CROI 2009: A Few Key Presentations on Antiretroviral Therapy

Key words: HIV/AIDS, Antiretroviral therapy, Conference coverage, CROI

In contrast to previous conferences, at this year’s Conference on Retroviruses and Opportunistic Infections (CROI), held February 8 through 11 in Montreal, there were few presentations on major clinical trials of antiretroviral therapy and little news on investigational agents was reported. Nevertheless, there were a number of important studies dealing with the treatment of HIV infection, a few of which I’ll summarize here.

MORE OBSERVATIONAL DATA ON WHEN TO START THERAPY
In my editorial in the February issue of The AIDS Reader,¹ I discussed the data from the North American AIDS Cohort Collaboration on Research and Design (NAACCORD) study presented at the Interscience Conference on Antimicrobial Agents and Chemotherapy/Infectious Diseases Society of America (ICAAC/IDSA) joint meeting last fall. That study found 70% lower mortality among patients who began antiretroviral therapy when their CD4⁺ cell count was between 350/µL and 500/µL than among those who waited until their CD4⁺ cell count had fallen below 350/µL.² In Montreal, the same investigators presented a similar analysis, now looking at initiation of therapy at CD4⁺ cell counts above 500/µL versus deferral of therapy until the CD4⁺ cell count dropped below that threshold.³ They again found a survival benefit with earlier therapy, this time of 60%.

A unique advantage of this study over other observational cohorts is the ability to directly address lead-time bias. Most cohort studies collect data from the time of initiation of therapy. This allows an assessment of prognosis after initiation of antiretroviral therapy but cannot directly answer the question of when to start, because events that happen to patients while they wait to begin therapy are not captured. In contrast, patients in these NA-ACCORD analyses enter the study in the same CD4⁺ cell count range and then either initiate therapy within 1.5 years of crossing a specific CD4 count threshold (the early treatment group) or do not (the deferred therapy group).

The biggest concern with all observational studies is that there may be unmeasured confounders that, in this case, affect both the decision to start therapy and the study end point, ie, all-cause mortality. The most obvious type of confounder would be a form of health-seeking behavior that resulted in early initiation of antiretroviral therapy but that also improved prognosis independent of antiretroviral therapy. The NA-ACCORD investigators noted that after controlling for hepatitis C and injection drug use, which were both independently associated with mortality, their findings were essentially the same. They also pointed out that the rates of virological suppression were similar among treated patients in both the early and deferred groups, which suggests that their findings could not be explained by differences in adherence. Finally, a sensitivity analysis found that for an unmeasured confounder to invalidate their findings, it would have to have a 4-fold effect.

The NA-ACCORD presentation was followed by a presentation from the Antiretroviral Therapy (ART) Cohort Collaboration (ART-CC) study group.⁴ In the ART-CC study, the investigators dealt with the issue of lead-time bias by inputting pretreatment data from historical, pre-HAART era cohorts to estimate what would have happened to participants before starting therapy. Their findings were consistent with the earlier NA-ACCORD presentation, which demonstrated a survival benefit with initiation of therapy at CD4⁺ cell counts of 350/µL to 500/µL but not a significant difference with initiation above 500/µL.

In my earlier editorial, I discussed the potential implications of NA-ACCORD on clinical practice. It remains to be seen whether patients, practicing clinicians, and guidelines panels will accept these results at face value or wait for the results of a planned clinical trial before deciding to start treatment at higher CD4⁺ cell counts.

THE SWITCHMRK STUDIES: SWITCHING TO RALTEGRAVIR
The two identical SWITCHMRK studies randomized patients with virological suppression who were receiving treatment with lopinavir/ritonavir (LPV/r) plus at least 2 NRTIs to either continue their current regimen or to switch from LPV/r to the integrase inhibitor raltegravir.⁵ While there were lipid benefits associated with this switch, raltegravir was not noninferior (and in this case, it’s safe to say that it was “inferior”) to LPV/r. The results were predictable given the study design, which allowed participants to enroll despite prior virological failure while they were receiving antiretroviral therapy. In fact, there were patients enrolled in this study who had received up to 22 years of antiretroviral therapy and up to 16 antiretroviral agents previously. Needless to say, this meant that some participants were receiving the equivalent of raltegravir monotherapy. Many of the participants for whom raltegravir therapy failed had evidence of integrase inhibitor resistance and were more likely to have experienced virological failure with previous regimens.

The SWITCHMRK trials reinforce some important lessons:
• Raltegravir has a lower genetic barrier to resistance than ritonavir-boosted protease inhibitors (PIs), and it is therefore less likely to provide durable suppression without adequate backup from the other drugs in the regimen.
• Single-drug switches, especially from high to low genetic barrier agents, should only be made after careful consideration of the likely activity of the other drugs in the regimen.
• Just because patients meet enrollment criteria for a clinical trial does not mean they should be enrolled.

