Response letter to H Honda et al. – Raltegravir use in warfarin treated HIV patients ( Int J STD AIDS 2012;23:903–904)

Sirs,

I read with interest the case report by H Honda et al., on “Safe use of raltegravir in HIV-1 infected patients treated with warfarin.” I wish to share my experience on this subject.

A 40-year-old woman (diagnosed HIV positive in 1997) had multi-class drug resistance and had achieved an undetectable viral load since 2008 with a regimen consisting of Truvada (tenofovir/emtricitabine) one tablet once daily, darunavir/ritonavir 600/100 mg twice daily and raltegravir 400 mg twice daily. She developed a large thrombus in the left common femoral vein extending into the left profunda vein following 10 h travel. She was started immediately on low-molecular weight heparin; after a loading dose of warfarin and serial titration of dose, the therapeutic INR (international normalized ratio) was achieved after 15 days. She needed an average dose of 33 mg per day of warfarin, overall weekly dose of 210 mg (see Table 1). Her viral load remained undetectable while on warfarin.

OPEN IN VIEWER

Table 1.

Warfarin dosing schedule in our patient.

Dosing schedule for warfarin	INR (international normalised ratio)	Comments
Days 1–3	Loading dose 6, 6 and 3 mg	1.0	Loading dose reduced in anticipation of drug-interactions (normal loading dose 9, 9, 1.5 mg according to Trust Guidance)
Days 4–8	12–15 mg	1.3	INR checked every two days till therapeutic range achieved.
Day 10	30 mg	1.4
Day 12	33–35 mg	1.8
Day 15	33–35 mg	2.5	First therapeutic INR (range 2–3)
Days 16–90	Average dose 33 mg	Median INR 3.5; (range 2.6–5.8)	INR checked every 4–5 days. Minor fluctuations but always above the therapeutic minimum.

Patients needing more than 15 mg/day of warfarin are considered warfarin resistant. ¹ Warfarin resistance can be classified as acquired or hereditary. Acquired resistance may be due to poor compliance, high vitamin K consumption, increased clearance and drug interactions. Hypoalbuminaemia, hyperalbuminaemia, hyperlipidaemia, diuretics and genetic factors leading to accelerated metabolism are pharmacokinetic factors that cause warfarin resistance. Warfarin differs from other drugs in that the dosage required varies among individuals due to factors mentioned above. Warfarin is a mixture of two enantiomers (mirror image isomers), S and R, and is metabolised by cytochrome P450 enzymes. S enantiomer is more potent and responsible for 60–70% of overall response but is metabolised faster and R enantiomer has a longer half-life. Duplication or multiplication of cytochrome P450 genes can contribute to a phenotype of rapid metabolism. Twice-daily darunavir can reduce the exposure of S-warfarin by 21%. ² Failure to achieve the desired therapeutic effect may lead to new thrombosis or, in the other extreme, life-threatening haemorrhage.

In our patient it is likely that she had more than one factor that led to accelerated metabolism, and hence the higher warfarin dose requirement. In the current era of combination antiretroviral therapy with people achieving a near-normal life-expectancy, the need for anti-coagulation because of various factors including heart valve replacements, cardiac arrhythmias, deep vein thromboses and pulmonary embolism are bound to rise and hence HIV physicians need to be more aware of not only the well-known drug interactions but also the pharmacokinetic and genetic factors that may play a role in the metabolism of warfarin. In patients on antiretroviral therapy needing long-term anticoagulants although the preferred choice is to choose a regimen with no significant interaction, this option is not always available in multi-drug resistant patients in whom protease inhibitors form a very important part of their regimen. To conclude, warfarin can be used in patients on boosted protease and raltegravir regimens provided very close observation and monitoring are maintained.