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HIV Medicine 2007 818 pages Download PDF, 3.7 MB Collaborators About  Other Languages 2007 Portuguese Vietnamese 2005 Russian Spanisch 2003 Persian (Farsi) Copyright Removal Mailing List Privacy
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32. Drugs
by Bernd Sebastian Kamps
and Christian Hoffmann
Download of HIV Medicine 2007
32. Drug Profiles
Bernd Sebastian Kamps and Christian Hoffmann
3TC - Lamivudine
A well-tolerated cytidine analog. Rapid development of resistance: only one point mutation (M184V)
is required, which, however, increases the sensitivity of AZT-resistant viruses and reduces viral
fitness. Also effective against hepatitis B virus.
Trade name: Epivir™; component of Combivir™, Trizivir™, and Kivexa™.
Epivir™ tablets: 150 mg or 300 mg; Epivir™ solution 10 mg/ml
Combivir™ tablets: 150 mg 3TC + 300 mg AZT
Trizivir™ tablets: 150 mg 3TC + 300 mg AZT + 300 mg abacavir
KivexaÔ tablets: 300 mg 3TC + 600 mg abacavir
Zeffix™ tablets: 100 mg. Only for HBV, never for HIV!!! (dose is too low!).
Drug class: (NRTI)
Manufacturer: GlaxoSmithKline
Indication: HIV infection (also chronic hepatitis B)
Oral dose: 300 mg qd or 150 mg bid. Children receive 4 mg/kg, up to a maximum of 150 mg bid. With
poor liver function, in particular reduced creatinine clearance, use just Epivir™ instead of the
combined preparations and adjust the dose.
CrCl (ml/min) Dose
30-49 150 mg qd
15-29 150 mg first dose, then 100 mg qd
5-14 150 mg first dose, then 50 mg qd
<5 50 mg first dose, then 25 mg qd
Side effects: rare when using the individual drug. Fatigue, nausea, vomiting, diarrhea, headache,
insomnia, myalgia are usually due to AZT and abacavir. Peripheral polyneuropathy, and very rarely
pancreatitis, lactic acidosis and anemia.
Internet sources:
USA: Epivir™: http://hiv.net/link.php?id=49
Combivir™: http://hiv.net/link.php?id=50
Trizivir™: http://hiv.net/link.php?id=51
References:
1. Bani-Sadr F, Palmer P, Scieux C, Molina JM. Ninety-six-week efficacy of combination therapy with
lamivudine and tenofovir in patients coinfected with HIV-1 and wild-type hepatitis B virus. Clin
Infect Dis 2004; 39: 1062-4. http://amedeo.com/lit.php?id=15472862
2. DeJesus E, McCarty D, Farthing CF, et al. Once-daily versus twice-daily lamivudine, in
combination with zidovudine and efavirenz, for the treatment of antiretroviral-naive adults with HIV
infection: a randomized equivalence trial. Clin Infect Dis 2004; 39: 411-8.
http://amedeo.com/lit.php?id=15307010
3. Miller V, Stark T, Loeliger AE, Lange JM. The impact of the M184V substitution in HIV-1 reverse
transcriptase on treatment response. HIV Med 2002, 3:135-45. http://amedeo.com/lit.php?id=12010361
4. Sension MG, Bellos NC, Johnson J, et al. Lamivudine 300 mg QD versus continued lamivudine 150 mg
BID with stavudine and a protease inhibitor in suppressed patients. HIV Clin Trials 2002; 3:361-70.
http://amedeo.com/lit.php?id=12407485
Abacavir (ABC
A guanosine analog with good CNS penetration; a component of some combination preparations. The
hypersensitivity reaction (HSR) is a substantial problem (see below); otherwise well tolerated, with
little mitochondrial toxicity.
Trade name: Ziagen™; component of Kivexa™/ Epzicom™ and Trizivir™
Ziagen™ tablets: 300 mg; Ziagen™ solution 20 mg/ml.
Kivexa/Epzicom™ tablets: 600 mg abacavir + 300 mg 3TC
Trizivir™ tablets: 300 mg abacavir + 150 mg 3TC + 300 mg AZT
Drug class: NRTI
Manufacturer: GlaxoSmithKline
Indications: HIV infection
Oral dose: 300 mg bid or 600 mg qd, with or without food.
Side effects: hypersensitivity reactions (HSR) in 2 to 8 %, usually within the first six weeks.
Pruritus and rash are common, but may also be absent. The HSR may present as just fever and slowly
developing malaise. Gastrointestinal complaints and fatigue are also possible. Elevated liver
function tests, insomnia and dizziness are rare.
Comments/Warnings: contraindicated in cases with abacavir hypersensitivity and after interruption of
therapy, if a prior HSR cannot be ruled out in retrospect. Re-exposure can cause acute
life-threatening HSR! With only mild symptoms (see below), abacavir should not be stopped too
quickly, as an intercurrent infection may simulate the HSR. Often, it is possible to observe the
course for one or two days. There is a genetic predisposition (HLA-Typ B5701), and HLA typing may
help in the future to reduce the risk of HSR. Patients should consult a doctor immediately if at
least two of the following symptoms occur:
§ fever
§ shortness of breath, sore throat or cough
§ rash (erythema and/or pruritus)
§ nausea or vomiting or diarrhea or abdominal pain
§ extreme fatigue, diffuse pain or general malaise
Interactions: 0.7 g/kg ethanol (e.g. 0.5 l wine) increases the AUC of abacavir by 41 % and increases
half-life by 26 %.
Internet sources:
USA: http://hiv.net/link.php?id=53
References:
1. Carr A, Workman C, Smith DE, et al. Abacavir substitution for nucleoside analogs in patients with
hiv lipoatrophy: a randomized trial. JAMA 2002, 288: 207-15. http://amedeo.com/lit.php?id=12095385
2. DeJesus E, Herrera G, Teofilo E, et al. Abacavir versus zidovudine combined with lamivudine and
efavirenz, for the treatment of antiretroviral-naive HIV-infected adults. Clin Infect Dis 2004; 39:
1038-46. http://amedeo.com/lit.php?id=15472858
3. Hewitt RG. Abacavir hypersensitivity reaction. Clin Infect Dis 2002, 34: 1137-42.
http://amedeo.com/lit.php?id=11915004
4. Mallal S, Nolan D, Witt C, et al. Association between presence of HLA-B*5701, HLA-DR7, and
HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet 2002, 359:
727-32. http://amedeo.com/lit.php?id=11888582
5. Martin A, Smith DE, Carr A, Ringland C, Amin J, Emery S et al. Reversibility of lipoatrophy in
HIV-infected patients 2 years after switching from a thymidine analogue to abacavir: the MITOX
Extension Study. AIDS 2004; 18: 1029-36. http://amedeo.com/lit.php?id=15096806
6. Moyle GJ, DeJesus E, Cahn P, et al. Abacavir once or twice daily combined with once-daily
lamivudine and efavirenz for the treatment of antiretroviral-naive HIV-infected adults. J AIDS 2005;
38: 417-25. Abstract: http://amedeo.com/lit.php?id=15764958
Acyclovir
Trade name: Zovirax™ (among many others)
Drug class: virostatic
Manufacturer: manufactured by several companies. Generics are generally cheaper than the originally
introduced formulation (Zovirax™).
