HIV Meds Quarterly

Fall 2009

Research Briefs

	Kaletra Dosage Adjustment for Patients on Efavirenz or Nevirapine
	Once-Daily Raltegravir
	Atazanavir and Lopinavir/Ritonavir in Hemodialysis

Reference Table

	Updates to the Database of ARV Drug Interactions

Kaletra Dosage Adjustment for Patients on Efavirenz or Nevirapine

Pharmacokinetic (PK) interactions among certain nonnucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) can significantly affect serum levels of these antiretrovirals (ARVs). It has long been known that lopinavir/ritonavir (Kaletra) levels are lowered by certain ARVs, including the NNRTIs efavirenz and nevirapine as well as the PIs fosamprenavir and nelfinavir. Recently, however, PK studies of the tablet formulation of lopinavir/ritonavir have been conducted, and the findings have yielded new dosage recommendations for combination therapy using these agents.

For all adults (both ARV naive and ARV experienced) who are taking lopinavir/ritonavir tablets in combination with nevirapine or efavirenz, the new recommended dosage for lopinavir/ritonavir is 500/125 mg BID. This dosage can be achieved either by taking two 200/50 mg tablets BID plus one 100/25 mg tablet BID, or by taking 2.5 of the 200/50 mg tablets BID. For adults who take lopinavir/ritonavir oral solution, the recommended dosage continues to be 533/133 mg (6.5 mL) BID when used in combination with nevirapine or efavirenz. (These dosing recommendations also apply when lopinavir/ritonavir is used in combination with fosamprenavir or nelfinavir, but note that dual-PI therapy in general is not recommended.)

For children, the recommended dosage of lopinavir/ritonavir is 300/75 mg/m ² when used with nevirapine, efavirenz, fosamprenavir, or nelfinavir; see package insert for further dosage information.

As before, lopinavir/ritonavir should not be administered once daily in regimens that include nevirapine or efavirenz.

References

Kaletra [package insert] . North Chicago, IL: Abbott Laboratories; April 2009.

Once-Daily Raltegravir

A small, nonrandomized simplification study recently evaluated the efficacy of raltegravir given once daily.

A group of 125 patients who were on a stable BID raltegravir-containing regimen with HIV RNA levels of <50 copies/mL was assigned to switch the raltegravir dosing to 800 mg QD (n = 63) or to continue raltegravir BID (n = 62), according to whether the antiretroviral (ARV) components of the subjects' individual background regimens required once- or twice-daily dosing. The two groups were adequately matched for baseline characteristics, and the median CD4 count was 536 cells/µL. All patients previously had been treated with regimens containing a protease inhibitor and had BID raltegravir substituted for a protease inhibitor before the initiation of the study.

Over a median follow-up period of 15 months, 1 patient in the once-daily raltegravir group developed virologic failure, compared with 4 patients in the twice-daily group; all 5 of these patients previously had experienced virologic failure on regimens containing nucleoside reverse transcriptase inhibitors (NRTIs). No details were given regarding the patients' previous ARV exposure or the resistance profiles of those experiencing virologic failure. Adherence rates were >90% in both groups. There were no significant differences between the groups in terms of CD4 cell counts or safety parameters.

Clinical Bottom Line

Given the long intranuclear half-life of raltegravir, there is great interest in exploring possibilities for once-daily dosing of this medication. This small pilot study presented few details about characteristics that may predict the success or failure of raltegravir-containing regimens (such as drug levels, patients' treatment histories, or HIV resistance test results), and further pharmacokinetic and clinical studies will be needed to evaluate the efficacy of once-daily raltegravir dosing. As in other raltegravir simplification studies, it appears that a potent ARV background is crucial to the success of a raltegravir-containing regimen, and that, regardless of the specific dosing strategy, raltegravir must be used in combination with other fully active agents (see for example, Raltegravir Substitution for Lopinavir/Ritonavir [SWITCHMRK Study] in the Spring 2009 installment of HIV Meds Quarterly ). Fortunately, several studies of QD raltegravir are now under way and the results of these hopefully will be available in the coming months.

References

Mena A, Blanco F, Cordoba M, et al. A pilot study assessing raltegravir QD versus BID in HIV patients included in a simplification trial. In: Program and abstracts of the 49th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2009); September 12-15, 2009; San Francisco. Abstract H-920.

Atazanavir and Lopinavir/Ritonavir in Hemodialysis

Renal function has minimal effect on the elimination of protease inhibitors (PIs), and dosage adjustments are not required for patients with chronic kidney disease. Hemodialysis also does not typically affect serum levels of drugs that are hepatically cleared, such as PIs. Despite this, and for reasons that are not understood, patients on hemodialysis appear to have reduced serum levels of the PIs atazanavir, lopinavir, and ritonavir .

Atazanavir and hemodialysis
Whereas atazanavir is minimally (2%) removed by hemodialysis, one study of atazanavir (unboosted) levels in hemodialysis patients demonstrated substantially lower plasma atazanavir concentrations compared with controls (geometric mean AUC, C _min , and C _max were 25-43% lower).(1)

Management recommendations for patients receiving hemodialysis include the following:

	Unboosted atazanavir should not be used.
	For treatment-naive patients, atazanavir must be boosted by ritonavir.
	For treatment-experienced patients, atazanavir (boosted or unboosted) is not recommended.

Lopinavir/ritonavir and hemodialysis
Lopinavir and ritonavir also are not cleared by hemodialysis, but a pharmacokinetic study showed that hemodialysis patients receiving lopinavir/ritonavir had lower concentrations of both lopinavir and ritonavir than did historical controls with normal renal function. The lopinavir AUC was 19% lower and C _min was 44% lower; the ritonavir C _min was 45% lower.(2)

Management recommendations for patients receiving hemodialysis include the following:

	Once-daily lopinavir/ritonavir should not be used.
	Caution should be exercised with patients whose HIV virus has PI resistance mutations; lopinavir and ritonavir levels may not be adequate for viral suppression.

Other PIs
Pharmacokinetic evaluations of most other PIs in hemodialysis patients have not been conducted, and it is not known whether other PIs cause lower-than-expected drug levels in hemodialysis patients. Further studies are needed to define dosing recommendations for PIs in the setting of hemodialysis. For additional information, see ( Dosing of Antiretroviral Drugs in Adults with Chronic Kidney Disease and Hemodialysis ).

References

1. Reyataz [package insert] . Princeton, NJ: Bristol-Myers Squibb; April 2009.

2. Gupta SK, Rosenkranz SL, Cramer YS, et al. The pharmacokinetics and pharmacogenomics of efavirenz and lopinavir/ritonavir in HIV-infected persons requiring hemodialysis . AIDS. 2008 Oct 1;22(15):1919-27.

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, go to the database, click on a specific drug name, and search for the interacting agent.