The upside of the results from the SWITCHMRK studies is that they remind us that raltegravir is not a magic bullet; we need to be careful how we use this valuable drug.

MORE ON ABACAVIR AND CARDIOVASCULAR RISK
At last year’s CROI, data from the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study were presented that suggested a 90% increase in risk of myocardial infarction (MI) in patients taking abacavir.⁶ This study was followed by an analysis from the Strategies for Management of Antiretroviral Therapy (SMART) study, which also found an association in participants with multiple cardiac risk factors.⁷ In contrast, a GlaxoSmithKline review of data from multiple clinical trials involving abacavir has found no such risk.⁸ Because of the lack of an obvious mechanism and the potential for bias in observational studies, these findings left considerable doubt about whether they were real or a result of the study’s methodology. However, data presented at this year’s CROI further supported the hypothesis that abacavir may increase the risk of MI.

The evidence is discussed in greater detail by Boyle and colleagues⁹ in a Research Focus column elsewhere in this issue (page 158). In short, a case-control study from a large French database found an increased risk of MI in patients recently treated with abacavir (within the past 6 months) or treated for a short duration (less than 1 year).¹⁰ A reanalysis of D:A:D data continued to find an association between MI and abacavir use but not between MI and tenofovir use.¹¹ The Australian STEAL study, which compared switches to tenofovir/emtricitabine with switches to abacavir/lamivudine, found 1 cardiovascular event in the tenofovir/emtricitabine arm and 8 in the abacavir/lamivudine arm (P = .048).¹²

On the other hand, an analysis from several AIDS Clinical Trials Group trials found no increased risk of cardiovascular events with abacavir use.¹³ In a masterful review of the data, Peter Reiss,¹⁴ a D:A:D investigator, said that the “score” is now 4 to 2 in favor of a cardiac risk with abacavir use. He added that participants in the 4 studies that demonstrated an association were approximately 7 to 10 years older than those in the negative studies, putting them at higher risk to begin with. In addition, the negative studies involved patients starting therapy, whereas many of the participants in the positive studies were already on an antiretroviral regimen and had viral suppression at the time of initiation of abacavir therapy. He postulated that the early reduction in inflammation and thrombogenesis that occurs with initiation of any antiretroviral regimen could mask subtle differences between individual agents, which might be observed only in comparisons of patients in whom viral replication is already suppressed.

While the evidence to date is far from definitive, the signal is getting stronger, and interest seems to be turning from confirming the association to determining its mechanism. The pathogenesis remains elusive. Data were presented that suggest increased platelet aggregation¹⁵ or altered endothelial function with abacavir,¹⁶ but the data are far from consistent across studies. For now, the approach advocated by the most recent revision of the Department of Health and Human Services treatment guidelines makes sense¹⁷: use tenofovir/emtricitabine as the preferred NRTI backbone when there are no contraindications. In a patient with renal dysfunction, consider using abacavir/lamivudine as an alternative, provided the patient is not at high risk for heart disease. Unfortunately, many patients with renal dysfunction also have risk factors for heart disease, and the best approach for this group remains undefined. There may be a role for NRTI-sparing regimens in this population, although data on such regimens are limited.

NEW PHARMACOLOGICAL BOOSTERS
Using ritonavir to inhibit the metabolism of other PIs has become the standard of care on the basis of improved efficacy, greater convenience, and a greater barrier to resistance seen with boosted PI regimens. Nevertheless, the drawbacks of using ritonavir are considerable, including high cost; need for refrigeration; lack of coformulation with PIs other than lopinavir; GI adverse effects; and metabolic toxicities, such as elevated lipid levels. Both Gilead Sciences¹⁸ and Sequoia Pharmaceuticals¹⁹ presented early data on their new cytochrome P-450 (CYP) 3A4 inhibitors, GS-9350 and SPI-452, respectively-compounds they hope will replace ritonavir as pharmacological boosters for PIs as well as other agents, including Gilead’s investigational integrase inhibitor, elvitegravir. Both GS-9350 and SPI-452 have demonstrated potent CYP3A4 inhibition in early phase 1 trials. GS-9350 has already been coformulated with elvitegravir, tenofovir, and emtricitabine as a “quad” pill, which is reportedly smaller than the currently available efavirenz/tenofovir/emtricitabine coformulated pill (Atripla) and will be competing with it directly in a phase 2 trial. The new booster allows Gilead Sciences to study elvitegravir for first-line use, which has sped up the development of this agent considerably.