Indications: treatment and prophylaxis of HSV and VZV infections.
Dose: for genital HSV infection: 400 mg po 5x/day for 7 days. In severe cases (ulcerating genital
herpes) intravenous treatment with 5-10 mg/kg iv tid. For HSV encephalitis or HSV esophagitis 10
mg/kg iv tid.
For dermatomal herpes zoster 800 mg po 5x/day for 7 days. In cases of disseminated or complicated
herpes zoster 10 mg/kg iv tid.
Side effects: rare. Headache, nausea and elevation of creatinine may occur. Phlebitis can occur with
intravenous dosing.
Comments/Warnings: Initiation of treatment for HSV should be within the first 24 hours after
appearance of symptoms if possible, for VZV within the first 4 days. Adequate fluid intake is
important.
Internet sources:
USA: http://hiv.net/link.php?id=55
References:
1. Conant MA, Schacker TW, Murphy RL, et al. Valaciclovir versus aciclovir for herpes simplex virus
infection in HIV-infected individuals: two randomized trials. Int J STD AIDS 2002, 13:12-21.
http://amedeo.com/lit.php?id=11802924
2. Gnann JW Jr, Whitley RJ. Clinical practice. Herpes zoster. N Engl J Med 2002, 347:340-6.
3. Ioannidis JP, Collier AC, Cooper DA, et al. Clinical efficacy of high-dose acyclovir in patients
with HIV infection: a meta-analysis of randomized individual patient data. J Infect Dis 1998,
178:349-59. http://amedeo.com/lit.php?id=9697714
4. Wagstaff AJ, Faulds D, Goa KL. Aciclovir. A reappraisal of its antiviral activity,
pharmacokinetic properties and therapeutic efficacy. Drugs 1994; 47:153-205.
http://amedeo.com/lit.php?id=7510619
Agenerase™ see Amprenavir
Ambisome™ see Amphotericin B
Amphotericin B
Trade names: Amphotericin B™, Ambisome™
Amphotericin B™: 50 mg amphotericin B powder/bottle
Liposomal amphotericin B: 50 mg vials of Ambisome™
Drug class: antimycotic
Manufacturer: Amphotericin B™: Bristol-Myers Squibb; Ambisome™: Gilead
Indications: Fungal infections, including aspergillosis, cryptococcosis, treatment-resistant
candidiasis, histoplasmosis, coccidioidomycosis.
Indications for Ambisome™: life-threatening situations with the mycoses listed above. Mainly in
cases of pre-existing impaired renal function, elevations in creatinine on amphotericin B
(creatinine > 2.0 mg/dl) or poor tolerability of amphotericin B infusions.
Ambisome™ is very expensive!
Dose (per day) of amphotericin B™:
Aspergillosis: 1.0 to 1.5 mg/kg
Candidiasis: 0.2 to 0.8 mg/kg
Coccidioidomycosis: 0.5 to 1.0 mg/kg
Cryptococcosis: 0.7 to 1.0 mg/kg
Histoplasmosis: 0.5 to 1.0 mg/kg
Dose of Ambisome™: initial daily dose of 1 mg/kg, if necessary this may be gradually increased to 3
mg/kg.
Side effects: nephrotoxicity! Hypokalemia! Gastrointestinal complaints. Frequent: fever, chills, and
hypotension approx. 10-20 min after starting infusion. Thrombophlebitis. Side effects are generally
less severe with Ambisome™.
Comments/Warnings: monitor daily electrolytes (central venous line because of hypokalemia and
usually necessary substitutions! Sodium should be kept at normal levels), creatinine, urea, ALT,
blood count. Do not combine with other nephrotoxic drugs.
Always prehydrate with 1000 ml 0.9 % NaCl. First test dose always with 5 mg in 250 ml 5 % glucose
over 30-60 min under monitoring of blood pressure and pulse for the first hour. If the test dose is
tolerated, half of the planned maintenance dose may subsequently be given on the same day. In cases
of fever/chills (can be impressive!): 50 mg pethidine iv plus 1 ampule clemastine (Tavegil™), may be
repeated after 30 min; steroids if complaints persist (prednisolone 1 mg/kg).
If side effects are severe, switch to Ambisome™, which is probably not more effective (apyrexia,
survival) than amphotericin B, but better tolerated and less nephrotoxic (no test dose, no
prehydration, no central line necessary). Never mix amphotericin infusions, and always protect from
light. Infuse slowly! The longer the infusion time (>3 hours), the better the tolerability! Always
use 5 % glucose as a diluent!
Internet sources:
USA: Ambisome™: http://hiv.net/link.php?id=58
References:
1. Arathoon EG, Gotuzzo E, Noriega LM, et al. Randomized, double-blind, multicenter study of
caspofungin versus amphotericin b for treatment of oropharyngeal and esophageal candidiases.
Antimicrob Agents Chemother 2002, 46: 451-7. http://amedeo.com/lit.php?id=11796357
2. Baddour LM, Perfect JR, Ostrosky-Zeichner L. Successful use of amphotericin B lipid complex in
the treatment of cryptococcosis. Clin Infect Dis 2005; 40: Suppl 6: Abstract:
http://amedeo.com/lit.php?id=15809927
3. Barchiesi F, Spreghini E, Schimizzi AM, et al. Posaconazole and amphotericin B combination
therapy against Cryptococcus neoformans infection. Antimicrob Agents Chemother 2004; 48: 3312-6.
http://amedeo.com/lit.php?id=15328090
4. Coukell AJ, Brogden RN. Liposomal amphotericin B. Therapeutic use in the management of fungal
infections and visceral leishmaniasis. Drugs 1998, 55:585-612. http://amedeo.com/lit.php?id=9561346
5. Johnson PC, Wheat LJ, Cloud GA, et al. Safety and efficacy of liposomal amphotericin B compared
with conventional amphotericin B for induction therapy of histoplasmosis in patients with AIDS. Ann
Intern Med 2002, 137:105-9. http://amedeo.com/lit.php?id=12118965
6. Larsen RA, Bauer M, Thomas AM, Graybill JR. Amphotericin B and fluconazole, a potent combination
therapy for cryptococcal meningitis. Antimicrob Agents Chemother 2004; 48: 985-91.
http://amedeo.com/lit.php?id=14982793
Amprenavir
Amprenavir should be replaced by fosamprenavir (see relevant section). Only the pediatric
formulations are still available.
