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Disseminate Retroviral News Responsibly
- Rajan TD (4 June 2007)
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Activity of a new NNRTI, TMC125 (etravirine), in the presence of an old mutation, Y181C
- Marie-Pierre de Béthune, Gaston Picchio, Brian Woodfall and Johan Vingerhoets (14 July 2007)
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Rajan TD, Consultant, CMPH Med College,5 Mumbai, India. Tel: 0091-22-66982747 Specialist, Skin & Sex Transm Diseases, Andheri, Mumbai, India. Tel: 0091-22-66982747
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It is heartening to read about the breakthrough in antiretroviral therapy. R5 inhibitors, and etravirine could change the face of HIV treatment. Or we may eventually learn that these drugs may simply help to give a better life to the harried patient, who is hanging on to hope for a better tomorrow. Unfortunately for these patients there is a lot of half-baked news which is leaked to the lay press and electronic media that causes confusion in their minds. Most of these patients get too excited whenever they read about newer interventions in HIV treatment and rush to their physician in the hope of some dramatic cure. Consequently, the physician is under tremendous strain to explain that the news is only about a research experience in some laboratory and that it would take a few months or years before the reported drug is made available locally. Any technical information pertaining to AIDS research should be carefully sifted for its impact on the general public. Scientists would be doing a disservice to humanity by raising unnecessary hopes of the suffering public, simply to gain an 'marketing' edge in the media. Competing interests: None declared |
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Marie-Pierre de Béthune, Vice President Global Clinical Virology Tibotec BVBA, Generaal de Wittelaan L11B4, B-2800 Mechelen, Belgium, Gaston Picchio, Brian Woodfall and Johan Vingerhoets
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Dear Sir, We read with great interest the Editorial in this Journal
by Hatano et al. describing the challenge that HIV
drug resistance represents and how three new antiretrovirals currently in
development may bring hope to patients infected with these difficult-to-treat
HIV variants1. The authors suggested
that many of the patients treated with first generation NNRTIs have developed
viruses that are cross-resistant to TMC125 (etravirine) and point to the
importance of the NNRTI mutation Y181C. In our hands, modest
increases in fold-change in EC50 value (FC) to TMC125 have been
observed in site-directed mutants carrying the Y181C mutation in vitro2. We have examined
the effect of Y181C on virological response to TMC125 based on pooled data from
the Phase III clinical trials with TMC125 (DUET-1 and DUET-2), conducted in
treatment experienced patients with evidence of NNRTI resistance. The data, recently
presented at the XVIth International HIV Drug
Resistance Workshop3, suggest that treatment with TMC125 leads to a
higher proportion of patients with undetectable viremia
(<50 HIV-1 RNA copies/mL) as compared with the
placebo regimen in the presence of this mutation. Additional information in
support of these recently described observations is provided below (Table 1). Analyses of pooled data
from DUET-1 and DUET-2 aimed at determining the baseline genetic determinants
of reduced virological response to TMC125, were
performed in the subset of patients not using enfuvirtide as a new drug and
excluding patients who discontinued for reasons other than virological failure.
They resulted in the identification of 13 mutations as being associated with a
reduced virological response to TMC125 (V90I, A98G, L100I, K101E, K101P, V106I,
V179 D, V179F, Y181C, Y181I, Y181V, G190A, and G190S). These TMC125
resistance-associated mutations (RAMs) were always observed in the presence of
a median of 2–5 NNRTI mutations from an expanded list recently described4.
The proportion of patients achieving a confirmed viral load <50 HIV-1 RNA
copies/mL at week 24 observed in those with the Y181C
mutation as the only TMC125 RAM (but with other NNRTI
mutations) at baseline or in those with the Y181C in
combination with other TMC125-RAMs at baseline are summarized in Table 1.
Notably, in the presence of Y181C as the only TMC125 RAM, the virological
response was comparable with the overall response. In the presence of Y181C
plus one additional TMC125-RAM at baseline, the virological response was still
higher in the TMC125 group than in the placebo group. This suggests that TMC125
in combination with other antiretroviral agents can be successful in the
presence of the Y181C mutation when the total number of TMC125-RAMs is lower
than three. References 1. Hatano H, Deeks SG. Drug
Resistant HIV: Promising research on three new drugs gives hope for chronically
infected patients. BMJ 2007; 334: 1124-1125. 2. Vingerhoets J, Azijn
H, Fransen E, De Baere I, Smeulders L, Jochmans D, et al. TMC125 displays a high genetic barrier to the
development of resistance: evidence from in vitro selection experiments. J Virol
2005:79:12773–82. 3.
Vingerhoets J, Buelens A, Peeters M, Picchio G, Tambuyzer L, Van Marck
H, et al. Impact of baseline NNRTI
mutations on the virological response to TMC125 in
the Phase III clinical trials DUET-1 and DUET-2. XVIth
International HIV Drug Resistance 4.
Tambuyzer
L, Vingerhoets J, Azijn H, Staes
M, Kraus G, Rimsky LT, et al. Development of a list of mutations associated
with NNRTI resistance for use in clinical research. 5th European HIV Drug
Resistance Workshop, Table 1:
Virological response to TMC125 by baseline NNRTI mutations
Competing interests: All authors are employees of Tibotec BVBA |
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