Discontinuing Non-Nucleoside Reverse Transcriptase Inhibitors

Abstract and Commentary

By Dean L. Winslow, MD, FACP, Chief, Division of AIDS Medicine, Santa Clara Valley Medical Center, Clinical Professor of Medicine, Stanford University School of Medicine Section Editor, HIV, is Associate Editor for Infectious Disease Alert.

Dr. Winslow is a consultant for Bayer Diagnostics and Pfizer/Agouron, and is on the speaker's bureau for Pfizer/Agouron.

Synopsis: The prolonged persistence of nnRTI after their discontinuation increases the risk of HIV resistance..

Source: Department of Health and Human Services. Guidelines for the use of antiretroviral agents in HIV-1 infected adults and adolescents. May 4, 2006; www.AIDSinfo.nih.gov

Due to the long half-lives of nevirapine and efavirenz, it is now recommended that when non-nucleoside reverse transcriptase inhibitor (nnRTI)-containing antiretroviral regimens are discontinued, backbone nucleoside analogs should be continued for 4-7 days to reduce the likelihood of development of nnRTI resistance.

Commentary

One of the reasons for the excellent clinical efficacy of nnRTI-containing antiretroviral therapy regimens is that, while limited by the potential for development of high-level resistance with a single amino acid substitution, the intrinsic potency of these regimens is higher than the other classes of agents. In addition to generally good tolerability, the prolonged half-lives of both nevirapine and efavirenz may also partially compensate for the occasional missing of doses, which is a fact of life in the real world of clinical medicine. In fact, levels of nnRTIs may be detectable for up to 8 weeks following discontinuation of the agent.1

This prolonged half-life (with resulting significant exposure of the virus in vivo to subinhibitory levels of the antiretroviral) has been shown to result in the development of nnRTI-resistant virus in 60% of women who were treated with single dose nevirapine for prevention of mother-to-child transmission of HIV. A recently published study conducted in South Africa shows that giving 4-7 days of zidovudine plus lamivudine, following a single dose of nevirapine, reduced the risk of postnatal resistance development in the mother from 60% to 10%-12%.2 While not formally studied in the routine clinical setting, based on these data, in order to prevent functional monotherapy with a nnRTI after discontinuing a HAART regimen, it seems prudent to continue the nucleosides for 4-7 days following discontinuation of the nnRTI in order to preserve this class of agents as a future option (hence, the recommendations made in the latest edition of the HHS antiretroviral therapy guidelines).

Another potentially, clinically significant piece of information is the recently developed evidence that certain host genetic polymorphisms (especially in the cytochrome P450 CYP2B6 isoform) may result in even slower rates of clearance. These polymorphisms appear to be more common in Hispanic and African American patients, and may increase both the likelihood and severity of nnRTI-related adverse effects in patients who have these polymorphisms.3,4 At Santa Clara Valley Medical Center in San Jose (where I currently practice), approximately 60% of our HIV clinic population is Latino. It is certainly my impression (although not yet supported by hard numbers) that the incidence of efavirenz-induced skin rashes is significantly higher in Latino patients than it is in non-Latino Caucasians.

The nnRTIs remain important agents in our armamentarium. Some of this new information has real clinical relevance and will help us use these agents in a more optimal fashion.

References

  1. Sadiq ST, et al. Efavirenz Detectable in Plasma 8 Weeks After Stopping Therapy and Subsequent Development of Non-Nucleoside Reverse Transcriptase Inhibitor-Associated Resistance. AIDS. 2005;19:1716-1717.
  2. McIntyre JA, et al. Addition of Short Course Combivir to Single Dose Viramune for the Prevention of Mother to Child Transmission of HIV-1 Can Significantly Decrease the Subsequent Development of Maternal and Paediatric NNRTI-Resistant Virus. 3rd International AIDS Society Conference on HIV Pathogenesis and Treatment; July 24-27, 2005; Rio de Janeiro. Abstract TuFo0204.
  3. Haas D, et al. A Common CYP2B6 Variant is Associated with Efavirenz Pharmacokinetics and Central Nervous System Side Effects: AACTG Study NWCS 214. 11th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2004; San Francisco. Abstract 133.
  4. Ribaudo H, et al. Relationships Between Efavirenz Pharmacokinetics, Side Effects, Drug Discontinuation, Virologic Response, and Race: Results from ACTG A5095/A5097s. 11th Conference on Opportunistic Infections; February 8-11, 2004; San Francisco. Abstract 132.