Trade name: Agenerase™
Soft capsules 50 mg.
Solution: 15 mg pro ml.
Drug class: protease inhibitor
Manufacturer: GlaxoSmithKline
Indications: Pediatric HIV patients with previous PI-treatment.
Oral dose: According to body weight: 2 x 20 mg/kg (capsules). 2 x 22.5 mg/kg (solution) - the
bioavailability of amprenavir oral solution is about 14 % less.
Side effects: mostly gastrointestinal. Occasional headache, fatigue, and rash in 5-10 %. See also
Fosamprenavir.
Comments/Warnings: amprenavir solution contains 50 % propylene glycol. It is therefore
contraindicated for concurrent administration with metronidazole.
Internet sources:
USA: Capsules: http://hiv.net/link.php?id=61
Solution: http://hiv.net/link.php?id=62
Combination with ritonavir: http://hiv.net/link.php?id=63
References:
1. Chapman TM, Plosker GL, Perry CM. Fosamprenavir: a review of its use in the management of
antiretroviral therapy-naive patients with HIV infection. Drugs 2004; 64: 2101-24.
http://amedeo.com/lit.php?id=15341507
2. Yogev R, Kovacs A, Chadwick EG, Homans JD, Lou Y, Symonds WT. Single-dose safety and
pharmacokinetics of amprenavir (141W94), a human immunodeficiency virus type 1 (HIV-1) protease
inhibitor, in HIV-infected children. Antimicrob Agents Chemother 2005; 49: 336-41. Abstract:
http://amedeo.com/lit.php?id=15616313
Atazanavir
Relatively well tolerated PI which can be given once daily. Favorable lipid profile in comparison to
other PIs. The most important side effects are elevated bilirubin levels, which not unusually
manifest as jaundice
Trade name: Reyataz™; abbr. AZV.
Hard capsules: 150 and 200 mg
Drug class: protease inhibitor (PI)
Manufacturer: Bristol-Myers Squibb
Indications: treatment-experienced adults with therapy failure.
Oral dose: 300 mg once daily combined with 100 mg ritonavir once daily, and taken with a meal.
Potentially can be given unboosted in cases with ritonavir intolerance: 400 mg once a day (not
officially licensed!).
Side effects: very frequent: hyperbilirubinemia (up to 50 %) also with jaundice,; more rarely
elevated transaminases. Diarrhea, nausea, vomiting, headache, insomnia, abdominal pain. In contrast
to other PIs: No dyslipidemia. The effect on lipodystrophy remains unknown. QT prolongation.
Comments/Warnings: capsules should be swallowed without chewing.
The following are contraindicated: cisapride, pimozide, midazolam, triazolam, simvastatin,
lovastatin, ergotamines, and calcium antagonists. Life-threatening interactions are possible with
concomitant administration of amiodarone, lidocaine (systemic dosing), tricyclic antidepressants and
quinidine (measure plasma levels!).
It should not be given with rifampin (reduces plasma levels of atazanavir by 90 %), St. John's wort,
and antacids; caution with sildenafil, vardenafil.
Caution proton pump inhibitors, antacids (see Interactions)!
When combined with efavirenz, the dose of ATV should be increased to 400 mg. With tenofovir, always
boost with ritonavir.
Do not combine with indinavir.
Rifabutin: reduce rifabutin dose by 75 % (instead of 300 mg daily, give only 150 mg every other day
or three times per week).
Clarithromycin: do not combine with boosted atazanavir.
Caution in liver damage. Contraindicated in liver cirrhosis, Child Pugh B and C.
Contraception: an alternative to the pill is recommended.
Internet sources:
USA: http://hiv.net/link.php?id=224
References:
1. Barreiro P, Rendon A, Rodriguez-Novoa S, Soriano V. Atazanavir: the advent of a new generation of
more convenient protease inhibitors. HIV Clin Trials 2005; 6: 50-61. Abstract:
http://amedeo.com/lit.php?id=15765311
2. Burger DM, Agarwala S, Child M, Been-Tiktak A, Wang Y, Bertz R. Effect of rifampin on
steady-state pharmacokinetics of atazanavir with ritonavir in healthy volunteers. Antimicrob Agents
Chemother 2006; 50: 3336-42. Abstract: http://amedeo.com/lit.php?id=17005814
3. Colombo S, Buclin T, Cavassini M, et al. Population pharmacokinetics of atazanavir in patients
with human immunodeficiency virus infection. Antimicrob Agents Chemother 2006; 50: 3801-8. Abstract:
http://amedeo.com/lit.php?id=16940065
4. Colonno R, Rose R, McLaren C, Thiry A, Parkin N, Friborg J. Identification of I50L as the
signature atazanavir (ATV)-resistance mutation in treatment-naive HIV-1-infected patients receiving
ATV-containing regimens. J Infect Dis 2004; 189: 1802-10. http://amedeo.com/lit.php?id=15122516
5. Goldsmith D, Perry C. Atazanavir. Drugs 2003; 63: 1679-93. http://amedeo.com/lit.php?id=12904086
6. Havlir DV, O'Marro SD. Atazanavir: new option for treatment of HIV infection. Clin Infect Dis
2004; 38: 1599-604. http://amedeo.com/lit.php?id=15156449
7. Johnson M, Grinsztejn B, Rodriguez C, et al. 96-week comparison of once-daily
atazanavir/ritonavir and twice-daily lopinavir/ritonavir in patients with multiple virologic
failures. AIDS 2006; 20: 711-8. Abstract: http://amedeo.com/lit.php?id=16514301
8. Mobius U, Lubach-Ruitman M, Castro-Frenzel B, et al. Switching to atazanavir improves metabolic
disorders in antiretroviral-experienced patients with severe hyperlipidemia. J Acquir Immune Defic
Syndr 2005; 39: 174-80. Abstract: http://amedeo.com/lit.php?id=15905733
9. Murphy RL, Sanne I, Cahn P, Phanuphak P, Percival L, Kelleher T et al. Dose-ranging, randomized,
clinical trial of atazanavir with lamivudine and stavudine in antiretroviral-naive subjects: 48-week
results. AIDS 2003; 17: 2603-14. http://amedeo.com/lit.php?id=14685054
10. Taburet AM, Piketty C, Chazallon C, et al. Interactions between atazanavir-ritonavir and
tenofovir in heavily pretreated human immunodeficiency virus-infected patients. Antimicrob Agents
Chemother 2004; 48: 2091-6. http://amedeo.com/lit.php?id=15155205
Atovaquone
Trade names: Wellvone™, Mepron™
Suspension with 750 mg/5 ml
Drug class: antibiotic
Manufacturer: GlaxoSmithKline
Indications: PCP prophylaxis in cases of cotrimoxazole hypersensitivity; reserve drug for mild to
moderate PCP cases and for cerebral toxoplasmosis.
