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written by Robert W. Shafer, M.D.
published on HIVresistanceWeb: April 1, 1999
Ongoing clinical trials suggest that efavirenz has greater antiretroviral activity than the other approved nonnucleoside RT inhibitors (NNRTIs) nevirapine and delavirdine. In previously untreated patients, triple-drug therapy with efavirenz plus two nucleoside analogues (NRTIs) has been demonstrated to reduce plasma HIV-1 RNA levels to a degree comparable to protease inhibitor (PI)-containing triple-drug therapy. At the 6th Conference on Retroviruses and Opportunistic Infections in Chicago, there were new abstracts on the use of efavirenz in both treatment-naïve patients and patients previously treated with NRTIs. Importantly (for visitors to this site at least) new data on the development and characteristics of viral resistance to efavirenz was presented.
Tashima presented follow-up data from DuPont Pharmaceutical's DMP 266-006 study. In an intent-to-treat analysis of 48 week data, 85% of patients receiving efavirenz + AZT + 3TC had HIV-1 RNA levels <400 copies/mL (68% had levels <50 copies/mL) [1]. Manion presented follow-up data from three other studies of efavirenz-containing HAART regimens in which HIV-1 RNA levels remained below 400 copies/mL in about 70% of patients followed for 36 to 84 weeks [2,3].
Albrecht presented data from ACTG 364 comparing efavirenz vs. nelfinavir vs. efavirenz + nelfinavir together with 1-2 "new" NRTIs in patients who had nearly 5 years of prior NRTI treatment [4]. By week 48, virologic failure (defined as RNA > 500 copies/mL) was significantly higher in the nelfinavir arm (65%) compared with the efavirenz (40%) and efavirenz + nelfinavir (26%) arms. The antiviral response in the efavirenz arm is surprising considering that its NRTI "partners" would be expected to have had reduced activity in this heavily pretreated group of patients.
There are no clinical data available on the response to one NNRTI in patients who have received another NNRTI. Such a response can only be inferred from the genetic mechanisms of resistance to each of the NNRTIs. K103N and Y181C are the most common mutations associated with virologic failure and drug resistance in patients receiving nevirapine and delavirdine. K103N is the most common mutation associated with virologic failure in patients receiving efavirenz. Mutations at codons 100, 106, 108, 188, 190, and 225 also contribute to efavirenz resistance, usually in combination with K103N.
The K103N mutation results in an approximately 20-fold decrease in susceptibility to efavirenz and an approximately 30-fold decrease in susceptibility to nevirapine and delavirdine [5,6]. Although these are not the highest possible levels of resistance to the NNRTIs (100-fold increases in resistance are possible), K103N by itself is often sufficient to abrogate the antiretroviral activity of each of the NNRTIs in clinical settings, suggesting that HIV-1 isolates developing K103N following therapy with one NNRTI will be cross-resistant to the remaining NNRTIs.
In contrast, several of the NNRTI mutations do not confer cross-resistance to all 3 approved NNRTIs. The most common example is Y181C, which causes high-level resistance to nevirapine and delavirdine but not to efavirenz. Another example is P236L, an uncommon mutation that causes high level resistance to delavirdine but not to nevirapine and efavirenz. In patients previously been treated with nevirapine or delavirdine who harbor HIV-1 isolates with Y181C or P236L, efavirenz may still have significant antiretroviral activity.
HIV-1 sequencing or phenotypic drug susceptibility testing may have clinical utility in this setting. Although neither test can exclude the possibility that K103N or other mutations associated with efavirenz resistance are not present in a minor but significant proportion of virions from treated patients, these tests may be helpful at identifying a subset of patients with an increased likelihood of responding to efavirenz despite having had virologic failure with nevirapine or delavirdine.
References
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- A phase III, multicenter, randomized, ope[n-label study to compare the antiretroviral activity and tolerability of efavirenz (EFV) + indinavir (IDV), versus EFV + zidovudine (ZDV) + lamivudine (3TC), versus IDV + ZDV + 3TC at 48 Weeks (Study DMP 266-006).
K. Tashima, S. Staszewski, R. Stryker, P Johnson, M. Nelson, J. Morales-Ramirez, D.J. Manion, D. Farina, D. Labriola, N. Ruiz, and The Study 006 Investigator Team. 6th Conference on Retroviruses and Opportunistic Infections. 31 Jan-4 Feb, 1999, Chicago, IL. Abstract LB16.
- Durability of response of efavirenz (SUSTIVATM, EFV)-containing regimens: Report of the post-control period results of studies with EFV.
Manion DJ, Faulkner E, Saxton TD, Labriola DF, Ruiz NM. 6th Conference on Retroviruses and Opportunistic Infections. 31 Jan-4 Feb, 1999, Chicago, IL. Abstract 382.
- Efficacy of efavirenz (SUSTIVATM) containing regimens in patients with baseline plasma HIV-RNA viral loads exceeding 100,000 copies/mL.
Manion DJ, Labriola DF, Ruiz NM. 6th Conference on Retroviruses and Opportunistic Infections. 31 Jan-4 Feb, 1999, Chicago, IL. Abstract 383.
- ACTG 364: Virologic efficacy of nelfinavir (NFV) and/or efavirenz (EFZ) in combination with new nucleoside analogs in nucleoside experienced subjects.
Albrecht M, Katzenstein D, Bosch, Liou S, Hammer S for the ACTG 364 Study Team. 6th Conference on Retroviruses and Opportunistic Infections. 31 Jan-4 Feb, 1999, Chicago, IL. Abstract 489.
- Genotypic correlates of in vivo resistance to efavirenz.
Bacheler LT, Anton B, Baker D, Becker M, Lasut A, Aujay M, Bolling L, Krakowski K, Bunville J, Wang V AND Abremski K. 6th Conference on Retroviruses and Opportunistic Infections. 31 Jan-4 Feb, 1999, Chicago, IL. Abstract 109.
- In vitro NNRTI resistance of recombinant HIV carrying mutations observed in efavirenz treatment failures.
Jeffrey S, Corbett J and Bacheler L. 6th Conference on Retroviruses and Opportunistic Infections. 6th Conference on Retroviruses and Opportunistic Infections. 31 Jan-4 Feb, 1999, Chicago, IL. Abstract 110.
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