Antiretroviral Resistance Topics

Hopkins HIV Report 2006 Mar; 18(2):6

Gregory M. Lucas, M.D., Ph.D.
Johns Hopkins

Antiretroviral resistance issues garnered substantial attention at CROI. Attempts to define pathways to resistance are clearly incorporated into early drug development, and much of the resistance focus this year was on drugs that have yet to be FDA-approved.

Resistance Correlates of Drugs in Late-Stage Development

Etravirine (TMC-125) and darunavir (TMC-114), are new additions to the non-nucleoside reverse transcriptase (NNRTI) and protease inhibitor (PI) classes, respectively, that have demonstrated potent activity in heavily pretreated patients. At CROI, baseline resistance profiles were correlated with virologic responses in clinical trials for each drug.

Twenty-four-week results of the TMC125C223 study, in which subjects with documented NNRTI-resistance were randomized to one of two doses of etravirine or to an optimized, nonNNRTI-containing regimen, were reported late last year [Grossman H, et al. 45th ICAAC, Abstract H-416c; Nadler J, et al. 10th EACS, Abstract LBPS3/7A]. The mean change in HIV RNA at week 24 was -1.18 log₁₀ c/mL in the arm receiving etravirine 800 mg twice daily, compared to -0.19 log₁₀ c/mL in the active control group (P<0.05). In Denver, Vingerhoets and colleagues assessed the association of baseline NNRTI mutations, fold-change in phenotypic resistance to etravirine, and 24-week viral load changes in a subset of participants in this trial [Conf Retrovir Opportunistic Infect 2006 Feb 5-8;13:abstract no. 154]. As expected, phenotypic fold-change increased and virologic response decreased with a higher number of NNRTI mutations at baseline (see Table below). However, the loss of virologic efficacy was much more attenuated than that observed with first-line NNRTIs, and no single mutation conferred >10-fold-change to etravirine. Twelve percent of baseline NNRTI mutation patterns were associated with >10-fold reduction in susceptibility to etravirine. Five specific codon mutations, K101P, V179E/F, Y181I/V, G190S, and M230L, were associated with resistance to etravirine, but resistance always required the presence of additional mutations.

Darunavir is a PI that has shown impressive results in heavily pretreated and PI-resistant participants in the POWER-1 and POWER-2 randomized controlled trials [Gallant J, HHR 2006;18(1):1]. De Meyer presented culled results from these studies and from POWER-3, a non-randomized, open-label, safety and efficacy study, to assess clinical resistance correlates for darunavir [Abstract 157]. Among subjects enrolled in POWER-1 and POWER-2, the authors reported that those with darunavir/ritonavir 600/100 mg twice daily were more likely to experience viral suppression than those randomized to a comparator PI, irrespective of the baseline susceptibility to the comparator PI. For example, 45% of darunavir/ritonavir recipients achieved HIV RNA <50 c/mL at 24 weeks, compared to 24% in the comparison arm with baseline susceptibility to the comparator PI, and just 7% in comparison subjects with baseline resistance to the comparator PI. A reduced virologic response rate to darunavir/ritonavir was found in patients with =10 baseline PI mutations. Mutations V32I, L33F, I47V, I54L, and L89V at baseline were associated with a lower rate of virologic response to darunavir/ritonavir, and emergence of these mutations was also observed in patients failing darunavir/ritonavir, though resistance appears to require the presence of multiple mutations, not just those listed. Unfortunately, this presentation, while helpful, does not leave us with a way to predict darunavir susceptibility based on genotype testing.

Different Enfuvirtide Resistance Pathways Associated with Variable Immunologic Response

Aquaro and colleagues evaluated the evolution of resistance mutations in the gp41 segment of the envelope protein in a cohort of 54 heavily experienced patients who added enfuvirtide (ENF) as a single drug to a failing regimen [Abstract 596]. The addition of ENF was accompanied by a fleeting decline in the median HIV RNA from 5.1 to 4.2 log₁₀ c/mL at week 8, with rebound to near baseline occurring shortly thereafter. However, a 136 cells/mm³ increase in the median CD4 count was observed in the cohort over 48 weeks. Resistance mutations in gp41 emerged rapidly during treatment and were detected in 45 of 54 patients (83.3%). Patients with emergent V38A/E or N126K mutations experienced a median 24week CD4 cell increase of approximately 95 cells/mm³, compared to a median decrease of 25 cells/mm³ in subjects with gp41 that remained wild type. In contrast, the Q40H and L45M mutations, which generally emerged together, were associated with a decline in CD4 cell count relative to patients with virus that remained wild type. None of the mutations was associated with differences in virologic response relative to those with wild type gp41. These results imply that different mutational pathways to ENF resistance in gp41 are associated with differences in pathogenic fitness that are independent and viral load, and challenge earlier suggestions that there was no benefit to continued use of ENF in patients who were not virologically suppressed.

