Library Volume 1, Issue 5: Resistance Reporter© from 2007 ICAAC and IDSA




47th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2007) and 45th Annual meeting of the Infectious Disease Society of America (IDSA 2007)

These important international conferences feature reports on the latest developments in the areas of basic clinical and prevention science. The members of Resistance Reporter©'s highly-respected editorial board were there for both conferences; we selected the 5 scientifically-important presentations that would best support your clinical practice. These selections have been grouped into two 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 FDA-approved agents and the importance of treating patients with at least 2 active agents
  • Section 2: Select presentations related to new agents in development and the importance of treating patients with at least 2 active agents

Section 1 (Section 2 Also Available)

Select presentations related to FDA-approved agents and the importance of treating patients with at least 2 active agents


48-Week Safety and Efficacy of Maraviroc, a Novel CCR5 Antagonist, in Combination with Optimized Background Therapy (OBT) for the Treatment of Antiretroviral-Experienced Patients Infected with Dual/Mixed-Tropic HIV-1

IDSA Abstract #LB-2, Goodrich JM

Because the maraviroc CCR5 entry inhibitor is only active against CCR5-using (R5) HIV-1 and not CXCR4-using (X4) or dual/mixed-tropic HIV-1, there is concern that administration of maraviroc to patients with dual-mixed or X4 virus may lead to faster disease progression. Goodrich and colleagues conducted a double-blind, placebo-controlled, phase IIb pilot study to assess the safety and efficacy of maraviroc in 186 treatment-experienced patients with non-R5-tropic HIV-1. Patients were randomly assigned to receive maraviroc once daily (n=63), maraviroc twice daily (n=61), or placebo (n=62), all in combination with optimized background therapy (OBT). The majority of patients had dual/mixed-tropic HIV-1 (90%) at baseline. After 48 weeks of treatment, there was no evidence that maraviroc adversely affected patients’ virologic or immunologic function in comparison with placebo. Among the subgroup of patients with dual/mixed HIV-1, there was no significant difference in viral suppression below 50 copies/mL between the maraviroc and placebo arms at Week 48 (18%-27% vs. 22%); the maraviroc arms showed similar CD4+ cell count increases in comparison with placebo (65-78 vs. 51 cells/mm3). Patients who had more active agents in their OBT achieved better virologic outcomes than those with fewer active agents. Most importantly, maraviroc proved to be as safe as placebo: Maraviroc was not associated with an increased incidence of discontinuation due to adverse events, grade 3 and 4 adverse events, liver function abnormalities, Centers for Disease Control (CDC) category C events, malignancies, or death.


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Development of Resistance in Patients with Virologic Failure on Darunavir/Ritonavir (DRV/r) or Lopinavir/Ritonavir (LPV/r): Results of a Randomized, Controlled, Phase III Trial in Treatment-Experienced Patients (TITAN)

ICAAC Abstract #H-1020, De Meyer S

TITAN is an ongoing, 96-week trial comparing darunavir/ritonavir with lopinavir/ritonavir in 595 treatment-naïve patients who were naïve to lopinavir/ritonavir at baseline. Using efficacy results collected through 48 weeks, De Meyer and colleagues assessed the emergence of resistance among TITAN patients who developed virologic failure during the study, defined as loss of HIV-1 RNA suppression below 400 copies/mL or never having achieved this level of suppression. A clinical cutoff fold-change of 10 was used to define loss of susceptibility to both darunavir and lopinavir. Baseline characteristics were somewhat unbalanced in that about 10% of patients had a lopinavir fold-change greater than 10, whereas only about 1.5% of patients had a darunavir fold-change greater than 10. The rate of virologic failure was approximately 2-fold higher in the lopinavir/ritonavir arm compared with the darunavir/ritonavir arm (22% vs. 10%). Similarly, more lopinavir/ritonavir-treated patients versus darunavir/ritonavir-treated patients developed primary PI mutations (36% [n=20] vs. 21% [n=6]) and NRTI resistance-associated mutations (27% [n=15] vs. 14% [n=4]) at virologic failure. In addition, more patients in the lopinavir/ritonavir arm versus the darunavir/ritonavir arm lost susceptibility to the PIs in their regimen (24% [n=13] vs. 11% [n=3]) and the NRTIs in their regimen (26% [n=14] vs. 11% [n=3]) at the time of virologic failure. All of these differences between the lopinavir/ritonavir and darunavir/ritonavir arms were similar or even greater after excluding patients who had a lopinavir fold-change greater than 10 at baseline and patients who had used 2 or more PIs at baseline. These cumulative findings suggest that darunavir has a higher genetic barrier to resistance than lopinavir.


