HIV Meds Quarterly

Spring 2009

Research Briefs

	Rosiglitazone and Heart Disease
	Antipsychotics and Sudden Cardiac Death
	New Pharmacokinetic Booster on the Horizon
	Interleukin-2: No Clinical Benefit
	Raltegravir Substitution for Lopinavir/Ritonavir (SWITCHMRK Study)
	Abacavir and Myocardial Infarction Risk: Additional Data

Reference Table

	Updates to the Database of ARV Drug Interactions

Fast Takes

	Darunavir: Traditional approval In January, the U.S. Food and Drug Administration granted traditional approval for the use of the integrase inhibitor raltegravir in treatment-experienced adults. It had been granted accelerated approval in 2007. As with other antiretroviral agents, it must be used in combination ARV regimens.

Guidelines

	New Guidelines: Adult OI prevention and treatment Adult Prevention and Treatment of Opportunistic Infections Guidelines Working Group. Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents . March 24, 2009. MMWR 2009; 58 (early release) pp 1-198.
	Updated: Pediatric ARV guidelines Working Group on Antiretroviral Therapy and Medical Management of HIV-Infected Children, François-Xavier Bagnoud Center at the University of Medicine and Dentistry of New Jersey (UMDNJ), Health Resources and Services Administration (HRSA), and National Institutes of Health (NIH). Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection . Updated February 23, 2009.
	Updated: Perinatal guidelines Public Health Service Task Force. Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States , April 29, 2009.

Rosiglitazone and Heart Disease

In HIV-infected patients, the thiazolidinedione medications rosiglitazone and pioglitazone have been used both for treatment of type 2 diabetes (their indication) and for treatment of lipodystrophy. However, in the general population, they have been associated with congestive heart failure (CHF) and myocardial infarction. A recent metaanalysis of 28,361 HIV-uninfected diabetic patients who initiated rosiglitazone or pioglitazone assessed the outcomes of all-cause mortality, myocardial infarction, stroke, and hospitalization for CHF. Patients were older than 65 years of age, had similar baseline characteristics, and were divided into two equal groups to receive either rosiglitazone or pioglitazone.

Cox regression modeling indicated that patients who received rosiglitazone had a 15% greater chance of mortality and a 13% greater chance of CHF than patients who received pioglitazone; these differences were statistically significant. There were no differences between groups in rates of myocardial infarction or stroke.

Clinical Bottom Line

Although large studies of cardiovascular outcomes involving HIV-infected patients on thiazolidinediones have not been conducted, clinicians should use caution when prescribing these drugs, particularly for older patients and those with cardiovascular risk factors. This study found that adverse cardiovascular effects result from rosiglitazone but not from pioglitazone; based on these data, pioglitazone should be used preferentially, if treatment with a thiazolidinediones is required.

References

1. Winkelmayer WC, Setoguchi S, Levin R, et al. Comparison of cardiovascular outcomes in elderly patients with diabetes who initiated rosiglitazone vs pioglitazone therapy. Arch Intern Med. 2008 Nov 24;168(21):2368-75.

Antipsychotics and Sudden Cardiac Death

Older antipsychotic medications are known to increase the risk of sudden cardiac death, largely through ventricular arrhythmias. Newer atypical antipsychotic agents (eg, olanzapine, risperidone) generally are believed to have better safety profiles, and are used widely, often by primary care providers and often for off-label indications such as insomnia. However, recent data indicate that greater prudence should be exercised when prescribing these medications.

A retrospective cohort study, from a Medicaid database, compared the incidence of sudden cardiac death in patients on typical agents (44,000) and atypical antipsychotic agents (46,000), and in persons not on antipsychotic medications (187,000) from 1990 to 2005.

Current users of either typical or atypical antipsychotic agents were twice as likely as nonusers to die of a sudden cardiac event. The incidence-rate ratio for atypical agents compared with typical agents was 1.14, a statistically nonsignificant difference. The risk of sudden cardiac death was dosage dependent and returned to baseline when the antipsychotic agent was discontinued.

