Haematuria in HIV--an interactive web.A 55 kg nursing sister presented to a private hospital complaining of lower abdominal pain and frank haematuria Noun 1. haematuria - the presence of blood in the urine; often a symptom of urinary tract disease
haematocyturia, hematocyturia - the presence of red blood cells in the urine . She was assessed as having a urinary tract infection urinary tract infection (UTI),
n infection in one or more of the structures that make up the urinary system. Occurs more often in women and is most commonly caused by bacteria. , and started on ciprofloxacin. When seen at our institution a day later she complained of colicky flank and lower abdominal pain, was pale and had a pulse of 112 beats per minute beats per minute Cardiac pacing The unit of measure for the frequency of heart depolarizations or contractions each minute–or pulse rate with a blood pressure of 110/70 mmHg. There was mild left iliac fossa discomfort and a distal sensory neuropathy. She had frank haematuria, a haemoglobin concentration 4.8 g/100 ml, a platelet count of 650 x [10.sup.9]/l and an International Normalised Ratio (INR INR
In currencies, this is the abbreviation for the Indian Rupee.
The currency market, also known as the Foreign Exchange market, is the largest financial market in the world, with a daily average volume of over US $1 trillion. ) that failed to clot. She settled after transfusion of fresh frozen plasma fresh frozen plasma
n. Abbr. FFP
Blood plasma frozen within 6 hours of collection.
fresh frozen plasma and packed cells. Her INR the following day was 6.1, and 2 days later was 1.6.
She was HIV HIV (Human Immunodeficiency Virus), either of two closely related retroviruses that invade T-helper lymphocytes and are responsible for AIDS. There are two types of HIV: HIV-1 and HIV-2. HIV-1 is responsible for the vast majority of AIDS in the United States. positive and 3 months earlier had been diagnosed as having disseminated tuberculosis based on general debility debility /de·bil·i·ty/ (de-bil´i-te) asthenia.
The state of being weak or feeble; infirmity. , an elevated C-reactive protein (CRP C-reactive protein (CRP)
A protein present in blood serum in various abnormal states, like inflammation.
Mentioned in: Pelvic Inflammatory Disease
n.pr See C-reactive protein. ), and a chest X-ray showing a miliary miliary /mil·i·ary/ (mil´e-ar?e)
1. like millet seeds.
2. characterized by lesions resembling millet seeds.
1. infiltrate. She had been started on weight-appropriate standard antituberculous therapy with rifampicin, isoniazid isoniazid (ī'sōnī`əzĭd), drug used to treat tuberculosis. Also known as isonicotinic acid hydrazide, isoniazid is the most effective antituberculosis drug currently available. , pyrazinamide and ethambutol ethambutol /etham·bu·tol/ (e-tham´bu-tol) an antibacterial, specifically effective against Mycobacterium; used with one or more other antituberculous drugs in the treatment of pulmonary tuberculosis, administered as the . Two weeks later she had presented with a painful swollen left calf, and a popliteal popliteal /pop·lit·e·al/ (pop?lit´e-il) pertaining to the area behind the knee.
Relating to the poples. deep vein thrombosis A blood clot (thrombos) in a vein deep within the muscle, typically in the thigh or calf. It is caused by disease or the lack of activity such as sitting for hours at a computer screen. was confirmed on Doppler ultrasound. She was anticoagulated with heparin and then warfarin with a planned therapy duration of warfarin of 6-8 weeks, assuming satisfactory clinical response. One week later her INR was 2.02 on warfarin 10 mg daily.
She was found to have a CD4 count of 19 x [10.sup.6]/l, and was entered into the ARV programme. An INR done during the preparation phase was 1.54, while on warfarin 10 mg daily, but when she was started on antiretrovirals, the INR was 2.22 on the same dose. Her antiretroviral regimen consisted of stavudine 30 mg twice daily, lamivudine 150 mg twice daily, and efavirenz efavirenz /ef·a·vi·renz/ (ef´ah-vi?renz) an antiretroviral, inhibiting reverse transcriptase; used in the treatment of HIV infection.
n. 600 mg at night. At that stage her anti-tuberculous therapy consisted of rifampicin 600 mg daily and isoniazid 300 mg daily.
She remained on warfarin because of ongoing active tuberculosis and general debility but was not started on cotrimoxazole in order to limit pill burden and medication-associated nausea.
Three weeks after starting ARVs she presented with the life-threatening haematuria described previously. Her warfarin was discontinued, and her tuberculosis resolved gradually on treatment. Thirty months later she was well, with an undetectable viral load and a CD4 count of 395 x [10.sup.6]/l.
