Zambian HIV Guidelines:: Maraviroc

	Zambia HIV National Guidelines
	Introduction HIV Counseling and Testing Sexually Transmitted Infections (STIs) General Principles of Antiretroviral Therapy for Chronic HIV Infection in Adults and Adolescents When to Start ARV Therapy for Chronic HIV Infection in Adults and Adolescents Initial Regimen for ARV Therapy Adherence Baseline evaluation and Monitoring Calculations: Ideal Body Weight, Body Mass Index and Creatinine Clearance ARV Therapy for Individuals with Tuberculosis Co-Infection Adverse Effects and Toxicity Immune Reconstitution Inflammatory Syndrome (IRIS) Changing or Stopping ART Treatment Failure Stopping ARV Therapy Post Exposure Prophylaxis Cotrimoxazole Prophylaxis WHO Staging in Adults and Adolescents Nutrition Care and Support Palliative Care in HIV and AIDS
	Guide Editors
	Editor In Chief Joel E. Gallant, MD, MPH Pharmacology Editor Paul Pham, PharmD, BCPS Zambia Guideline Team Peter Mwaba MMed PhD FRCP Alywn Mwinga MMed Isaac Zulu MMed MPH Velepie Mtonga MMed Albert Mwango MBChB Jabbin Mulwanda MMed FCS

Drugs>Antiretrovirals>

Maraviroc

Maureen M. Forrestel, Pharm.D. and Paul A. Pham, Pharm.D.
04-24-2008

Currently not available in Zambia.
Active against NRTI-, NNRTI-, and PI-resistant strains, but patients must tested for R5-tropism before MVC use (cost of tropism assay (Trofile) approx. $2000, and not available in Zambia)

Zambia Information Author: Paul A. Pham, Pharm. D.

INDICATIONS

FDA

Used in combination with other antiretroviral agents in treatment-experienced adult patients infected with CCR5 (R5)-tropic HIV-1.

FORMS

brand name	generic	Mfg	brand forms	cost*
Selzentry (U.S); Celsentri (Europe)	Maraviroc (MVC)	Pfizer	oral tablet 150 mg and 300 mg	Approx. $900/month

*Prices represent cost per unit specified and are representative of "Average Wholesale Price" (AWP). AWP Prices were obtained and gathered by Lakshmi Vasist Pharm D using the Red Book, manufacturer's information, and the McKesson database.

^Dosage is indicated in mg unless otherwise noted.

USUAL ADULT DOSING

MVC 300 mg PO bid with or without food
With PIs (except TPV/r) : MVC 150 mg PO bid. (use standard dose with TPV/r)
With LPV/r + EFV: MVC 150 mg PO bid
With SQV/r + EFV: MVC 150 mg PO bid
With EFV: MVC 600 mg PO bid
With NVP: no data, consider MVC 300 mg PO bid
With DLV: MVC 150 mg PO bid

RENAL DOSING

DOSING FOR GLOMERULAR FILTRATION OF 50-80

Usual dose.

DOSING FOR GLOMERULAR FILTRATION OF 10-50

Usual dose likely.

DOSING FOR GLOMERULAR FILTRATION OF <10 ML/MIN

Usual dose likely.

DOSING IN HEMODIALYSIS

Usual dose likely. Dose post-HD on days of dialysis.

DOSING IN PERITONEAL DIALYSIS

Usual dose likely.

DOSING IN HEMOFILTRATION

Usual dose likely.

ADVERSE DRUG REACTIONS

GENERAL

MVC generally well tolerated in clinical trials, with similar rates of study discontinuation vs. placebo.

COMMON

Diarrhea, nausea, headache and fatigue, that occurred at rates similar to or less than those of placebo.

OCCASIONAL

Cough, fever and upper respiratory tract infection (pneumonia was uncommon)
Rash
AST/ALT elevation
CK elevation
Myalgia
Abdominal pain
Dizziness
Orthostatic hypotension (dose dependent, uncommon at the recommended dose)

RARE

Hepatotoxicity with allergic features (rash, eosinophilia, elevated IgE)
Cardiac events related to coronary artery disease (1.3%)

DRUG INTERACTIONS

MVC does not inhibit or induce CYP3A4. As MVC is a substrate of CYP 3A4 and P-gp, the dose should be adjusted when co-administered with CYP3A4 and/or P-gp inhibitors or inducers. Drug-drug interactions are unlikely with NRTIs and enfuvirtide.