The pharmacological boosting of PIs with SPI-452 leads to drug levels similar to those seen with low-dose ritonavir. Sequoia Pharmaceuticals is moving forward with further studies using SPI-452 in combination with atazanavir and darunavir. As is typically the case with phase 1 studies, SPI-452 was described as being “well tolerated,” although the fairly high incidence of headache, nausea, vomiting, and diarrhea was concerning, given how important it is that any new booster be better tolerated than ritonavir.

CONCLUSIONS
Treatment studies presented at this year’s CROI provide us with important information but will lead only to incremental changes in practice rather than paradigm shifts. That’s to be expected; paradigm shifts can‚t happen every year. But the paucity of clinical trial data in Montreal may be a sign of the coming “dry spell” in new drug development. Just as we have to be financially responsible to weather the current economic crisis, we also have to use our existing drugs carefully, since it seems unlikely that there will be any antiretroviral “bailouts” for many years.

References:

References1. Gallant JE. When to start antiretroviral therapy? NA-ACCORD stimulates the debate. AIDS Reader. 2009;19:49-50, 61.
2. Kitahata MM, Gange SJ, Moore RD, et al. Initiating rather than deferring HAART at a CD4⁺ count between 351-500 cells/mm³ is associated with improved survival. 48th Annual ICAAC/IDSA 46th Annual Meeting; October 25-28, 2008; Washington, DC. Abstract H-896b.
3. Kitahata M, Gange S, Moore R, et al; North American AIDS Cohort Collaboration on Research and Design. Initiating rather than deferring HAART at a CD4⁺ count > 500 cells/mm³ is associated with improved survival. 16th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2009; Montreal. Abstract 71.
4. Sterne J; When to Start Consortium. When should HIV-1-infected persons initiate ART? Collaborative analysis of HIV cohort studies. 16th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2009; Montreal. Abstract 72LB.
5. Eron J, Andrade J, Zajdenverg R, et al. Switching from stable lopinavir/ritonavir-based to raltegravir-based combination ART resulted in a superior lipid profile at week 12 but did not demonstrate non-inferior virologic efficacy at week 24. 16th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2009; Montreal. Abstract 70aLB.
6. D:A:D Study Group; Sabin CA, Worm SW, Weber R, et al. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study: a multi-cohort collaboration [published correction appears in Lancet. 2008;372:292]. Lancet. 2008;371:1417-1426.
7. Lundgren J , Neuhaus J, Babiker A, et al; SMART/INSIGHT Study Group; D:A:D Study Group. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the SMART study. XVII International AIDS Conference; August 3-8, 2008; Mexico City. Abstract THAB0305.
8. Cutrell A, Brothers C, Yeo J, et al. Abacavir and the potential risk of myocardial infarction. Lancet. 2008;371:1413.
9. Boyle BA, Cohen CJ, DeJesus E, et al. Update on antiretroviral therapy-16th CROI. AIDS Reader. 2009;19:158-160.
10. Lang S, Mary-Krause M, Cotte L, et al. Impact of specific NRTI and PI exposure on the risk of myocardial infarction: a case-control study nested within FHDH ANRS CO4. 16th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2009; Montreal. Abstract 43LB.
11. Lundgren J, Reiss P, Worm S, et al. Risk of myocardial infarction with exposure to specific ARV from the PI, NNRTI, and NRTI drug classes: the D:A:D Study. 16th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2009; Montreal. Abstract 44LB.
12. Cooper D, Bloch M, Humphries A, et al; STEAL Study Investigators. Simplification with fixed-dose tenofovir/emtricitabine or abacavir/lamivudine in adults with suppressed HIV replication: the STEAL study, a randomized, open-label, 96-week, non-inferiority trial. 16th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2009; Montreal. Abstract 576.
13. Benson C, Ribaudo H, Zheng E, et al; ACTG A5001/ALLRT Protocol Team. No association of abacavir use with risk of myocardial infarction or severe cardiovascular disease events: results from ACTG A5001. 16th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2009; Montreal. Abstract 721.
14. Reiss P. Abacavir and cardiovascular risk. 16th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2009; Montreal. Abstract 152.
15. Satchell C, O‚Connor E, Peace A, et al. Platelet hyper-reactivity in HIV-1-infected patients on abacavir-containing ART. 16th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2009; Montreal. Abstract 151LB.
16. Hsue P, Wu Y, Schnell A, et al. Association of abacavir and HIV disease factors with endothelial function in patients on long-term suppressive ART. 16th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2009; Montreal. Abstract 723.
17. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. November 3, 2008:1-139. http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed February 15, 2009.
18. Mathias A, Lee M, Callebaut C, et al. GS-9350: a pharmacoenhancer without anti-HIV activity. 16th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2009; Montreal. Abstract 40.
19. Gulnik S, Eissenstat M, Afonina E, et al. Preclinical and early clinical evaluation of SPI-452, a new pharmacokinetic enhancer. 16th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2009; Montreal. Abstract 41.