Many HIV-positive patients placed on ARVs either are being treated for intercurrent intercurrent /in·ter·cur·rent/ (-kur´ent) occurring during and modifying the course of another disease.
adj. opportunistic infections or develop them as part of an immune reconstitution syndrome. They may also be on other prophylactic medications. A combination of three antiretrovirals, four antituberculous agents, co-trimoxazole (two drugs) and fluconazole fluconazole /flu·con·a·zole/ (floo-kon´ah-zol) a triazoleantifungal used in the systemic treatment of candidiasis and cryptococcal meningitis.
n. is a common finding in ill AIDS patients who may also be hypoalbuminaemic and bed-ridden. Chronic meningitides or inflammatory CNS See Continuous net settlement.
See continuous net settlement (CNS). granulomata may have led to patients being placed on anti-epileptic treatment as well.
The development of deep vein thrombosis is also common under such circumstances. Warfarin is a highly protein-bound drug with a narrow therapeutic index. It is hepatically metabolised by highly inducible and inhibitable enzymes, so complex drug-drug interactions can be anticipated in the context of polypharmacy.
Exploring medication interactions in this field is complicated by the rapid rate of development and marketing of ARVs which means that sometimes clinical drug interaction studies may lag behind registration and marketing milestones. A further problem in evaluating potential medication interactions is that studies in healthy volunteers (1) may miss effects in sick older patients on multiple medications, and it is not always easy to determine the clinical magnitude of detected effects.
In our index patient, the potentially important medication interactions were between warfarin, rifampicin, efavirenz and ciprofloxacin.
A retrospective study (2) looking at the effect of ciprofloxacin on anticoagulation stability found that patients were on average 70 years old and on a mean of 6.5 different medications. Another study found that 19% of patients taking a fluoroquinolone (levofloxacin) concomitantly with warfarin developed an INR greater than 4.0, and 44% reached this level if on cotrimoxazole. (3) The mechanism for the interaction with the quinolones is unclear, but reduced protein binding and reduced metabolism have been proposed. In this patient haematuria was already present when ciprofloxacin was introduced, so it is unlikely to have been the main culprit.
Warfarin is a racemic racemic /ra·ce·mic/ (ra-se´mik) optically inactive, being composed of equal amounts of dextrorotatory and levorotatory isomers.
adj. Abbr. mixture of two enantiomers enantiomers (i·nanˑ·tē··merz),
n. that are metabolised by different inducible isoforms of the cytochrome P450 family. The more biologically active S-isomer is metabolised mainly by CYP CYP
In currencies, this is the abbreviation for the Cyprus Pound.
The currency market, also known as the Foreign Exchange market, is the largest financial market in the world, with a daily average volume of over US $1 trillion. 2C9 and the R-isomer by CYP3A4. Rifampicin induces CYP3A4-mediated metabolism (reduced levels of simvastatin, verapamil verapamil /ve·rap·a·mil/ (ve-rap´ah-mil) a calcium channel blocker that dilates coronary arteries and decreases myocardial oxygen demand, used as the hydrochloride salt in the treatment of angina pectoris and of hypertension and the and azoles such as ketoconazole and fluconazole) as well as CYP2C9-mediated metabolism (reduced levels of S-warfarin and glibenclamide). (4) Reversal of enzyme induction is seen within 2-3 weeks of stopping rifampicin, leading to potentially dangerous overanticoagulation if the higher warfarin doses are not subsequently reduced. At higher doses, isoniazid may inhibit the metabolism of warfarin, phenytoin phenytoin /phen·y·to·in/ (fen´i-toin?) an anticonvulsant used in the control of various kinds of epilepsy and of seizures associated with neurosurgery.
n. and carbamazepine carbamazepine /car·ba·maz·e·pine/ (kahr?bah-maz´e-pen) an anticonvulsant and analgesic used in the treatment of pain associated with trigeminal neuralgia and in epilepsy manifested by certain types of seizures. . (5) The clinical significance of this is usually swamped by the rifampicin effect. In this patient the INR appeared to have been stabilised on antituberculous therapy, but a late effect is possible.
Efavirenz and ritonavir ritonavir /ri·to·na·vir/ (ri-to´nah-vir) an HIV protease inhibitor used in treatment of HIV infection and AIDS.
n. are both inhibitors and inducers of CYP3A4, so their effect on warfarin and phenytoin levels is variable. (6) However, in this patient the timing of the over-anticoagulation event suggests that efavirenz was acting as an inhibitor of warfarin metabolism at that stage, and was the main contributing agent leading to her acute presentation. Stavudine and lamivudine are not major substrates of the cytochrome P450 system, so are unlikely to have contributed to this adverse event. (7) Nevirapine nevirapine /ne·vir·a·pine/ (ne-vir´ah-pen) a nonnucleoside inhibitor of HIV-1reverse transcriptase, used in combination with other antiretroviral agents in the treatment of HIV infection. is listed as an inducer of CYP3A4, leading to potentially important reductions in INR requiring higher warfarin dosages. It may also lead to lower levels of phenytoin and oral contraceptives. Ritonavir may also induce glucuronidation, potentially reducing levels of zidovudine, valproate valproate /val·pro·ate/ (val-pro´at) a salt of valproic acid; the sodium salt has the same uses as the acid.