Dose: for treatment 750-1,500 mg bid (1-2 measuring spoons of 5 ml bid) for 21 days. For prophylaxis
750 mg bid (1 measuring spoon of 5 ml bid) or 1,500 mg qd.
Side effects: gastrointestinal complaints such as nausea, vomiting and diarrhea are frequent (often
mild), as are rashes, which occur in approx. 20 %. More rarely headache, insomnia. Elevated liver
enzymes, elevated amylase. Anemia, leucopenia (rare).
Comments/Warnings: take atovaquone where possible with fatty dishes, as this improves absorption. In
most countries, atovaquone is considerably more expensive than other drugs for PCP prophylaxis.
Rifampin, possibly also rifabutin lower plasma levels of atovaquone by approx. 50 %. The combination
with these two drugs is therefore not recommended. Fluconazole probably increases levels.
Lopinavir seems to lower the plasma concentration of atovaquone. Dose adjustment may be necessary.
Internet sources:
UK: http://hiv.net/link.php?id=174
References:
1. Chirgwin K, Hafner R, Leport C, et al. Randomized phase II trial of atovaquone with pyrimethamine
or sulfadiazine for treatment of toxoplasmic encephalitis in patients with AIDS: ACTG 237/ANRS 039
Study. Clin Infect Dis 2002, 34:1243-50. http://amedeo.com/lit.php?id=11941551
2. El-Sadr WM, Murphy RL, Yurik TM, et al. Atovaquone compared with dapsone for the prevention of
Pneumocystis carinii pneumonia in patients with HIV infection who cannot tolerate trimethoprim,
sulfonamides, or both. N Engl J Med 1998, 339:1889-95. http://amedeo.com/lit.php?id=9862944
3. Hughes WT, Dankner WM, Yogev R, et al. Comparison of atovaquone and azithromycin with
trimethoprim-sulfamethoxazole for the prevention of serious bacterial infections in children with
HIV infection. CID 2005; 40: 136-45. http://amedeo.com/lit.php?id=15614703
4. Rosenberg DM, McCarthy W, Slavinsky J, et al. Atovaquone suspension for treatment of Pneumocystis
carinii pneumonia in HIV-infected patients. AIDS 2001, 15:211-4.
http://amedeo.com/lit.php?id=11216929
Atripla®
Atripla® is the first complete HAART in a single combination tablet (300 mg tenofovir, 200 mg
emtricitabin and 600 mg efavirenz), which in addition, ony needs to be taken once daily. Atripla®
was licensed in 2006 in the USA; the license in Europe is expected at the end of 2007.
Manufacturer: Gilead, Bristol-Myers Squibb, MSD
Indications: Adult patients with HIV infection.
Dose: 1 tablet in the evening on an empty stomach (half an hour before or 2 hours after eating).
Contra-indications, side effects: see also the sections on Truvada® und Sustiva®.
Internet sources:
UK: http://hiv.net/link.php?id=260
References:
1. Frampton JE, Croom KF. Efavirenz/emtricitabine/tenofovir disoproxil fumarate: triple combination
tablet. Drugs 2006; 66: 1501-12 Abstract: http://amedeo.com/lit.php?id=16906786
2. Gallant JE, DeJesus E, Arribas JR, et al. Tenofovir DF, emtricitabine, and efavirenz vs.
zidovudine, lamivudine, and efavirenz for HIV. N Engl J Med 2006; 354: 251-60. Abstract:
http://amedeo.com/lit.php?id=16421366
Azithromycin
Trade names: Ultreon™, Zithromax™, Azithromycin-CT™, diverse generics
Ultreon™ tablets with 600 mg
Zithromax™ tablets with 250 mg and 500 mg
Zithromax™ powder for suspension with 200 mg per 5 ml
Drug class: macrolide antibiotic
Manufacturer: Pfizer, Mack-Illert, various other companies
Indications: treatment and prophylaxis of MAC infection. Infections of the upper and lower
respiratory tract, otitis media. Uncomplicated gonorrhea, uncomplicated genital infections with
Chlamydia trachomatis, chancroid.
Dose: primary prophylaxis of MAC infection: 1,200 mg weekly (2 tablets Ultreon™ 600 mg per week).
MAC treatment: 1 tablet Ultreon™ 600 mg qd, only in combination with ethambutol and rifabutin.
Uncomplicated gonorrhea: 1,000 mg azithromycin as a single dose.
Uncomplicated genital infections with Chlamydia trachomatis: if an alternative to doxycycline is
needed, 1,000 mg azithromycin may be given as a single dose.
Chancroid: 1,000 mg azithromycin as a single dose.
Side effects: mainly gastrointestinal with stomach cramps, nausea, vomiting, diarrhea. Rarely,
elevations of transaminases, cholestatic jaundice. Reversible ototoxicity with high doses. Rarely
taste disturbances.
Comments/Warnings: caution in cases of known macrolide allergy! Reduced absorption of azithromycin
with concurrent dosing of Mg- and Al-containing antacids. These drugs should be taken one hour
before or two hours after azithromycin.
Internet sources:
USA: http://hiv.net/link.php?id=176
References:
1. Dunne M, Fessel J, Kumar P, et al. A randomized, double-blind trial comparing azithromycin and
clarithromycin in the treatment of disseminated Mycobacterium avium infection in patients with HIV.
Clin Infect Dis 2000; 31:1245-52. http://amedeo.com/lit.php?id=11073759
2. Havlir DV, Dube MP, Sattler FR, et al. Prophylaxis against disseminated Mycobacterium avium
complex with weekly azithromycin, daily rifabutin, or both. N Engl J Med 1996, 335:392-8.
http://amedeo.com/lit.php?id=8676932
3. Oldfield EC 3rd, Fessel WJ, Dunne MW, et al. Once weekly azithromycin therapy for prevention of
Mycobacterium avium complex infection in patients with AIDS: a randomized, double-blind,
placebo-controlled multicenter trial. Clin Infect Dis 1998, 26:611-9.
http://amedeo.com/lit.php?id=9524832
4. Phillips P, Chan K, Hogg R, et al. Azithromycin prophylaxis for Mycobacterium avium complex
during the era of HAART: evaluation of a provincial program. Clin Infect Dis 2002, 34: 371-8.
http://amedeo.com/lit.php?id=11774085
5. Sendi PP, Craig BA, Meier G, et al. Cost-effectiveness of azithromycin for preventing
Mycobacterium avium complex infection in HIV-positive patients in the era of HAART. J Antimicrob
Chemother 1999, 44:811-7. http://amedeo.com/lit.php?id=10590283
AZT - Zidovudine
AZT, a thymidine analog and the oldest HIV drug, continues to be a component of many HAART regimens
and transmission prophylaxis. Extensive data, good CNS penetration. The most important side effect
is myelotoxicity which may cause severe anemia. Unfortunately, once daily dosing is not possible.
