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A K103N resistance mutation is not an absolute contraindication to adding efavirenz to a salvage regimen: a case report
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AIDS: Volume 19(12) 12 August 2005 p 1337-1338
Letter To The Editor
Kolber, Michael A
Division of Infectious Diseases, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA.
Non-nucleoside reverse transcriptase inhibitors (NNRTI) are an important component in the therapeutic armamentarium against HIV-1 disease. They have been a first-line agent in antiretroviral therapy, and play an important role in the prevention of mother-to-child transmission of HIV-1 disease. Unfortunately, this class of antiretroviral agents is susceptible to the development of resistance if compliance is not excellent as a result of the fact that single point mutations are sufficient to confer high-level resistance. Once this resistance occurs these drugs are not usually used again in therapeutic regimens. A case study is presented that demonstrates that the re-introduction of efavirenz to a potent non-suppressive regimen can lower the viral burden further.
The patient was 45-year-old African-American women with a history of an HIV diagnosis in 1996. She was followed at another facility until 2000, when she presented to the outpatient Jackson Memorial/University of Miami Adult HIV clinic with a CD4 cell count of 15 cells/mm3 and a viral load greater than 750 000 copies/ml. At that time she was taking saquinavir and combivir. Her regimen of highly active antiretroviral therapy (HAART)was changed to efavirenz, abacavir and stavudine. Her viral load dropped to below the level of detectability (200 copies/ml) for approximately one year, after which it became detectable, as shown in Fig. 1a. During this time her CD4 cell count steadily increased (Fig. 1b). After two elevated viral load measurements a genotype was performed that showed multiple mutations to NNRTI (K103N,V108I, A98G) and nucleoside reverse transcriptase inhibitor (M41L,T215Y) classes. Her HAART regimen was subsequently changed to lopinavir boosted with ritonavir with didanosine (once a day) and lamivudine. Her viral load continued to be elevated, and at one point the patient admitted to a period of poor compliance secondary to depression (Fig. 1a). During that time another HIV genotype was performed and the dominant species demonstrated mutations at L63P and L90M. No NNRTI mutations were seen in this genotype. After the patient started back on the protease inhibitor (PI)-containing regimen her viral load dropped to approximately 1500 copies/ml. After three viral loads that were approximately the same (over 28 weeks) efavirenz was re-introduced into the existing PI-containing regimen. The following two viral loads demonstrated approximately a five to sixfold drop (approximately 250 copies/ml) that has persisted for 45 weeks since the addition. The CD4 cell count has demonstrated some fluctuations during this period, but the CD4 percentage has remained relatively unchanged (Fig. 1b).
In general, for those HIV-1-infected individuals who have a K103N mutation in their viral genotype, the intensification of a failing HAART regimen with efavirenz is not performed. This is because archived species persist [1], and failure to suppress suboptimal salvage regimens results in the rapid emergence of resistant virus [2]. In the present case, treatment options were limited because the patient did not want to inject herself with a fusion inhibitor. Therefore, it was reasoned that if the boosted PI regimen maintained pressure on the archived virus and minor species, then the addition of efavirenz to the regimen with the optimized nucleoside background, the dominant breakthrough virus might be suppressed. The fact that a persistent, greater than fivefold drop in viral burden occurred after efavirenz reintroduction suggests that this was indeed the case. This change in viral load is more than 0.5 log10 (copies/ml) and has been considered significant to confer clinical benefit [3]. The L90M mutation was most likely generated while the patient was on the failed saquinavir regimen [4], and conferred a reduced susceptibility to lopinavir [5]. This could explain the inability of the boosted PI combination to suppress the viral burden successfully after the development of NNRTI resistance. Whether a persistent K103N mutation was present in any minor variant viral species was not evaluated. However, if a K103N mutation did persist in the background of other mutations, the fact that the patient's viral load dropped suggests that the underlying virus was less fit. This case demonstrates that, in certain infected individuals with a history of a K103N viral mutation, by maintaining antiretroviral pressure on existing susceptible virus, it is possible to reintroduce efavirenz and decrease the viral burden if the breakthrough virus has no NNRTI mutations.
References
1. Siliciano JD, Siliciano RF. A long-term latent reservoir for HIV-1: discovery and clinical implications. J Antimicrob Chemother 2004; 54:6-9.
2. Casado JL, Moreno A, Hertogs K, Dronda F, Moreno S. Extent and importance of cross-resistance to efavirenz after nevirapine failure. AIDS Res Hum Retroviruses 2002; 18:771-775.
3. Murray JS, Elashoff MR, Iacono-Connors LC, Cvetkovich TA, Struble KA. The use of plasma HIV RNA as a study endpoint in efficacy trials of antiretroviral drugs. AIDS 1999; 13:797-804.
4. Jacobsen H, Haenggi M, Ott M, Duncan IB, Andreoni M, Vella S, Mous J. Reduced sensitivity to saquinavir: an update on genotyping from phase I/II trials. Antiviral Res 1996; 29:95-97.
5. Kempf DJ, Isaacson JD, King MS, Brun SC, Xu Y, Real K, et al. Identification of genotypic changes in human immunodeficiency virus protease that correlate with reduced susceptibility to the protease inhibitor lopinavir among viral isolates from protease inhibitor-experienced patients. J Virol 2001; 75:7462-7469.
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