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Fine-tuning Antiretroviral Strategies: An Expert Interview With Calvin Cohen, MD


Editor's Note:
Clinical researchers continue to explore important differences between antiretrovirals and the ways they are combined in drug regimens. Although dramatic leaps in management strategies have become less common, the accumulation of incremental advances is having a substantial effect on how drugs should optimally be used in the clinic. Following the 10th European AIDS Conference (EAC), held November 17-20, 2005 in Dublin, Ireland, Medscape interviewed Calvin J. Cohen, MD, Research Director at both Community Research Initiative of New England and Harvard Vanguard Medical Associates in Boston, Massachusetts, about his perspective on important new clinical data presented at the meeting.

Medscape: A number of studies at EAC assessed various antiretroviral management strategies, such as simplified treatment regimens, head-to-head efficacy comparisons, and nucleoside reverse transcriptase inhibitor (NRTI)-containing vs -sparing regimens, among other topics. Regarding this last issue, NRTI-sparing regimens are being examined as a potential strategy to minimize the risk of certain toxicities associated with NRTIs and to conserve drug class options. Were there notable studies that explored the viability of this approach?

Dr. Cohen: This meeting did contribute data to the ongoing discussion of whether 2 NRTIs plus a third agent is generally the best type of regimen to use, and we saw the first results from a study done in France called ANRS 121 ("Hippocampe") that are relevant to this issue.[10] A total of 117 treatment-naive patients were randomized to 1 of 3 arms: 2 NRTIs plus a nonnucleoside reverse transcriptase inhibitor (NNRTI), 2 NRTIs plus a protease inhibitor (PI), or an NNRTI plus a PI. The choice of which specific agents to use from these classes was left up to the prescribing investigator, which makes this a test of strategy that may not be applicable to all possible combinations within these broad categories. The study was designed to continue for 96 weeks but was stopped prematurely by the Data Safety Monitoring Board (DSMB) due to the inferiority of the NNRTI/PI arm.

The patients enrolled were only somewhat more advanced than has been seen in other recent studies, with a baseline CD4+ cell count of about 205 cells/mcL and viral load of 5 log10 copies/mL. In the NRTI-sparing arm, the majority of patients received efavirenz (Sustiva) (63%) vs nevirapine (Viramune) (37%), and the majority received dose-adjusted lopinavir/ritonavir (Kaletra) as the boosted PI. In the comparator arms, the majority again received efavirenz or lopinavir/ritonavir with 2 NRTIs. By an intent-to-treat analysis at Week 24, the virologic response (defined as viral load < 50 copies/mL) was 80.7% in standard PI or NNRTI therapy vs 60% in the NRTI-sparing arm ([95% CI: 4.1-35.7], P = .01). Of note, there were more "treatment interruptions" as well as switches in the NRTI-sparing strategy, which suggests that the observed outcome of this study may be driven more by tolerability issues than by intrinsic antiviral activity. As a result of the inferior outcome, the DSMB stopped this study in July 2005. Although results of ongoing studies in the United States testing similar strategies are expected in the near future, it is reasonable to conclude at this time that our most proven regimens continue to be those based on the validated 2 NRTIs plus a potent "third agent" approach.

Medscape: Regarding direct comparisons of NRTI pairs, did we see any new information on which pairs might be preferable for use in treatment of antiretroviral therapy (ART)-naive patients, or perhaps in special patient populations?

Dr. Cohen: In terms of which 2 NRTIs to pick, studies have been presented for many years showing the similarities and differences between various combinations of NRTIs. The current US Department of Health and Human Services (DHHS) "preferred" options of zidovudine/lamivudine (Combivir) or tenofovir/emtricitabine (Truvada) in combination with efavirenz has been the focus of randomized studies. At this year's EAC, we did see some new evidence about this topic.

On the basis of the differences seen that suggest benefits to the use of tenofovir/emtricitabine over zidovudine/lamivudine, a study was presented called COMET, which provides initial data about the outcomes of switching from a virologically suppressive regimen containing zidovudine/lamivudine to one based on tenofovir/emtricitabine.[5] The design was simple: patients who were virologically controlled (HIV RNA < 400 copies/mL) on zidovudine/lamivudine/efavirenz were switched to tenofovir/emtricitabine/efavirenz at baseline and monitored for several parameters of efficacy and toxicity. Patients went from a twice-daily to a once-daily regimen; therefore, it was not surprising that the most common reason cited for patient participation in the study was regimen simplification.