Clinical Bottom Line

Atypical antipsychotics do not appear to be "safer" than the typical agents, at least with regard to the risk of sudden cardiac death. Before prescribing antipsychotics, clinicians are advised to review the individual patient's risk of sudden cardiac death, consider interactions with ARVs or other medications that may increase the exposure to the antipsychotic agent, and ensure that the antipsychotic agent is being used for an accepted indication.

References

1. Ray WA, Chung CP, Murray KT, et al. Atypical antipsychotic drugs and the risk of sudden cardiac death. N Engl J Med. 2009 Jan 15;360(3):225-35.

New Pharmacokinetic Booster on the Horizon

Many protease inhibitors require the pharmacokinetic boosting effects of ritonavir to achieve adequate serum levels. But because of issues such as tolerability, cost, and lack of coformulated preparations, many clinicians have yearned for alternatives to ritonavir. Researchers at the 16th Conference on Retroviruses and Opportunistic Infections in Montreal in February presented data on two alternative pharmacokinetic enhancers that are now in clinical development. The more promising of these two at present is GS-9350. This compound, which is in phase III studies, is a potent and specific CYP 3A4 inhibitor, but is devoid of any anti-HIV activity. Studies in humans have demonstrated that the compound is well tolerated. GS-9350 is intended to be a pharmacoenhancer for elvitegravir, an investigational integrase inhibitor, so that once-daily dosing of elvitegravir is possible. Current development plans are to combine GS-9350 with elvitegravir, tenofovir, and emtricitabine in a 4-drug fixed-dose combination tablet. However, GS-9350 also will be studied as a booster for protease inhibitors.

References

1. Mathias A, Lee M, Callebaut C, et al. GS-9350: a pharmaco-enhancer without anti-HIV activity. In: Program and abstracts of the 16th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2009; Montreal. Abstract 40.

Interleukin-2: No Clinical Benefit

It is well known that recombinant interleukin-2 (IL-2) increases CD4 counts in HIV-infected persons, beyond the effect of antiretroviral therapy (ART) alone, but it has not been clear as to whether these CD4 gains translate into clinical benefit. At the 16th Conference on Retroviruses and Opportunistic Infections in Montreal in February, the long-awaited results from two large randomized clinical trials of IL-2 therapy were presented; these findings definitively answer the question.(1,2)

More than 5,800 patients already on ART were randomized to receive subcutaneous IL-2 with ART or to receive ART alone, and were followed for a median of more than 7 years. The ESPRIT study examined patients with baseline CD4 counts of ≥300 cells/µL whereas the SILCAAT study looked at patients with baseline CD4 counts of 50-299 cells/µL. The studies had somewhat different protocols, but both found statistically significantly higher CD4 cell counts in IL-2 groups than in controls, and no differences in rates of HIV RNA suppression. However, there were no differences between treatment groups in the primary study outcomes of opportunistic disease or death . Additionally, the ESPRIT study noted a higher rate of Grade 4 clinical events in the IL-2 group.

Clinical Bottom Line

In patients on ART, IL-2 increases the CD4 cell count but does not confer clinical benefit. Further research is needed to define possible approaches to immune-based therapies.

References

1. Losso M, Abrams D, INSIGHT ESPRIT Study Group. Effect of interleukin-2 on clinical outcomes in patients with a CD4+ cell count of 300/mm3: primary results of the ESPRIT study. In: Program and abstracts of the 16th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2009; Montreal. Abstract 90aLB.
2. Levy Y, SILCAAT Sci Committee. Effect of interleukin-2 on clinical outcomes in patients with CD4+ cell count 50 to 299/mm3: primary results of the SILCAAT study. In: Program and abstracts of the 16th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2009; Montreal. Abstract 90bLB.