Trade name: Retrovir™; component of Combivir™ and Trizivir™
Retrovir™ capsules: 100 mg or 250 mg
Retrovir™ tablets: 300 mg
Retrovir™ syrup: 10 mg/ml
Retrovir™ infusion bottles: 200 ml (10 mg/ml)
Combivir™ tablets: 300 mg AZT + 150 mg 3TC
Trizivir™ tablets: 300 mg AZT + 150 mg 3TC + 300 mg abacavir
Manufacturer: GlaxoSmithKline
Indications: HIV infection. Prevention of maternal-fetal HIV transmission.
Dose: 250 mg bid. In Combivir™ and Trizivir™ 300 mg bid.
Creatinine clearance below 20 ml/min: 300 to 400 mg daily.
Hemodialysis: 300 mg daily. Hepatic failure: 100 mg tid.
Side effects: nausea, vomiting, abdominal discomfort, headache, myalgia, and dizziness. Macrocytic
anemia (MCV almost always elevated), rarely neutropenia. Also elevations in LDH, CPK, transaminases.
Rarely lactic acidosis.
Comments/Warnings: do not combine with d4T! There is increased myelotoxicity if used with other
myelosuppressive drugs, especially ganciclovir, but also co-trimoxazole, dapsone, pyrimethamine,
interferon, sulfadiazine, amphotericin B, ribavirin and various other chemotherapeutic agents.
Anemia can develop even after months on AZT.
As ribavirin antagonizes the antiviral activity of AZT in vitro, concurrent use of AZT and ribavirin
should be avoided.
Initially monthly monitoring of blood count, transaminases, CPK and bilirubin. Gastrointestinal
complaints can be treated symptomatically and usually subside after a few weeks.
AZT should always be a component of transmission prophylaxis!
Internet sources:
USA: Retrovir™ tablets: http://hiv.net/link.php?id=66
Retrovir™ IV infusion: http://hiv.net/link.php?id=67
Combivir™: http://hiv.net/link.php?id=68
Trizivir™: http://hiv.net/link.php?id=69
References:
1. Antoniou T, Gough K, Yoong D, Arbess G. Severe anemia secondary to a probable drug interaction
between zidovudine and valproic acid. Clin Infect Dis 2004; 38: e38-40. Epub 2004 Feb 11.
http://amedeo.com/lit.php?id=14986271
2. Burger DM, Meenhorst PL, Koks CHW, Beijnen JH. Drug interactions with Zidovudine. AIDS 1993,
7:445-60.
3. Dunn D. Short-term risk of disease progression in HIV-1-infected children receiving no
antiretroviral therapy or zidovudine monotherapy: a meta-analysis. Lancet 2003; 362: 1605-11.
http://amedeo.com/lit.php?id=14630440
4. Ekpini RA, Nkengasong JN, Sibailly T, et al. Changes in plasma HIV-1-RNA viral load and CD4 cell
counts, and lack of zidovudine resistance among pregnant women receiving short-course zidovudine.
AIDS 2002, 16: 625-30. http://amedeo.com/lit.php?id=11873007
5. Fischl MA: The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and
AIDS-related complex. A double-blind, placebo-con-trolled trial. N Engl J Med 1987, 317:185 -91.
http://amedeo.com/lit.php?id=3299089
6. Kirkland LR, Fischl MA, Tashima KT, et al. Response to lamivudine-zidovudine plus abacavir twice
daily in antiretroviral-naive, incarcerated patients with HIV Infection taking directly observed
treatment. Clin Infect Dis 2002, 34: 511-8. http://amedeo.com/lit.php?id=11797179
7. Leroy V, Karon JM, Alioum A, et al. Twenty-four month efficacy of a maternal short-course
zidovudine regimen to prevent mother-to-child transmission of HIV-1 in West Africa. AIDS 2002, 16:
631-41. http://amedeo.com/lit.php?id=11873008
8. Rabaud C, Burty C, Grandidier M, et al. Tolerability of postexposure prophylaxis with the
combination of zidovudine-lamivudine and lopinavir-ritonavir for HIV infection. Clin Infect Dis
2005; 40: 303-5. http://amedeo.com/lit.php?id=15655751
9. Ruane PJ, Richmond GJ, DeJesus E, et al. Pharmacodynamic effects of zidovudine 600 mg once/day
versus 300 mg twice/day in therapy-naive patients infected with human immunodeficiency virus.
Pharmacotherapy 2004; 24: 307-12. http://amedeo.com/lit.php?id=15040643
Caelyx™ see Doxorubicin, liposomal
Cidofovir
Trade name: Vistide™
Vials with 375 mg in 5 ml
Drug class: virostatic
Manufacturer: Gilead
Indications: CMV retinitis in HIV-infected patients without renal dysfunction, mainly in cases of
resistance/contraindications to ganciclovir or foscavir. As an adjunctive treatment to HAART for PML
patients, although efficacy is uncertain.
Dose: induction 5 mg/kg iv weekly, by day 21 maintenance therapy with 5 mg/kg iv every two weeks. A
treatment plan (comedication, hydration, etc.) is necessary!
Side effects: renal failure! Isolated cases of acute renal failure after single dose. Less frequent:
neutropenia, dyspnea, alopecia, decreased intraocular pressure, iritis, uveitis.
Fever, chills, headache, rash, nausea/vomiting tend to be due to probenecid, usually subside within
12 hours and are lessened with food intake, antipyretics, anti-emetics.
Comments/Warnings: with normal renal function, the following scheme is recommended (protocol):
-3 h 2 g probenecid (4 tbl. of 500 mg)
-3 to -1 h 1000-2000 ml 0.9 % NaCl
0 to + 2 h Cidofovir in 500 ml 0.9 % NaCl over 1-2 h. 1000 ml 0.9 % NaCl in parallel
+4 h 1 g probenecid (2 tbl. of 500 mg)
+10 h 1 g probenecid (2 tbl. of 500 mg)
Check renal function (serum creatinine, electrolytes, proteinuria) before each dose. If serum
creatinine increases by more than 0.3 mg/dl: reduce dose to 3 mg/kg. If serum creatinine increases
by more than 0.5 mg/dl above levels prior to treatment: discontinue. Cidofovir is contraindicated at
serum creatinine levels > 1.5 mg/dl or creatinine clearance = 55 ml/min or proteinuria > 100 mg/dl.
