Library Volume 1, Issue 3: Resistance Reporter© from the HIV Drug Resistance Workshop 2007



XVI International HIV Drug Resistance Workshop, June 12-16, 2007

This important conference focuses on topics related to HIV drug resistance, and the organizers traditionally only allow a select number of attendees (~250). But of course, members of Resistance Reporter©'s highly respected editorial board were there; we selected the 6 scientifically-important presentations that would best support your clinical practice. These selections have been grouped into three sections that provide clinically-relevant information related to a specific topic. The selections and summaries we have provided are of truly noteworthy research; hot links to the abstracts and suggestions for related reading makes broadening your existing knowledge on a complex topic logical and easy.


  • Section 1: Select presentations related to resistance to integrase inhibitors
  • Section 2: Select presentations related to resistance to CCR5 inhibitors
  • Section 3: Select presentations related to resistance to TMC125


Section 1 (Section 2 and Section 3 Also Available)

Select presentations related to resistance to integrase inhibitors


Resistance to the HIV-Integrase Inhibitor Raltegravir: Analysis of Protocol 005, a Phase II Study in Patients with Triple-Class Resistant HIV-1 Infection

Abstract #8, Hazuda DJ

The HIV integrase inhibitor raltegravir, formerly known as MK-0518, is quite potent in treatment-experienced patients. Raltegravir produced HIV-1 RNA levels below 400 copies/mL at week 24 in ~70% of triple-class-experienced patients in combination with optimized background therapy in a phase II trial, compared with a 16% response rate for patients on placebo plus optimized background therapy . To identify mutations that may confer resistance to raltegravir, viral isolates obtained from 38 raltegravir-treated patients who experienced virologic failure were analyzed. Integrase mutations were found in 35 individuals and fell into two genetic pathways. The N155H mutation reduced viral susceptibility to raltegravir by 10-fold, while the Q148 H/R/K did so by 25 fold; addition of secondary mutations L74M, E92Q, G163R to N155H or E138K, G140S/A to Q148H/R/K resulted in high level resistance. For example, the addition of G140S to Q148H or the addition of E138A + G140A to Q148K increased viral resistance to raltegravir over 500-fold. While certain secondary mutations appeared to moderate replication defects, all resulted in increased resistance suggesting that N155H and Q148H/R/K may confer incomplete resistance in isolation. Viral variants containing the N155H or Q148H/R/K mutations were cross-resistant to several different integrase inhibitors, consistent with a common mechanism of action among these agents.


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Resistance and Cross-Resistance to First Generation Integrase Inhibitors: Insights from a Phase II Study of Elvitegravir (GS-9137)

Abstract #9, McColl DJ

Viral isolates were obtained from 30 very highly treatment-experienced patients who received elvitegravir 250 mg/day and who experienced treatment failure during the GS-US-183-0105 trial. The baseline 50% inhibitory concentration (IC50) for the isolates analyzed ranged from 0.91- to 2.53-fold compared to the assay control virus. The most common integrase mutations that emerged during elvitegravir treatment in 28 patients with baseline and on-treatment genotype data included E92Q (in 39%), E138K (in 39%), Q148R/K/H (in 39%), N155H (in 39%), S147G (in 32%), and T66I/A/K (in 18%)—many of which were previously identified as raltegravir resistance mutations (see Abstract #8). Indeed, viral samples from patients who experienced elvitegravir virologic failure showed a mean fold change to elvitegravir greater than 151-fold (range: 1.02-301) as well as a mean fold change to raltegravir greater than 28-fold (range: 0.78-256+), thereby providing evidence for cross-resistance between these two agents. The replication capacity of the viral isolates declined from a median of 108% at baseline to 54% at the time of virologic failure (P≤.005).


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Section 2 (Section 1 and Section 3 Also Available)

Select presentations related to resistance to CCR5 inhibitors


CXCR4-Using Virus Detected in Patients Receiving Maraviroc in the Phase III Studies MOTIVATE 1 and 2 Originates From a Pre-Existing Minority of CXCR4-Using Virus

Abstract #56, Lewis M

The CCR5 antagonist maraviroc has demonstrated impressive activity in combination with optimized background therapy in the MOTIVATE 1 and 2 phase III trials conducted in treatment-experienced patients. Although only patients with CCR5-tropic virus, determined at screening, were included in the MOTIVATE studies, CXCR4-using virus emerged in some patients during maraviroc treatment. Extensive phenotype testing and env gene sequencing of 240 clones obtained at baseline and during treatment from 20 patients (16 on maraviroc, 4 on placebo) revealed that CXCR4-using virus that emerged during maraviroc treatment was already present at baseline in 14 of the patients. Ten patients harbored CXCR4-using virus at baseline at a low frequency (1%-6%), whereas 4 patients harbored a higher proportion of CXCR4-using virus at baseline (> 10%). For the other 6 patients, the CXCR4-using clones identified during treatment appeared to be phylogenetically distinct from the baseline clones and the CCR5-using clones obtained during treatment, indicating a separate ancestral origin and not a shift in viral tropism. Consistent with this view, the CXCR4-using clones contained between 7 and 17 amino acid changes in the 35-amino acid V3 loop, which plays an important role in coreceptor recognition, further suggesting that a shift in viral tropism did not occur through mutational evolution. Patients on maraviroc demonstrated an almost complete loss of CCR5-using virus during treatment—a phenomenon that may have enabled CXCR4-using virus present at baseline to emerge.