For the endpoint at Week 24, the data were available for the first 217 patients who were enrolled. Investigators reported that 94% of patients maintained virologic suppression to < 400 copies/mL. By contrast, there were 17% of patients whose viral load was between 50 copies/mL and 400 copies/mL at entry who at Week 24 had a viral load < 50 copies/mL. Not surprisingly, the substitution was safe: There was a significant increase in hemoglobin and neutrophil count observed at Week 24, and a significant improvement in total cholesterol, triglycerides, and LDL cholesterol by Week 12, though there was a statistically significant decline in the HDL cholesterol. The switch was well tolerated, with a consistent improvement in scores on questionnaires that assessed patient satisfaction with their health and medication side effects. Finally, in terms of lab toxicities, 6 patients had grade 1-2 elevations in creatinine; 4 of them returned to normal by Week 24, but the other 2 sustained grade 1 elevations.

Although this is a preliminary analysis, these data largely corroborate data from Study 934[3] and show that substitution of once-daily NRTIs, and coformulated tenofovir/emtricitabine specifically, can be successfully done in a high percentage of patients who are otherwise virologically controlled. Further details are awaited to also understand baseline risk factors, if any, for the 6% who had a virologic rebound to > 400 copies/mL by Week 24.

These data also subjectively document significant improvements by patient questionnaire, and they demonstrate a low rate of adverse events. For example, about one third of the patients reported an absence of fatigue while on the zidovudine/lamivudine regimen, and after the substitution, about one half reported this assessment.

In terms of this issue's relevance to special patient populations, at this year's EAC investigators presented new data about an important subset of patients (n = 16) in Study 934 who were coinfected with hepatitis C virus (HCV).[4] As many know, data from Study 934 had been presented most recently at the IAS Conference on HIV Pathogenesis and Treatment in Rio. (See Medscape's complete IAS conference coverage at Investigators reported the overall superiority of a tenofovir (Viread) plus emtricitabine (Emtriva) pair over the coformulated zidovudine/lamivudine tablet on several measures.[3] The results from this substudy largely mirrored those observed in the overall study. Of note, there were no significant differences in the rates of transaminase elevations in the 2 arms, and both arms had minimal changes in these lab values from baseline. As in the overall study, the percentage with HIV suppression was numerically greater in the tenofovir/emtricitabine arm, although this difference was not statistically significant. There was, however, a significantly greater increase in the CD4+ cell count over 48 weeks on the tenofovir/emtricitabine arm (+200 cells/mcL vs +125 cells/mcL; P = .026).

Medscape: What about new data on other types of treatment switches beyond NRTI substitutions?

Dr. Cohen: The final 48-week results of the SWAN study were presented at this conference.[6] This study was an evaluation of the activity and safety of a change from any PI in a suppressive regimen to a new regimen containing atazanavir (Reyataz). Notably, the investigators preferentially used atazanavir without ritonavir (Norvir) unless tenofovir was a part of the NRTI backbone; this situation was observed in only 9% of those enrolled. The 48-week results largely validate the 24-week results reported at the IAS conference in Rio. As shown earlier, the use of atazanavir was associated with preserved virologic suppression vs other PIs (with no difference in the rates of viral suppression vs the boosted PI lopinavir), but was statistically superior (5% vs 22% maintained a viral load < 50 copies/mL; P < .001) when compared with other unboosted PIs, primarily nelfinavir (Viracept). It is impressive that there was no statistical difference in maintenance of viral suppression between (primarily) unboosted atazanavir and a boosted PI, with a confidence interval suggesting no more than a 10% difference in rates of suppression between unboosted atazanavir and the boosted PIs used. As expected, there was significant improvement in some lipid subfractions compared with other PIs, as there were declines in total cholesterol, non-HDL cholesterol, and triglycerides with this substitution. However, there were no statistical differences in the other lipid subfractions, specifically LDL and HDL cholesterol.

Medscape: For many ART-naive patients, certain once-daily drugs and even entire once-daily combination regimens have become a treatment trend in recent years. What studies of interest did you see that examined the pharmacology or clinical efficacy of antiretroviral drugs that are dosed once daily?

Dr. Cohen: There is a continued move among clinical researchers to explore how to make initial regimens as simple as possible. This has led to a series of studies of various types that are exploring how to maximize several factors that contribute to regimen simplicity.