Always ensure adequate hydration!
Discontinue nephrotoxic drugs such as aminoglycosides, amphotericin B, foscarnet, iv pentamidine or
vancomycin at least 7 days prior to treatment.
Probenecid is necessary to reduce nephrotoxicity.
Interactions with acetaminophen, acyclovir, ACE inhibitors, ASA, barbiturates, benzodiazepines,
bumetanide, clofibrate, methotrexate, famotidine, furosemide, and theophylline.
Internet sources:
USA: http://hiv.net/link.php?id=71
References:
1. Cundy KC, Petty BG, Flaherty J, et al. Clinical pharmacokinetics of cidofovir in HIV-infected
patients. Antimicrob Agents Chemother 1995, 39:1247-52. http://amedeo.com/lit.php?id=7574510
2. Marra CM, Rajicic N, Barker DE, et al. A pilot study of cidofovir for progressive multifocal
leukoencephalopathy in AIDS. AIDS 2002, 16:1791-1797. http://amedeo.com/lit.php?id=12218391
3. Plosker GL, Noble S. Cidofovir: a review of its use in cytomegalovirus retinitis in patients with
AIDS. Drugs 1999, 58:325-45. http://amedeo.com/lit.php?id=10473024
Clarithromycin
Trade names: Klacid™, Mavid™, Clarithromycin-CT™, diverse generics
Mavid™ tablets with 500 mg
Klacid™ tablets with 250 mg
Drug class: antibiotic
Manufacturer: Abbott, various other companies
Indications: prophylaxis and treatment of MAC disease. Infections of respiratory tract, ENT, and the
skin.
Dose: 500 mg bid, both for primary prophylaxis and for maintenance therapy. 50 % dose reduction and
good hydration if creatinine clearance is = 30 ml/min.
Side effects: mainly gastrointestinal complaints (nausea, vomiting, abdominal discomfort, rarely
tenesmus, diarrhea). Allergic reactions, headache, elevated transaminases, alkaline phosphatase and
bilirubin.
Comments/Warnings: no concurrent treatment with rifampin, carbamazepine, cisapride, terfenadine,
pimozide and other macrolide antibiotics such as erythromycin or azithromycin.
Lopinavir and ritonavir increase clarithromycin levels. Clarithromycin and AZT should be taken 1-2
hours apart.
Internet sources:
USA: http://hiv.net/link.php?id=73 (trade name: Biaxin)
References:
1. Benson CA, Williams PL, Currier JS, et al. A prospective, randomized trial examining the efficacy
and safety of clarithromycin in combination with ethambutol, rifabutin, or both for the treatment of
disseminated Mycobacterium avium complex disease in persons Clin Infect Dis 2003; 37: 1234-43.
http://amedeo.com/lit.php?id=14557969
2. Chaisson RE, Benson CA, Dube MP, et al. Clarithromycin therapy for bacteremic Mycobacterium avium
complex disease. A randomized, double-blind, dose-ranging study in patients with AIDS. Ann Intern
Med 1994, 121:905-11. http://amedeo.com/lit.php?id=7978715
3. Dunne M, Fessel J, Kumar P, et al. A randomized, double-blind trial comparing azithromycin and
clarithromycin in the treatment of disseminated Mycobacterium avium infection in patients with HIV.
Clin Infect Dis 2000, 31:1245-52. http://amedeo.com/lit.php?id=11073759
4. Pierce M, Crampton S, Henry D, et al. A randomized trial of clarithromycin as prophylaxis
against disseminated Mycobacterium avium complex infection in patients with advanced AIDS. N Engl J
Med 1996, 335:384-91. http://amedeo.com/lit.php?id=8663871
5. Shafran SD, Singer J, Zarowny DP, et al. A comparison of two regimens for the treatment of
Mycobacterium avium complex bacteremia in AIDS: rifabutin, ethambutol, and clarithromycin versus
rifampin, ethambutol, clofazimine, and ciprofloxacin. N Engl J Med 1996, 335:377-83.
http://amedeo.com/lit.php?id=8676931
Clindamycin
Trade names: e.g. Aclinda™, Clinabeta™, Clindamycin-ratiopharm™, Sobelin™
Drug class: antibiotic
Manufacturer: Clindamycin is manufactured by several different companies.
Indications: for HIV patients: mainly toxoplasmic encephalitis (TE)
Dose: 600 mg iv every 6 h or 600 mg po every 6 h (always with pyrimethamine for TE therapy). Half
dose for (oral) maintenance therapy. In renal failure, reduce dose to a quarter or a third.
Side effects: diarrhea in 10-30 % of patients. Allergies are also frequent and often require
discontinuation.
In cases of infection with Clostridium difficile pseudomembranous colitis: the spectrum ranges from
mild to severe diarrhea with blood and mucous, leukocytosis, fever and severe abdominal cramps,
which may progress to peritonitis, shock and toxic megacolon.
Comments/Warnings: clindamycin is contraindicated in inflammatory bowel disease and
antibiotic-induced colitis. Caution with reduced hepatic or renal function and in asthma. No
concurrent administration of antiperistaltics!
For diarrheas on clindamycin: discontinue and give vancomycin.
Internet sources:
USA: http://hiv.net/link.php?id=76 (trade name Cleocin™).
References:
1. Dannemann B, McCutchan JA, Israelski D, et al. Treatment of toxoplasmic encephalitis in patients
with AIDS. A randomized trial comparing pyrimethamine plus clindamycin to pyrimethamine plus
sulfadiazine. Ann Intern Med 1992, 116:33-43. http://amedeo.com/lit.php?id=1727093
2. Katlama C, De Wit S, O'Doherty E, Van Glabeke M, Clumeck N. Pyrimethamine-clindamycin vs.
pyrimethamine-sulfadiazine as acute and long-term therapy for toxoplasmic encephalitis in patients
with AIDS. Clin Infect Dis 1996, 22:268-75. http://amedeo.com/lit.php?id=8838183
Combivir™
Tablets containing 150 mg 3TC + 300 mg AZT
Drug class: NRTI
Manufacturer: GlaxoSmithKline
Indications: HIV infection
Oral dose: 1 tablet bid
In cases of reduced renal function (creatinine clearance below 50 ml/min) and anemia, Combivir™
should be replaced with the individual drugs to allow for adjustment of 3TC and AZT doses.
Warnings and side effects: see chapters on 3TC and AZT.