Drug-to-Drug Interactions

Drug-to-Drug Interaction

Drug	Effect of Interaction	Recommendations/Comments
Nevirapine	MVC serum concentration was not significantly affected compared to historical controls in a single dose study; however, MVC AUC may be decreased at steady state.	Dose: MVC 300 mg bid + standard dose NVP.
Efavirenz	MVC AUC decreased by 45%.	Increase MVC to 600 mg bid with EFV co-administration.
Atazanavir	MVC AUC increased 257%	Decrease MVC to 150 mg bid with ATV co-administration.
Tenofovir	No significant interaction	Use standard doses. MVC 300 mg bid.
Delavirdine	May increase MVC serum concentrations	Dose: MVC 150 mg bid.
Erythromycin	May increase MVC serum concentrations	Dose: MVC 150 mg bid.
Saquinavir/ritonavir	MVC AUC increased 732%	Decrease MVCto 150 mg bid with SQV/r co-administration.
Lopinavir/ritonavir	MVC AUC increased 283%	Decrease MVCto 150 mg bid with LPV/r co-administration.
Atazanavir/ritonavir	MVC AUC increased 388%	Decrease MVC to 150 mg bid with ATV/r co-administration.
Tipranavir/ritonavir	No significant interaction	Use standard doses. MVC 300 mg bid.
Lopinavir/ritonavir + efavirenz	MVC AUC increased 153%	Decrease MVC to 150 mg bid with LPV/r+EFV co-administration.
Saquinavir/ritonavir + efavirenz	MVC AUC increased 400%	Decrease MVC to 150 mg bid with SQV/r+EFV co-administration.
Darunavir/ritonavir	MVC AUC increased 344% with co-administration.	Decrease MVC to 150 mg bid with DRV/r co-administration.
Carbamezapine	MVC AUC may significantly decrease with carbamezapine co-administration.	Increase MVC to 600 mg bid with co-administration, or consider alternative anticonvulsant (i.e valproic acid or levetiracetam).
Clarithromycin	May increase MVC serum concentrations	Dose: MVC 150 mg bid.
Ethinylestradiol	No significant interaction	Use standard doses. Consider an additional barrier form of contraception.
Itraconazole	May increase MVC serum concentrations	Dose: MVC 150 mg bid.
Ketoconazole	MVC AUC increased 5-fold with co-administration.	Dose: MVC 150 mg bid.
Levonorgestrel	No significant interaction	Use standard doses. Consider an additional barrier form of contraception.
Midazolam	Midazolam AUC increased by 18%.	Unlikely to be clinically significant.Use standard doses.
Nefazodone	May increase MVC serum concentrations	Dose: MVC 150 mg bid.
Phenobarbital	MVC AUC may significantly decrease with phenobarbital co-administration.	Increase MVC to 600 mg bid with co-administration, or consider alternative anticonvulsant (i.e valproic acid or levetiracetam).
Phenytoin	MVC AUC may significantly decrease with phenytoin co-administration.	Increase MVC dose to 600 mg bid with co-administration, or consider alternative anticonvulsant (i.e valproic acid or levetiracetam).
Rifabutin	May decrease MVC serum concentrations	Increase MVC to 600 mg bid with co-administration.
Rifampin	MVC AUC decreased 66% with co-administration.	Increase MVC to 600 mg bid with co-administration.
Sulfamethoxazole-trimethoprim	MVC AUC increased 10%	Use standard dose. MVC 300 mg bid.
Telithromycin	May increase MVC serum concentrations	Dose: MVC 150 mg bid.

RESISTANCE

MVC-resistant viruses that emerged in vitro contained amino acid substitutions/deletions in the V3 loop of the HIV-1 envelope (gp120), with the primary substitutions isolated being A19T and I26V. MVC failure can also be due to a tropism shift, leading to the emergence of X4 or dual/mixed-tropic virus that is not inhibited by MVC. Tropism shifts probably represent selection of pre-existing minority variants rather than true shift of R5-tropic virus.

PHARMACOLOGY

Pharmacology

COMMENTS

MVC is the first CCR antagonist. There is no cross-resistance to currently available drugs. MVC was effective when used in combination with OBT in heavily treatment-experienced pats with R5-tropic virus and multiple resistance mutations who were failing therapy. Use of MVC in these pts resulted in a mean VL reduction of almost 2 logs andVL suppression to </-50 in 45% of treated pts.

MVC not recommended in pts with dual/mixed (D/M)- or X4-tropic virus due to lack of efficacy.
Tropism assay should be performed prior to initiation of treatment with MVC. The Trofile™ (Monogram Biosciences, Inc.) co-receptor tropism assay is the only commercially available assay; it detectspresence of R5-, X4-, or dual/mixed-tropic virus.
Tropism assay requires VL >1000, which means that MVC cannot be used to substitute for other drugs in a suppressive regimen.
Sensitivity of tropism assay to detect D/M or X4-tropic virus is 100% when it comprises at least 10% of total viral population, and 83%when it comprises at least 5% of population. In MOTIVATE trials 7.6% of participants had R5-tropic virus at screening but had D/M-tropic virus at baseline (4-6 wks later), presumably representing failure of initial assay to detect D/M- or X4-tropic virus present at low levels.
Samples can be sent to Monogram Biosciences for processing, either directly or by the processing laboratory. Practitioners should contact Monogram Biosciences, Inc. for further information on sample processing and reimbursement (http://www.trofileassay.com).
Although MVC clearly has a role in the management of treatment-experienced pts, the lack of long-term safety data, non-viral target, high cost of the tropism assay, inconvenience of bid dosing, and failure to meet non-inferiority threshold compared to EFV for <50 threshold in the MERIT trial MVC is unlikely be used in treatment-naive pts in the near future.

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