Genotypic Correlates of Phenotypic Resistance to Efavirenz in Virus Isolates from Patients Failing Nonnucleoside Reverse Transcriptase Inhibitor Therapy

Bacheler, Lee T.; Jeffrey, Susan; Hanna, George J.; D’Aquila, Richard T.; Wallace, Lany; Logue, Kelly; Cordova, Beverly C.; Hertogs, Kurt; Larder, Brendan A.; Buckery, Renay; Baker, David; Gallagher, Karen; Scarnati, Helen; Tritch, Radonna; Rizzo, C.

doi:10.1128/jvi.75.11.4999-5008.2001

Cited by 213 publications

(175 citation statements)

References 25 publications

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“…Among the novel NNRTI-resistance associated mutations, it is well-known that K101E is associated with a 10-fold resistance to nevirapine and a fivefold resistance to efavirenz; K101Q determines a twofold resistance and K101P, a greater than 20-fold resistance to each NNRTI, respectively [Bacheler et al, 2001;Rhee et al, 2004]. In our patient series, all these amino acid variants were represented.…”

Section: Discussionmentioning

confidence: 67%

Impact of unreported HIV‐1 reverse transcriptase mutations on phenotypic resistance to nucleoside and non‐nucleoside inhibitors

Saracino

Monno

Scudeller

et al. 2005

Journal of Medical Virology

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An extended spectrum of HIV-1 reverse-transcriptase (RT) mutations in HAART-treated patients has been recently described. To verify the possible association of previously unreported RT mutations with a decrease of phenotypic susceptibility to nucleoside (NRTIs) and non-nucleoside (NNRTIs) RT inhibitors, the RT sequence of 328 HIV-1-positive patients (102 naïve and 226 treated with HAART participating in either the PhenGen or Genpherex study) was analyzed. All treated patients were tested at the time of therapeutic failure with both phenotypic (Antivirogram 1 , Virco) and genotypic analyses (VircoGen TM ); the frequency of RT substitutions (positions 1-240) with respect to consensus B was compared to that of naïve patients using a Chi-square test. Amino acid changes at 13 positions not included in the IAS list of resistance-associated mutations were detected more frequently in treated than in naïve subjects. The mutations involving 10 of these positions were associated with a reduced susceptibility to antiretroviral drugs; K20R, T39A, K43EQN, E203KD, H208Y, and D218E were correlated with NRTI resistance while mutations K101EQP, H221Y, K223EQ, L228HR were associated to NNRTI resistance. A correlation was found between K20R and lamivudine resistance (P ¼ 0.006) while T39A (P ¼ 0.005), K43EQN (<0.001), E203KD (P ¼ 0.010), and H208Y (P ¼ < 0.001) seemed to be associated with a previous use of zidovudine and stavudine and with the development of thymidine analog resistance. For H208Y, an association with use/resistance to abacavir (P ¼ 0.004) was also noted. D218E showed a weak association to didanosine resistance (P ¼ 0.013). The data confirm that previously unreported mutations are associated with antiretroviral drug experience and, more importantly, with a reduced susceptibility to NRTIs and NNRTIs.

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Section: Discussionmentioning

confidence: 67%

Impact of unreported HIV‐1 reverse transcriptase mutations on phenotypic resistance to nucleoside and non‐nucleoside inhibitors

Saracino

Monno

Scudeller

et al. 2005

Journal of Medical Virology

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“…For instance, P225H, the only TDR mutation from the WHO list observed in patient MBA 1323 (Table 2), is an NNRTIassociated nonpolymorphic mutation that usually occurs in combination with K103N. 21,22 In vitro, P225H alone causes only a 3-fold increase in IC 50 against NVP, 42,43 but a 150-fold increase if it occurred in combination with K103N. 43 Patient MBA 1323 subsequently received 3TC/AZT/NVP (two fully active drugs) and stayed on this same regimen with suppressed viral load for almost 5 years until the study cutoff, suggesting that the observation of a lone transmitted P225H in this particular case did not impact treatment outcome.…”

Section: Discussionmentioning

confidence: 99%

Prevalence and Virologic Consequences of Transmitted HIV-1 Drug Resistance in Uganda

Lee

Bangsberg

Muzoora

et al. 2014

AIDS Research and Human Retroviruses

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Few reports have examined the impact of HIV-1 transmitted drug resistance (TDR) in resource-limited settings where there are fewer regimen choices and limited pretherapy/posttherapy resistance testing. In this study, we examined TDR prevalence in Kampala and Mbarara, Uganda and assessed its virologic consequences after antiretroviral therapy initiation. We sequenced the HIV-1 protease/reverse transcriptase from n = 81 and n = 491 treatment-naive participants of the Uganda AIDS Rural Treatment Outcomes (UARTO) pilot study in Kampala (AMU 2002(AMU -2004 and main cohort in Mbarara (MBA 2005(MBA -2010. TDR-associated mutations were defined by the WHO 2009 surveillance mutation list. Posttreatment viral load data were available for both populations. Overall TDR prevalence was 7% (Kampala) and 3% (Mbarara) with no significant time trend. There was a slight but statistically nonsignificant trend indicating that the presence of TDR was associated with a worse treatment outcome. Virologic suppression (£ 400 copies/ml within 6 months posttherapy initiation) was achieved in 87% and 96% of participants with wildtype viruses versus 67% and 83% of participants with TDR (AMU, MBA p = 0.2 and 0.1); time to suppression (log-rank p = 0.3 and p = 0.05). Overall, 85% and 96% of study participants achieved suppression regardless of TDR status. Surprisingly, among the TDR cases, approximately half still achieved suppression; the presence of pretherapy K103N while on nevirapine and fewer active drugs in the first regimen were most often observed with failures. The majority of patients benefited from the local HIV care system even without resistance monitoring. Overall, TDR prevalence was relatively low and its presence did not always imply treatment failure.

