppressed to undetectable levels once antiretroviral therapy was resumed. However, the viral load was not completely suppressed in three individuals after the resumption of antiviral therapy (SCE-06, JKF-12, and PFZ-15). These results led us to investigate whether drug-resistant mutations had developed during STI.
 
Previous studies of HIV-1-infected subjects undergoing STI have shown little evidence of the selection for drug-resistant viral strains during interruption periods. However, a recent report by Martinez-Picado and colleagues described the development of a drug-resistant mutation in two chronically infected HIV-1 patients at the end of both the second and third STI. These patients developed the M184V mutation during the trial protocol, and as a result, developed phenotypic resistance to the antiretroviral drug lamivudine. To investigate whether drug-resistant mutations emerged during our STI trial, HIV-1 RNA was extracted from the plasma of non-suppressed individuals at successive timepoints during the STI cycles. The consensus sequence of viral RNA was genotyped using a standardized assay (TRUGENE HIV-1 Genotyping Kit; Visible Genetics Inc., Suwanee, GA, USA), and the protease and reverse transcriptase genes were monitored for mutations associated with drug resistance. When possible, the genotype of the baseline viral population was determined before the start of the STI study, while patients were still receiving antiretroviral therapy.
 
Two of the three non-suppressed patients developed drug-resistant mutations during the third STI (SCE-06 and PFZ-15). The reverse transcriptase mutations, K101E and K103N, were first detected in SCE-06 at the end of the third STI, conferring resistance to non-nucleoside reverse transcriptase inhibitors (NNRTI). The protease inhibitor (PI)-resistant mutation M46L was first detected in PFZ-15 at the end of the third STI cycle, despite the fact that this individual had never received a PI-containing drug regimen. This mutation has previously been detected in PI-na´ve patients, and probably represents a normal, albeit infrequent, variation in HIV-1 populations. No mutations associated with phenotypic drug resistance were detected in the third subject, JKF-12, during or after the STI trial, providing evidence that drug resistance did not contribute to the persistent viremia in this case. The lack of evidence for drug resistance to the prescribed regimens in JKF-12 and PFZ-15 suggests that insufficient drug exposure, rather than drug resistance, accounted for virological failure, as has been found in previous studies. Insufficient drug exposure could be a consequence of incomplete adherence, which may be more common in patients electing STI treatment strategies.
 
The development of the K101E and K103N mutations in SCE-06 was probably a result of selective pressure caused by the patient's drug regimen, which contained the NNRTI, efavirenz. These particular mutations have previously been detected in patients receiving efavirenz, and have been associated with NNRTI treatment failure. The development of these mutations led us to investigate another subject on the trial who was receiving an efavirenz-containing drug regimen (JAF-01). The K103N mutation was detected in this subject at the end of the second STI. Despite the emergence of this mutation, JAF-01 was able to suppress viral load post-STI.
 
Interestingly, the K103N mutation arose in both of the subjects on this study receiving efavirenz-containing drug regimens. This is of particular importance, as the half-life of this drug is longer than other antiretroviral drugs used in this study. Efavirenz remains in the body for 40-55 h after the last dose is ingested (Sustiva at www.pdr.net), whereas most of the nucleoside reverse transcriptase inhibitors and PI are cleared in less than 12 h, and some are cleared as early as 1 h after ingestion. As a result, a window of time is created after stopping drugs when the virus population is exposed to the NNRTI alone, potentially enhancing the selection of drug-resistant viral strains within the host. Nevirapine is another NNRTI with a fairly long half-life. Clearance of this drug can take up to 25-30 h. Two patients on this study were receiving regimens containing nevirapine; however, they were not screened for the emergence of drug-resistant mutations.
 
We conclude that the repeated termination and resumption of multi-drug therapy in chronically HIV-1-infected individuals may lead to the development of drug-resistant viral strains, particularly in those individuals receiving antiretroviral drugs that are metabolized slowly or are inactivated by single mutations. It may prove beneficial to select drug regimens and schedule STI in a way that ensures that the levels of all drugs are phased out and phased back into circulation on a similar time scale, rather than opting for abrupt transitions in therapy.
 
Becky Schweighardta; Gabriel M. Ortiza; Robert M. Granta; Melissa Wellonsb; G. Diego Mirallesc; Leondios G. Kostrikisd; John A. Bartlettb; Douglas F. Nixona. aGladstone Institute of Virology and Immunology, University of California, San Francisco, CA, USA; bDuke Center for AIDS Research, Duke University Medical Center, Durham, NC, USA; cTrimeris Pharmaceuticals, Durham, NC, USA; and dUniversity of Athens, Medical School, Athens, Greece.
 
 
 
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