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Characterization of Maraviroc Resistance in Patients Failing Treatment With CCR5-Tropic Virus in MOTIVATE 1 and MOTIVATE 2

Abstract #10, Mori J

In another analysis of MOTIVATE patients, baseline and on-treatment HIV samples from individuals with CCR5-using virus in whom maraviroc failed were assessed to identify phenotypic and genotypic markers of maraviroc resistance. Out of these analyses, only a reduced maximal percentage inhibition (MPI) emerged as a phenotypic marker of maraviroc resistance in vivo; differences in the IC50 fold change between baseline samples and on-treatment samples and between any samples and the reference virus were not predictive for maraviroc resistance. None of the 37 [38] viral clones assessed at baseline or the 25 clones assessed on treatment for patients on placebo had an MPI below 95%, whereas MPI values below this level were observed for 6 of 15 [4 of 12] patients who failed with maraviroc treatment. Further investigation of on-treatment clones from these 6 patients revealed several amino acid changes in the V3 loop from baseline that were important in conferring maraviroc resistance; no cross-resistance to enfuvirtide was observed. These amino acid changes were different from patient to patient, reflecting the heterogeneity of the gp160 sequence.


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Safety and Efficacy of the HIV-1 Integrase Inhibitor Raltegravir (MK-0518) in Treatment-Experienced Patients with Multidrug-Resistant Virus: a Phase II Randomized Controlled Trial

Abstract #13, Tsibris AMN

To better understand the in vivo emergence of resistance to the CCR5 inhibitor vicriviroc, Tsibris and colleagues assessed viral samples from 8 patients who experienced virologic failure at 16 weeks of vicriviroc treatment during the phase IIb ACTG A5211 trial. No consistent increase in the IC50 was found in patient samples throughout 24 weeks of treatment. The largest IC50 change observed in comparison with a control strain was 2.83-fold. Sequencing of the env gene identified amino acid changes in the V3 loop that emerged after virologic failure, but not before, in 4 individuals randomized to receive vicriviroc at 5 mg or 10 mg daily. No such changes were found in 2 individuals assigned to placebo or in 2 individuals assigned to vicriviroc 15 mg. These amino acid changes differed between individuals. Clonal analysis of another patient assigned to vicriviroc 10 mg who demonstrated a progressive increase in phenotypic resistance to vicriviroc identified the emergence of multiple changes in the V3 loop. These recombinant viruses were exclusively R5. Analysis of a sample from this patient obtained 5 months after vicriviroc discontinuation showed a return toward genotypically wild-type, vicriviroc-sensitive, R5-tropic only virus, suggesting that wild-type virus has a fitness advantage over vircriviroc-resistant virus.


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Section 3 (Section 1 and Section 2 Also Available)

Select presentations related to resistance to TMC125


Impact of Baseline NNRTI Mutations on the Virologic Response to TMC125 in the Phase III Clinical Trials of DUET-1 and DUET-2

Abstract #32, Vingerhoets J

Etravirine is purported to have activity against NNRTI-resistant HIV and a high genetic barrier to resistance. This study assessed the effects of genotype and baseline phenotype on the 24-week virologic response to etravirine among treatment-experienced patients participating in the randomized DUET-1 and DUET-2 trials. None of the patients included in the analysis received enfuvirtide as a new drug in their optimized background regimen and patients who discontinued treatment for reasons other than virological failure were also excluded. Forty-four NNRTI resistance-associated mutations were studied in patients who had a suboptimal virologic response to treatment; only those present in 5 or more patients at baseline (n=26) were included in the final analysis. Thirteen mutations were associated with a decreased virologic response to etravirine: V90I, A98G, L100I, K101E/P, V106I, V179D/F, Y181C/I/V, and G190A/S. Many of these mutations occurred in conjunction with other NNRTI-associated mutations. Y181V, G190S, and V179F had the strongest effect on virologic response, but these mutations were present in fewer than 5% of patients. The number of etravirine-associated mutations present at baseline was a very strong predictor of virologic response (P=.0008), and the poorest virologic response to etravirine was observed in patients with 3 or more etravirine-associated mutations at baseline.


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