Internet sources:
USA: http://hiv.net/link.php?id=68
Co-trimoxazole
Trade names: diverse generics.
Tablets: 80/400 mg and 160/800 mg (forte) trimethoprim/sulfamethoxazole (TMP/SMX)
Syrup: 1 ml with 8/40 mg
Ampules: 80/400 mg
Drug class: antibiotic
Manufacturer: co-trimoxazole is manufactured by several companies
Indications: prophylaxis and treatment of Pneumocystis pneumonia (PCP). Prophylaxis and treatment
(reserve drug) of cerebral toxoplasmosis.
Dose: PCP prophylaxis: 80/400 mg qd or 160/800 mg TMP/SMX 3 x/week. PCP therapy: 5 mg/kg (based on
trimethoprim) po or iv every 8 h for 21 days, therefore usually 4 to 5 ampules ŕ 80/400 mg every 8
h. Toxoplasmosis prophylaxis: 1 tablet (160/800 mg) qd.
Reduced renal function: halve dose with creatinine clearance of 15 to 50 ml/min. Co-trimoxazole is
contraindicated below 15 ml/min.
Side effects: allergies. In high doses, myelotoxicity (anemia, neutropenia!), nausea, vomiting,
headache, raised transaminases. In cases of mild allergy, treatment can often be continued.
Comments/Warnings: caution with sulfonamide allergy! Oral suspension for children can be used for
desensitization: increase the dose slowly over six days from 12.5, 25, 37.5, 50 and 75 to 100 % of
the 480 mg tablet dose (details in Leoung 2001, see below).
Co-trimoxazole can increase levels of anticoagulants and phenytoin and reduce the efficacy of oral
contraceptives.
References:
1. Bozzette SA, Finkelstein DM, Spector SA, et al. A randomized trial of three antipneumocystis
agents in patients with advanced HIV. N Engl J Med 1995, 332:693-9.
http://amedeo.com/lit.php?id=7854375
2. Duval X, Pajot O, Le Moing V, et al. Maintenance therapy with cotrimoxazole for toxoplasmic
encephalitis in the era of highly active antiretroviral therapy. AIDS 2004; 18: 1342-4.
http://amedeo.com/lit.php?id=15362670
3. El-Sadr WM, Luskin-Hawk R, Yurik TM, et al. A randomized trial of daily and thrice-weekly
trimethoprim-sulfamethoxazole for the prevention of Pneumocystis carinii pneumonia in HIV-infected
persons. Clin Infect Dis 1999, 29:775-783. http://amedeo.com/lit.php?id=10589887
4. Leoung GS, Stanford JF, Giordano MF, et al. Trimethoprim-sulfamethoxazole (TMP-SMZ) dose
escalation versus direct rechallenge for pneumocystis carinii pneumonia prophylaxis in HIV-infected
patients with previous adverse reaction to TMP-SMZ. J Infect Dis 2001, 184:992-7.
http://amedeo.com/lit.php?id=11574913
5. Para MF, Finkelstein D, Becker S, et al. Reduced toxicity with gradual initiation of
trimethoprim-sulfamethoxazole as primary prophylaxis for Pneumocystis carinii pneumonia. ACTG 268. J
Acquir Immune Defic Syndr 2000, 24:337-43. http://amedeo.com/lit.php?id=11015150
Crixivan™ see Indinavir
d4T - Stavudine
Stavudine is a thymidine analog. Subjective tolerability is good; the drug was long considered an
important alternative to AZT. Due to the mitochondrial toxicity (lipoatrophy, lactic acidosis,
peripheral neuropathy), particularly in combination with ddI, the (long-term) use of d4T is no
longer recommended.
Trade name: Zerit™
Hard capsules: 15, 20, 30, and 40 mg
Solution: 200 mg of 1 mg/ml
Drug class: NRTI
Manufacturer: Bristol-Myers Squibb
Indications: HIV infection
Oral dose: 40 mg bid for body weight > 60 kg, but 30 mg bid for body weight < 60 kg.
In renal failure:
Weight CrCl 26-50 ml/min CrCl below 26 ml/min (incl. dialysis patients)*
<60 kg 15 mg bid 15 mg qd
>60 kg 20 mg bid 20 mg qd
*Hemodialysis: take d4T after dialysis, and at the same time on non-dialysis days.
Side effects: more mitochondrial toxicity, and lipoatrophy than other NRTIs. Peripheral neuropathy
(PNP), especially in combination with ddI (up to 24 %). Rare: diarrhea, nausea, headache. Hepatic
steatosis, pancreatitis. Very rare, but potentially fatal: lactic acidosis, especially in
combination with ddI (and in pregnancy!).
Comments/Warnings: d4T should not be combined with AZT. D4T is contraindicated in PNP.
Avoid neurotoxic medication with other neurotoxic drugs (ethambutol, cisplatin, INH, vincristine,
etc.).
d4T can be taken on an empty stomach or with a light meal.
References:
1. Domingo P, Labarga P, Palacios R, Guerro MF, Terron JA, Elias MJ et al. Improvement of
dyslipidemia in patients switching from stavudine to tenofovir: preliminary results. AIDS 2004; 18:
1475-8. http://amedeo.com/lit.php?id=15199328
2. Gallant JE, Staszewski S, Pozniak AL, et al. Efficacy and safety of tenofovir DF vs stavudine in
combination therapy in antiretroviral-naive patients: a 3-year randomized trial. JAMA 2004; 292:
191-201. http://amedeo.com/lit.php?id=15249568
3. John M, McKinnon EJ, James IR, et al. randomized, controlled, 48-week study of switching
stavudine and/or protease inhibitors to combivir/abacavir to prevent or reverse lipoatrophy in
hiv-infected patients. J Acquir Immune Defic Syndr 2003; 33: 29-33.
http://amedeo.com/lit.php?id=12792352
4. Llibre JM, Domingo P, Palacios R, et al. Sustained improvement of dyslipidaemia in HAART-treated
patients replacing stavudine with tenofovir. AIDS 2006; 20: 1407-14. Abstract:
http://amedeo.com/lit.php?id=16791015
5. McComsey GA, Paulsen DM, Lonergan JT, et al. Improvements in lipoatrophy, mitochondrial DNA
levels and fat apoptosis after replacing stavudine with abacavir or zidovudine. AIDS 2005; 19:
15-23. Abstract: http://amedeo.com/lit.php?id=15627029
6. Saag MS, Cahn P, Raffi F, et al. Efficacy and safety of emtricitabine vs stavudine in combination
therapy in antiretroviral-naive patients: a randomized trial. JAMA 2004; 292: 180-9.
http://amedeo.com/lit.php?id=15249567
7. Shah SS, Rodriguez T, McGowan JP. Miller Fisher variant of Guillain-Barre syndrome associated
with lactic acidosis and stavudine therapy. Clin Infect Dis 2003; 36: e131-3.
http://amedeo.com/lit.php?id=12746793
Dapsone
Trade name: diverse generics.