One factor that has fueled this enthusiasm is the recognition that several of our antiretrovirals can be dosed once daily and still provide a "pharmacologic cushion." In other words, the true dosing interval could be less than once daily, given the actual half-life of these particular antiretrovirals. One in vitro study documenting this subject was presented by Ledford and colleagues.[1] In this study, researchers at Gilead noted that prior work on half-lives (as based on serum measurements as well as intracellular levels) showed that tenofovir has a reported intracellular half-life of over 60 hours. By contrast, similar work documented that abacavir (Ziagen) has an intracellular half-life of about 19 hours. Researchers tested another assay to substantiate intracellular activity over time with timed drug exposures in vitro. They used an assay to measure what they called "persistence" in the cells that were exposed to drug, and then the external drug was washed away. They could then test the duration of time the drug remains active by challenging the cells with HIV and noting when the antiviral effect was active vs no longer active. This measure could be viewed as a potential parallel to the impact of "real-world" periodic adherence lapses, as it provides an assessment of how different antiretrovirals remain active over time.

As would be anticipated by the previously reported half-lives, the intracellular antiviral activity did again document a difference between the 2 agents evaluated. Using a CD4-based cell line, tenofovir had lost about 2.4-fold activity 24 hours after the drug was removed, whereas abacavir had lost 243-fold activity at this same time point. In fact, even at 6 hours there was some evidence of a decrease in antiviral activity, but again, more for abacavir than for tenofovir.

Although intriguing, these data serve primarily to fuel interest in the outcomes of ongoing studies that are randomizing participants to combinations based on 1 agent or the other, in order to assess the degree to which these assays are clinically relevant. Nevertheless, they do suggest that just as we see differences in other antiretroviral drug classes with regard to half-lives (ie, PIs and NNRTIs), there also may be similar differences of interest among nucleosides/nucleotides that have relevance in certain clinical situations.

Medscape: What about specific once-daily regimens? Any new efficacy data you would like to share on certain regimens that might be of interest to clinicians?

Dr. Cohen: For several years, there has been a focus on once-daily regimens, because there is a body of data that supports the hypothesis that when pill burden is reduced to just a few pills for an entire regimen, patients prefer having the option of taking them all just once daily. Not surprisingly, we have now seen data about yet another novel regimen that explores the ability to combine once-daily agents. Investigators from the VeLLA study[2] presented data for the first time from 23 Latino/Latina patients who all took the combination of coformulated tenofovir/emtricitabine and ritonavir -boosted atazanavir. It is also not surprising that they observed in this initial report the expected high efficacy and safety given the components of the regimen, with 2 dropouts due to adverse events.

Medscape: On the topic of side effects, data on the long-term adverse effects of ART were of course an area of interest at this conference, as they have been for many years now. What were some of the notable clinical data on highly active antiretroviral therapy (HAART)-associated adverse events?

Dr. Cohen: One study did report about a 1.5% decrease in bone density in the hip when patients were switched from stavudine (Zerit) to tenofovir in combination antiretroviral regimens[7] Interestingly, this bone density change was not seen in the spine, as there was no change in this measurement 1 year after this substitution. Prior assessments of initial bone density loss after a year of tenofovir have been reassuring, reporting gradual restoration of bone density.

Lipodystrophy also continues to be an important issue that motivates both patients and clinicians about regimen choice. At this meeting, data were analyzed from the RAVE study. [8] Investigators in this study randomized patients with lipoatrophy, as documented by clinician and patient, to receive either abacavir or tenofovir. The primary data have been presented previously and demonstrated equivalence of improvement in lipoatrophy among patients randomized to either abacavir or tenofovir,[9] but this analysis focused on baseline predictors of improvement in lipoatrophy. Here, the main predictors of outcome were surprising: The authors reported that age was relevant (older patients recovered less fat), and use of zidovudine at baseline also led to less fat increase following the switch, even when controlling for baseline degrees of lipoatrophy. Using another model that focused on which factors were associated with restoration of peripheral fat; they again noted that baseline zidovudine use was problematic for fat restoration, along with longer duration of ART and white race, which were also associated with less robust restoration of fat. Although these data warrant validation in another data set, the authors suggest that patients experiencing lipoatrophy on zidovudine may be better managed by an earlier change to a regimen that is less associated with progressive lipoatrophy.

Medscape: In closing, was there any other clinical information from the meeting that you would like to share?

Dr. Cohen: Yes, there was an update of a study that explored the interpretations from 2 different phenotypic tests. VanHoutte and coworkers[11] reported on the results of a study that used the genotypic sequence from ~150 isolates and compared the phenotypic readings that a clinician would get using either the PhenoSense report (Monogram Biosciences; South San Francisco, California) or the VircoType, formerly called the "virtual phenotype" report (Virco; Mechelen, Belgium). They noted that there was a striking similarity in these 2 reports given a genotypic sequence, with about 90% agreement in the fold-change to the drugs tested (excluding atazanavir and tenofovir, which were not included in these analyses). Although based on historic sequences, this study nevertheless provides initial evidence to reassure clinicians that both phenotypic tests provide similar results and that either can be utilized when considering a change in regimen.