n. , and lamotrigine. (8)
Drugs not present in this patient but commonly encountered in similar scenarios have variable and not always predictable effects on anticoagulation status. In a small study on volunteers, fluconazole inhibited the metabolism of both the S and R enantiomers of warfarin via its effects on CYP2C9 and CYP3A4 respectively. (9)
The anti-epileptics phenytoin and carbamazepine are important enzyme inducers, with potential to reduce the efficacy of the NNRTIs. For this reason it is commonly suggested that valproate may be an appropriate alternative, although it has been reported to exacerbate zidovudine-induced anaemia (10) (perhaps due to impaired zidovudine glucuronidation.)
A further possibility in this patient was differential adherence, such as continuing the same dose of warfarin but stopping or reducing antituberculous medication. On close enquiry she remained adamant that this was not the case.
Polypharmacy is common in AIDS patients, with considerable potential for serious medication interactions. Basic principles of management include:
* Ensure adequate access to details about all the medication the patient may be taking. This may entail a request for all medication at home to be brought in by a relative.
* Try to eliminate all non-essential medication during the often relatively short period that the patient will be on warfarin.
* Remember to watch for the opposite effect when stopping interacting medication in situations where ongoing anticoagulation is desirable. For example, the warfarin dose will usually need to be reduced gradually over the subsequent month after stopping rifampicin, to avoid over-anticoagulation as the induction wears off.
* In patients prescribed warfarin, the frequency of INR monitoring can be estimated from the expected timing and severity of potential interactions, which may occur either days or weeks after starting a new therapy. (11) In the absence of clear information about these, it may be advisable to err on the side of caution and opt for a 'half a week, one week, one week' guide--check the INR 3 or 4 days after the medication change, and again 1 week and then 2 weeks later, assuming no remarkable change on the first measurement. In this patient, life-threatening bleeding might have been avoided by earlier and more frequent INR testing.
(1.) Israel DS, Stotka J, Rock W, et al. Effect of ciprofloxacin on the pharmacokinetics and pharmacodynamics of warfarin. Clin Infect Dis 1996; 22: 251-256.
(2.) Ellis RJ, Mayo MS, Bodensteiner DM. Ciprofloxacin-warfarin coagulopathy: a case series. Am J Hematol 2000; 63: 28-31.
(3.) Glasheen JJ, Fugit RV, Prochazka AV. The risk of overanticoagulation with antibiotic use in outpatients on stable warfarin regimens. J Gen Intern Med 2005; 20: 653-656.
(4.) Niemi M, Backman JT, Fromm MF, et al. Pharmacokinetic interactions with rifampicin: clinical relevance. Clin Pharmacokinet 2003: 42: 819-850.
(5.) Self TH, Chrisman CR, Baciewicz AM, et al. Isoniazid drug and food interactions. Am J Med Sci 1999; 317: 304-311.
(6.) Von Moltke LL, Greenblatt DJ, Granda BW, et al. Inhibition of human cytochrome P450 isoforms by nonnucleoside reverse transcriptase inhibitors. J Clin Pharmacol 2001; 41: 85-91.
(7.) Piscitelli SC, Kelly G, Walker RE, et al. A multiple drug interaction study of stavudine with agents for opportunistic infections in human immunodeficiency virus-infected patients. Antimicrob Agents Chemother 1999; 43: 647-650.
(8.) Hirata-Koizumi M, Saito M, Miyake S, et al. Adverse events caused by drug interactions involving glucuronoconjugates of zidovudine, valproic acid and lamotrigine, and analysis of how such potential events are discussed in package inserts of Japan, UK and USA. J Clin Pharm Therapeutics 2007; 32: 177-185.
(9.) Black DJ, Kunze KL, Wienkers LC, et al. Warfarin-fluconazole II. A metabolically based drug interaction: in vivo studies. Drug Metabol Dispos 1996; 24: 422-428.
(10.) Anoniou T, Gough K, Yoong D, et al. Severe anaemia secondary to probable drug interaction between zidovudine and valproic acid. Clin Infect Dis 2004; 38: e38-40.
(11.) Harder S, Thurmann P. Clinically important drug interactions with anticoagulants. An update. Clin Pharmacokinet 1996; 30(6): 416-444.
A PARRISH, MB ChB, DA (SA), FCP (SA),
MMed (Med), MMedSci (Clin Epi)
Department of Medicine, Cecilia Makiwane
Hospital, East London
M BLOCKMAN, MB ChB, BPharm, MMed, Dip
Int Res Ethics
Division of Clinical Pharmacology, University
of Cape Town
G COLLETT, BPharm
Pharmacy Department, Cecilia Makiwane
Hospital, East London