AZT is Key with K65R

The K65R mutation in reverse transcriptase is selected by non-thymidine-containing NRTI combinations and decreases the activity of tenofovir, abacavir, didanosine, lamivudine and emtricitabine. However the K65R mutation confers hypersusceptibility to zidovudine (AZT) and rarely, if ever, occurs in concert with thymidine analog mutations (TAMs). For this reason an AZT-containing regimen is preferred when K65R is known to exist. Staszewski and colleagues highlighted this point in a case series of three patients in whom AZT was added as a single drug to a failing regimen in the presence of K65R [Conf Retrovir Opportunistic Infect 2006 Feb 5-8;13:abstract no. 635]. No patient had TAMs or a history of TAMS, two patients had M184V, and two patients had NNRTI resistance. No patient had clinically significant PI resistance. The patients experienced 1.4 to 3 log₁₀ c/mL viral load declines with the addition of AZT, and all achieved durable HIV RNA <50 c/mL for more than 1 year. While adding a single drug to a failing regimen is not recommended as a clinical strategy, this study emphasizes the clinical relevance of K65Rmediated hypersusceptibility to AZT.

Boosted ATV Clinical Cut-Off Validated

A clinical cut-off for an antiretroviral drug is the fold-change in HIV susceptibility to the drug that provides the greatest statistical discrimination between virologic response rates above and below the cut-off. The previously defined cut-off for ritonavir (RTV)-boosted atazanavir (ATV) of 5.2 was confirmed by Coakley and associates in a retrospective analysis of data from BMS-045 [Conf Retrovir Opportunistic Infect 2006 Feb 5-8;13:abstract no. 634]. In the first 2 weeks of this trial in triple-class experienced patients, a subset of participants switched from a failing NNRTI or PI to ATV 300 mg and RTV 100 mg daily, without altering other drugs in their regimen. Coakley and colleagues examined 2-week virologic responses, defined as a decline in HIV RNA >1 log₁₀ c/mL. They found that a 5.2-fold reduction in susceptibility to ATV at baseline best distinguished responders from non-responders. The virologic response rate was 89% in patients with baseline susceptibility below this cut-off, while the response rate was just 26% in those above the cut-off.

Does Antiretroviral Resistance Testing Improve Mortality?

Palella and coworkers from the HIV Outpatient Study (HOPS) presented data suggesting that having a resistance test (either genotype or phenotype) performed in clinical practice was associated with improved survival [Conf Retrovir Opportunistic Infect 2006 Feb 5-8;13:abstract no. 654]. Compared to 3,351 HAART-experienced patients in the cohort who had not had a resistance test, the 1,263 patients who had resistance testing were younger, were more likely to be white, and were more likely to have private insurance, all factors that were also associated with longer survival. However, the tested group also had significantly lower CD4 cell counts and higher viral loads, factors associated with shorter survival. Adjusting for these variables, the authors found that resistance testing was associated with a 60% reduction in the risk of death.

They reached a similar conclusion in a separate analysis in which they compared mortality in triple-class-exposed, persistently viremic patients who had a resistance test performed with a comparison group (matched on injection drug use, insurance status, nadir CD4 cell count and calendar year of nadir CD4 cell count) that did not have resistance testing. Mortality in the tested group was 7.9% versus 21.8% in the untested group. The authors hypothesized that mortality differences were explained by more effective selection of antiretroviral drugs in patients in whom resistance testing had been obtained. However, they were not able to test this hypothesis directly. Additionally, it is also possible that failure to have resistance testing, particularly in situations where resistance testing is strongly recommended in clinical practice guidelines, was a marker for adverse patient characteristics (such has nonadherence) or poorer quality of overall HIV care.

Conclusion

Etravirine and darunavir are promising new additions to the NNRTI and PI classes, respectively, that appear to maintain good activity in heavily experienced patients. In each case, specific mutations have been identified that are associated with a poorer response to these drugs. The imminent availability of these agents underlines the importance of avoiding PIs and NNRTIs in “holding regimen” situations, where viral suppression is not possible but therapy is needed to delay clinical disease progression. Clearly, the new drugs lose their activity when an extensive number of resistance mutations have emerged due to prolonged exposure to nonsuppressive therapy. Resistance mutations arise quickly when enfuvirtide is added as a single active drug to a failing regimen. Interestingly, however, some enfuvirtide resistance mutations appear to be associated with increases in CD4 cell counts, while other patterns are associated with declining CD4 cell counts. Finally, the clinical benefit of K65R-mediated hypersusceptibility to AZT was highlighted in a small case series, and a clinical phenotypic susceptibility cut-off was confirmed for RTV-boosted ATV.

2006-03-10
HHR-2006-03-02

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