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Changes in HIV-1 Co-Receptor Tropism for Patients Participating in the Maraviroc Motivate 1 and 2 Clinical Trials

ICAAC Abstract #H-715, Van Der Ryst E

MOTIVATE 1 and 2 are ongoing, double-blind, placebo-controlled, phase III studies of maraviroc in treatment-experienced patients with R5-tropic HIV-1. Van Der Ryst and colleagues analyzed data from all patients who have failed treatment during the MOTIVATE trials to correlate changes in HIV-1 tropism with treatment failure. Of 1049 patients with R5-tropic HIV-1 at screening, 242 (23%) subsequently failed treatment, of whom 145 failed on maraviroc (2;2;1 randomization to MVC QD;MVC BID:PCB).  Maraviroc recipients who failed treatment were more likely to have dual/mixed or X4 virus at failure (n=63) than R5 virus (n=35). Although CD4+ cell count increases were observed in patients despite maraviroc failure, those who failed with dual/mixed or X4 virus demonstrated smaller increases in CD4+ cell count compared with those who failed with R5 virus (37-56 vs. 61-138 cells/mm3) perhaps in part because the time to maraviroc failure occurred 30 days sooner for patients who failed with dual/mixed or X4 virus compared with those who failed with R5 virus. The investigators stated that these results suggest that pre-existing dual/mixed or X4 minority variants can rapidly emerge under maraviroc selective pressure and lead to failure, whereas failure with R5 virus may require de novo selection of resistance mutations that require more time to develop. Consistent with this interpretation, 30 of 31 patients who failed with dual/mixed or X4 virus who had at least one month of follow-up reverted back to R5 virus. No difference in the incidence of CDC category C events was seen between patients who failed maraviroc with R5 versus dual/mixed or X4 virus.


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Section 2 (Section 1 Also Available)

Select presentations related to new agents in development and the importance of treating patients with at least 2 active agents


The HIV Integrase Inhibitor Elvitegravir (EVG/r) has Potent and Durable Activity in Treatment-Experienced Patients with Active Optimized Background Therapy (OBT)

ICAAC Abstract #H-714, Zolopa AR

This randomized, partially blinded, active-controlled phase IIb trial compared the noninferiority of elvitegravir/ritonavir versus a comparator PI (CPI)/ritonavir in 278 treatment-experienced patients with a viral load of at least 1000 copies/mL and at least 1 PI resistance mutation at baseline. Patients received 1 of 3 doses of elvitegravir/ritonavir (20, 50, or 125 mg once daily) or a CPI/ritonavir, all in combination with OBT that consisted of NRTIs with or without enfuvirtide. Results for the elvitegravir/ritonavir 125-mg arm (n=73) and the CPI/ritonavir arm (n=63) were presented, as the elvitegravir/ritonavir 20-mg and 50-mg arms were discontinued due to inferior performance. Elvitegravir/ritonavir 125 mg produced a significant decrease in HIV-1 RNA compared with a CPI/ritonavir at 24 weeks (mean overall time-weighted average change from baseline in HIV-1 RNA: -1.7 vs. -1.2 log10 copies/mL; P=.02). Although the virologic response to elvitegravir/ritonavir was rapid and pronounced, having an OBT that contained at least 1 active agent was found to be essential for maintaining the response. Indeed, the best virologic responses at 24 weeks were attained by patients who received elvitegravir/ritonavir in combination with first-time use of enfuvirtide, with or without active NRTIs, as opposed to those who received at least 1 active NRTI without enfuvirtide or those who had no active agents in their OBT (mean change from baseline in HIV-1 RNA: -2.9 vs. -1.7 and -0.7 log10 copies/mL; P<.02 and P<.0001, respectively). In addition, elvitegravir/ritonavir-treated patients who had a boosted PI added to their OBT after 16 weeks demonstrated steady improvements in virologic control, with an additional 1-log10 copies/mL decline in viral load. 


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Two-Year Follow-Up of Treatment-Experienced Patients on Vicriviroc (VCV)

ICAAC Abstract #H-1030, Gulick R

This study (Trial P04100) assessed the long-term efficacy, safety, and tolerability of vicriviroc 15 mg once daily by rolling over patients from the 48-week AIDS Clinical Trials Group 5211 (A5211) trial into long-term ritonavir-boosted vicriviroc therapy plus OBT. To be eligible for P04100, patients could have either R5 virus or dual/mixed virus that was R5 at start of A5211 but that underwent a tropism shift during the study, so long as patients were virologically and immunologically stable. Seventy-nine of 118 patients (67%) who completed 48 weeks of vicriviroc treatment in A5211 entered into P04100, and the total median duration of vicriviroc treatment across the 2 studies was 840 days (2.30 years). Durable virologic suppression and immune preservation was observed during extended vicriviroc treatment. The mean change in HIV-1 RNA was -2.1, -2.4, -2.2, and -2.2 log10 copies/mL at Months 12 (P04100 entry), 18, 21, and 24, respectively, while the mean change in CD4+ cell count at these respective time points was +129.5, +115.1, +112.3, and +118.6 cells/mm3. Extended vicriviroc treatment was determined to be safe given that no treatment-related hepatic toxicities, cardiac toxicities, AIDS-related opportunistic infections, or systemic malignancies were observed. The majority of reported adverse events were mild or moderate in severity (i.e., grade 1-2), with only 1 grade 3 event reported in more than 1% of patients (fatigue: 3%). During P04100, 4 patients experienced virologic failure. Two individuals had a shift in viral tropism to dual/mixed or X4 virus at the time of virologic failure, and resistance test results available for 3 of the 4 patients showed no evidence of vicriviroc resistance.


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