Raltegravir Substitution for Lopinavir/Ritonavir (SWITCHMRK Study)

For patients who develop adverse reactions or have significant drug-drug interactions on antiretroviral (ARV) therapy, clinicians often replace the problematic ARV with a comparable one, if such an option exists. Increasingly, the integrase inhibitor raltegravir is considered a possible substitute for other ARVs because it is well tolerated, has few significant drug-drug interactions, is potent, and has no cross-resistance with agents in other ARV classes. Several small studies have shown that using raltegravir to replace enfuvirtide in virologically suppressed individuals on potent ARV regimens is likely to maintain virologic control (see, for example, Raltegravir Substitution for Enfuvirtide in the Spring 2008 installment of HIV Meds Quarterly ). However, raltegravir substitution has not been studied in other contexts. Jointly presented at the 16th Conference on Retroviruses and Opportunistic Infections in Montreal in February, the results from two studies in which raltegravir was substituted for lopinavir/ritonavir (LPV/r) demonstrate the importance of careful patient selection for this strategy.(1)

These were parallel randomized, controlled, double-blind noninferiority studies of patients with HIV RNA suppression on stable regimens consisting of LPV/r plus 2 or more nucleoside reverse transcriptase inhibitors (NRTIs). A total of 702 patients were randomized to substitute raltegravir for LPV/r or to continue LPV/r (twice daily), and all continued receiving their NRTIs. At 24 weeks, by intention-to-treat analysis, the raltegravir groups had lower rates of virologic suppression: In combined analysis, 89% of raltegravir vs 94% of LPV/r recipients had HIV RNA viral loads of <50 copies/mL (the criterion of noninferiority was not met). Integrase resistance mutations (as well as reverse transcriptase mutations) were detected in most patients with virologic failure.

The increase in virologic failure after substitution of raltegravir for LPV/r probably is explained by baseline NRTI resistance in many of the study patients, as well as by raltegravir's comparatively low genetic barrier to resistance. The study protocols did not exclude patients who had a history of ARV resistance or virologic failure on previous regimens, and study subjects had substantial previous exposure to ARVs [a median of 3-4 years (and up to 22 years)] and had used a median of 5-6 (maximum 16) ARVs. In fact, of the patients with virologic failure on raltegravir, 84% were not on their first ARV regimen, and of these, two thirds reported a history of virologic failure on a previous regimen. In many of these patients, the raltegravir may have been functioning as monotherapy.

Clinical Bottom Line

In substitution strategies, it is crucial to consider the potency of the overall ARV regimen, particularly when using raltegravir to replace an ARV with a higher genetic barrier to resistance. If raltegravir is used as a substitute for another ARV, it must be combined with other fully active agents.

References

1. 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. In: Program and abstracts of the 16th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2009; Montreal. Abstract 70aLB.

Abacavir and Myocardial Infarction Risk: Additional Data

The question of whether abacavir increases the risk of myocardial infarction (MI) initially arose with a study from the D:A:D cohort last year, followed by conflicting analyses from other studies (see previous HMQ reports Abacavir and Didanosine Associated with Increased Risk of Myocardial Infarction and Abacavir and Risk of Myocardial Infarction: The SMART Study ). In the intervening time, several studies have attempted to clarify this important issue and to elucidate possible causative mechanisms. At the 16th Conference on Retroviruses and Opportunistic Infections (CROI) in Montreal in February this year, findings from a number of investigations were presented, including:

	An update from the D:A:D Study with data from one additional year of follow-up; the conclusion about abacavir was the same: current or recent use is associated with increased rates of MI (relative rate: 1.68).(1) Importantly, the study compiled sufficient data this year to allow analysis of tenofovir; tenofovir was not associated with increased MI risk. This provides further evidence against the theory that channeling bias is responsible for the abacavir findings.
	A case-control study from the French Hospital Database found that current or recent abacavir use was associated with MI risk (odds ratio: 1.97), but only for subjects who had been on abacavir ≤1 year (in patients on abacavir >1 year, or in those with past use of abacavir, there was no statistically significant increased risk of MI). Tenofovir was not associated with MI risk.(2)
	A 96-week simplification study, in which subjects with suppressed HIV RNA were randomized to switch the NRTI components of their antiretroviral treatment (ART) regimens to abacavir/lamivudine or tenofovir/emtricitabine, found higher rates of cardiovascular disease in the abacavir arm (2.2 vs 0.3; p = .046).(3)
	On the other hand, analysis of data from 5 AIDS Clinical Trials Group randomized controlled trials of initial ART regimens found no significant associations between recent abacavir use and MI or severe cardiovascular disease.(4)

In evaluations of possible mechanisms to explain the observed adverse cardiovascular effects of abacavir, the following results were reported:

	A small study of patients with suppressed HIV viremia demonstrated endothelial dysfunction in those on abacavir-containing ART, as measured by impairment of flow-mediated vasodilation of the brachial artery.(5)
	Another small study showed increased platelet reactivity in patients taking abacavir, compared with those on other NRTIs.(6)
	Measurement of biomarkers from the MACS and WIHS cohorts showed no significant changes in C-reactive protein, d-dimer, or IL-6 after initiation of abacavir.(7)

Clinical Bottom Line

Although the clinical studies continue to yield conflicting results, it is becoming a bit clearer that the studies with larger, more robust data sets tend to find an association between abacavir and MI risk. Additionally, there now are some hints about the mechanism of that effect. However, the questions about abacavir and possible cardiovascular risks remain puzzling; it is hoped that additional research will clarify the issue. For an excellent overview of current knowledge about abacavir and cardiovascular risk, please view the webcast of Dr. Peter Reiss's plenary session presentation at CROI.(8)

Meanwhile, clinicians should continue to work with patients to decrease their traditional cardiovascular risk factors, and to control HIV infection, which itself is a risk for atherosclerosis.

References

1. Lundgren J, Reiss P, Worm S, et al; Aquataine, AHOD, ATHENA, INSIGHT, EuroSIDA, ICONA, Nice, SHCS, St Pierre cohorts, and D:A:D Study Group. Risk of myocardial infarction with exposure to specific ARV from the PI, NNRTI, and NRTI drug classes: The D:A:D Study. In: Program and abstracts of the 16th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2009; Montreal. Abstract 44LB.
2. Lang S, Mary-Krause M, Cotte L, et al; Clinical Epi Group of the French Hospital Database on HIV. Impact of specific NRTI and PI exposure on the risk of myocardial infarction: a case-control study nested within FHDH ANRS CO4. In: Program and abstracts of the 16th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2009; Montreal. Abstract 43LB.
3. 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. In: Program and abstracts of the 16th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2009; Montreal. Abstract 576.
4. 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. In: Program and abstracts of the 16th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2009; Montreal. Abstract 721.
5. 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. In: Program and abstracts of the 16th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2009; Montreal. Abstract 723.
6. Satchell C, O'Connor E, Peace A, et al. Platelet hyper-reactivity in HIV-1-infected patients on abacavir-containing ART. In: Program and abstracts of the 16th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2009; Montreal. Abstract 151LB.
7. Palella F, Gange S, Elion R, et al. Inflammatory markers among abacavir and non-abacavir recipients in the Womens' Interagency HIV Study and the Multicenter AIDS Cohort Study. In: Program and abstracts of the 16th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2009; Montreal. Abstract 150LB.
8. Reiss P. Abacavir and cardiovascular risk. In: Program and abstracts of the 16th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2009; Montreal. Abstract 152.

Updates to the Database of ARV Drug Interactions

The following table summarizes recent additions to the HIV InSite Database of Antiretroviral Drug Interactions . For a full description of the updates, including references to the studies from which the data were derived, click on a specific drug name in the table below and search for the interacting agent.