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“…The new generation NNRTIs, e.g. Efavirenz, select for a panel of resistance mutations K103N, V106I, V108I, Y181C, Y188H Y188L, G190S, P225H, and F227L, indicating that a majority of the NNIBP residues are potential sites for drug-resistant mutations [6].The Ôfirst generationÕ NNRTIs, such as the currently marketed drugs Nevirapine and Delavirdine show orders of magnitude decreases in binding as a result of single point mutations [7,8] …”

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confidence: 99%

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confidence: 99%

Structural basis for the inhibitory efficacy of efavirenz (DMP‐266), MSC194 and PNU142721 towards the HIV‐1 RT K103N mutant

Lindberg

Sigurðsson

Löwgren

et al. 2002

European Journal of Biochemistry

136

135

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The K103N substitution is a frequently observed HIV-1 RT mutation in patients who do not respond to combinationtherapy. The drugs Efavirenz, MSC194 and PNU142721 belong to the recent generation of NNRTIs characterized by an improved resistance profile to the most common single point mutations within HIV-1 RT, including the K103N mutation. In the present study we present structural observations from Efavirenz in complex with wild-type protein and the K103N mutant and PNU142721 and MSC194 in complex with the K103N mutant. The structures unanimously indicate that the K103N substitution induces only minor positional adjustments of the three inhibitors and the residues lining the binding pocket. Thus, compared to the corresponding wild-type structures, these inhibitors bind to the mutant in a conservative mode rather than through major rearrangements. The structures implicate that the reduced inhibitory efficacy should be attributed to the changes in the chemical environment in the vicinity of the substituted N103 residue. This is supported by changes in hydrophobic and electrostatic interactions to the inhibitors between wild-type and K103N mutant complexes. These potent inhibitors accommodate to the K103N mutation by forming new interactions to the N103 side chain. Our results are consistent with the proposal by Hsiou et al. [Hsiou, Y., Ding, J., Das, K., Clark, A.D. Jr, Boyer, P.L., Lewi, P., Janssen, P.A., Kleim, J.P., Rosner, M., Hughes, S.H. & Arnold, E. (2001) J. Mol. Biol. 309, 437-445] that inhibitors with good activity against the K103N mutant would be expected to have favorable interactions with the mutant asparagines side chain, thereby compensating for resistance caused by stabilization of the mutant enzyme due to a hydrogen-bond network involving the N103 and Y188 side chains.Keywords: drug-resistance; HIV; NNRTI; reverse transcriptase.The use of highly active antiretroviral therapy (HAART) involving multidrug combinations has significantly reduced the death rates of HIV-1 infected individuals receiving such treatment [1]. Inhibitors of the HIV-1 reverse transcriptase (RT) constitute a cornerstone in this therapy and are commonly used in combination with inhibitors of the HIV-1 protease. The RT inhibitors belong to two classes, the nucleoside inhibitors and the non-nucleoside inhibitors (NNRTI). Whereas the NRTIs are nucleoside analogues with chain-terminating properties and affinity to active site residues, the NNRTIs include a wide range of series of chemical compounds characterized by noncompetitive binding to an allosteric site some 10 Å away from the active site. Structural comparison of RT in complex with template/primer and NNRTIs together with native RT complexes have shown that the NNRTIs inhibit the polymerase activity through long-range and short-range structural distortions in several of the RT subdomains. The distortions involve repositioning of residues in the nonnucleoside binding pocket (NNIBP) that impose steric impediments on the thumb subdomain flexibility forcing it to remain in the ...

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Genotypic Correlates of Phenotypic Resistance to Efavirenz in Virus Isolates from Patients Failing Nonnucleoside Reverse Transcriptase Inhibitor Therapy

Cited by 213 publications

References 25 publications

Impact of unreported HIV‐1 reverse transcriptase mutations on phenotypic resistance to nucleoside and non‐nucleoside inhibitors

Impact of unreported HIV‐1 reverse transcriptase mutations on phenotypic resistance to nucleoside and non‐nucleoside inhibitors

Prevalence and Virologic Consequences of Transmitted HIV-1 Drug Resistance in Uganda

Structural basis for the inhibitory efficacy of efavirenz (DMP‐266), MSC194 and PNU142721 towards the HIV‐1 RT K103N mutant

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