The following chapter describes the resistance profiles of several newly developed antiretroviral drugs.
• Etravirine (TMC125), a second generation NNRTI, is effective against viruses with NNRTI mutations such as L100I, K103N, Y188L and/or G190A/S.
In a study on 25 virus isolates with one or two NNRTI-associated mutations, etravirine was still active in 18 isolates with only a small change in IC50 (less than 4-fold). A more than 10-fold increase in IC50 was observed in only 3 virus isolates. The corresponding resistance profile noted in one case was the combination L100I+K103N, and in the two other cases the single mutations Y181I and F227C. However, the prevalence of these mutations is small; 3 % for L100I+K103N and < 0.5 % for Y181I and F227C (Andries 2004). Etravirine has a higher genetic barrier than other NNRTIs due to its flexible binding to the reverse transcriptase. High-grade resistance is observed only with multiple mutations. After several in-vitro passages the dominant virus population showed the RT mutation V179F (a new variant at this position) and Y181C. Further mutations that were selected for in vitro were L100I, E138K, Y188H, G190E, M230L, M230L and V179I (Brillant 2004, Vingerhoets 2005).
In a placebo-controlled study with etravirine, virological outcome was - adjusted for other NNRTI mutations and the use of T-20 - comparable with or without K103N. The mutation Y181C was related to reduced virological response (Vingerhoets 2006).
In patients with documented NNRTI resistance and at least three primary PI mutations, virological response to etravirine plus optimized backbone decreased with the number of NNRTI mutations. In patients without NNRTI mutations at baseline, the mean viral load reduction at week 48 was 1.67 log in the 800 mg study arm. With one, two or three mutations viral load reductions were 1.38, 0.90 and 0.54 logs (Cohen 2006).
In the Duet trials, 13 TMC125 resistance associated mutations (RAMs) were identified: V90I, A98G, L100I, K101E/P, V106I, V179D/F, Y181C/I/V, G190A/S. In the presence of 0-2 TMC125 RAMs virological response was not compromised, but with three or more RAMs, virological response was markedly reduced (Mills 2007, Katlama 2007).
• TMC278 (Rilpivirin), another second generation NNRTI, also has a unique profile of activity against NNRTI-resistant viruses and displays a high genetic barrier comparable to that of TMC125 (Goebel 2005, De Béthune 2005).
• CCR5 antagonists: On failing therapy with maraviroc or vicriviroc amino acid changes in the V3 loop of the HIV-1 envelope glycoprotein gp120 were observed, but the pattern of amino acid changes was different between patients. Plateaus in maximal percentage inhibition were identified as a phenotypic marker of maraviroc resistance. In contrast, shifts in IC50 were not identified as a common phenotypic marker of maraviroc resistance. These findings are consistent with the use by maraviroc resistant HIV variants of both free CCR5 molecules and those occupied by maraviroc. In some cases a shift from CCR5-to CXCR4-tropic virus was observed. However, also in the controls arm several co-receptor shifts occurred. Genotypic and phenotypic evaluations of maraviroc failures still deserve further examination (Landovitz 2006, Greaves 2006, Mori 2007).
• Integrase inhibitors: Genotypic analysis of patients with failing first-line therapy with raltegravir, tenofovir and lamivudine indicated two cases with the signature mutation N155H, in one of two along with additional integrase resistance mutations. Some patients failed while harbouring only a 3TC mutation (Markowitz 2007). In treatment experienced patients raltegravir failure was generally associated with one of two genetic pathways: N155H or Q148K/R/H. Secondary mutations commonly observed with N155H included V151I, T97A, G163R, L74M and E92Q. Viruses that evolved resistance via the Q148H/R/K pathway tended to select E138K and G140S/A. Another pathway involved in raltegravir resistance is Y143R/C together with L74A/I, E92Q, T97A, I203M, and S230R (Cooper 2007, Steigbigel 2007, Hazuda 2007).
The emergence of subsequent mutations in addition to the signature mutations N155H or Q148K/R/H leads to an increase in resistance. Both pathways also confer resistance to elvitegravir. The most frequent mutations that emerged under elvitegravir were E92Q, E138K, Q148R/H/K, and N155H. There is high grade cross resistance between raltegravir and elvitegravir in the presence of Q148H/R+G140S (Mc Coll 2007, DeJesus 2007)
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