Tablets: 50 mg
Drug class: antibiotic
Indications: reserve drug for prophylaxis of PCP and toxoplasmosis.
Dose: 100 mg daily. Alternative: 50 mg qd plus pyrimethamine 50 mg bid/week plus folinic acid 30
mg/week.
Side effects: allergies (pruritus, rash), fever. Frequently hemolytic anemia (with almost obligatory
elevation of LDH!), hepatitis.
Comments/Warnings: dapsone is contraindicated in severe anemia and must be used with caution in
G-6-PD deficiency. It is contraindicated in Mediterranean G-6-PD deficiency. No simultaneous
administration with ddI, antacids and H2 blockers (to be taken at least two hours apart).
Development of LDH on dapsone is not useful for diagnostic purposes. Rifabutin, rifampin lower
dapsone levels.
References:
1. El-Sadr WM, Murphy RL, Yurik TM, et al. Atovaquone compared with dapsone for the prevention of
Pneumocystis carinii pneumonia in patients with HIV infection who cannot tolerate trimethoprim,
sulfonamides, or both. N Engl J Med 1998, 339:1889-95. http://amedeo.com/lit.php?id=9862944
2. Girard PM, Landman R, Gaudebout C, et al. Dapsone-pyrimethamine compared with aerosolized
pentamidine as primary prophylaxis against Pneumocystis carinii pneumonia and toxoplasmosis in HIV
infection. N Engl J Med 1993, 328:1514-20. http://amedeo.com/lit.php?id=8479488
3. Torres RA, Barr M, Thorn M, et al. Randomized trial of dapsone and aerosolized pentamidine for
the prophylaxis of pneumocystis carinii pneumonia and toxoplasmic encephalitis. Am J Med 1993,
95:573-83. http://amedeo.com/lit.php?id=8018144
Daraprim™ see pyrimethamine
Darunavir (TMC-114)
Darunavir is a new, well-tolerated PI with considerable activity against PI-resistant viruses, and
was recently licensed in Europe and the USA. Darunavir is boosted with ritonavir.
Trade name: Prezista™
Tablets: 300 mg
Drug class: Protease inhibitor
Manufacturer: Tibotec
Indications: intensively pre-treated patients with treatment failure (for example strains resistant
to two or more PIs).
Dose: 600 mg bid (2 tablets each time) plus 100 mg ritonavir bid.
Side effects: moderate gastrointestinal complaints and dyslipidemia, although the dyslipidemia is
not as pronounced as with other PIs. Rash (7 %) in the first 2 weeks.
Interactions: relevant interactions occur with lopinavir - the plasma levels of darunavir fall, and
the combination should be avoided. Because darunavir is metabolized via the cytochrome P450 system,
numerous other interactions should be considered. The following drugs should therefore not be used
in combination:
St. John's wort, astemizole, terfenadine, cisapride, pimozide, midazolam, triazolam, ergotamine
derivatives, rifapin, phenobarbital, phenytoin, carbamazepine. For example:
- In combination with efavirenz, there is the possibility of reduced darunavir and increased
efavirenz levels.
- Instead of pravastatin, atorvastatin can be used in the lowest doses (10 mg). The dose of
rifabutin has to be reduced to 150 mg every two days. Darunavir raises the levels of calcium
antagaonists; reduces methadone levels; interferes with birth control pills.
- Maximum doses of PDE5 inhibitors with darunavir administration: 10 mg Cialis™ in 72 hours; 2,5 mg
Levitra™ in 72 hours; 25 mg Viagra™ in 48 hours.
For further information (itraconazole, voriconazole, ketoconazole, cyclosporine, SSRIs, etc) see
product information.
Comments/warnings: darunavir should be taken at mealtimes. Caution with sulfonamide allergy.
References:
1. Arasteh K, Clumeck N, Pozniak A, et al. TMC114/ritonavir substitution for protease inhibitor(s)
in a non-suppressive antiretroviral regimen: a 14-day proof-of-principle trial. AIDS 2005; 19:
943-7. Abstract: http://amedeo.com/lit.php?id=15905675
2. De Meyer S, Azijn H, Surleraux D, et al. TMC114, a novel HIV type 1 protease inhibitor active
against protease inhibitor-resistant viruses, including a broad range of clinical isolates.
Antimicrob Agents Chemother 2005; 49: 2314-21. http://amedeo.com/lit.php?id=15917527
3. Kovalevsky AY, Tie Y, Liu F, et al. Effectiveness of nonpeptide clinical inhibitor TMC-114 on
HIV-1 protease with highly drug resistant mutations D30N, I50V, and L90M. J Med Chem 2006; 49:
1379-87. Abstract: http://amedeo.com/lit.php?id=16480273
4. Poveda E, Blanco F, Garcia-Gasco P, et al. Successful rescue therapy with darunavir (TMC114) in
HIV-infected patients who have failed several ritonavir-boosted protease inhibitors. AIDS 2006; 20:
1558-60. Abstract: http://amedeo.com/lit.php?id=16847414
5. Sekar VJ, Lefebvre E, De Paepe E, et al. Pharmacokinetic interaction between TMC114/r and
omeprazole or ranitidine in HIV-negative healthy volunteers. Antimicrob Agents Chemother 2007;
Abstract: http://amedeo.com/lit.php?id=17210768
6. Surleraux DL, Tahri A, Verschueren WG, et al. Discovery and selection of TMC114, a next
generation HIV-1 protease inhibitor. J Med Chem 2005; 48: 1813-22. Abstract:
http://amedeo.com/lit.php?id=15771427
Daunorubicin, liposomal
Trade name: DaunoXome™
50 mg vials of liposomal daunorubicin
Drug class: cytostatic
Manufacturer: Gilead
Indications: Kaposi's sarcoma in patients with CD4 cells < 200/µl and in cases of severe
mucocutaneous or visceral KS.
Dose: 40 mg/m2 i.v. over 30-60 minutes, every 2-3 wks.
Side effects: during infusion: back pain, flushing. Symptoms usually resolve when the infusion is
slowed or stopped. Fatigue, headaches, chills. Pancytopenia, elevated transaminases and alkaline
phosphatase.
In myelosuppression (neutrophils < 1,000/µl): delay the next dose and treat with G-CSF if necessary.
Caution cardiotoxicity - cardiomyopathy!
Comments/Warnings: contraindicated if there is hypersensitivity to anthracyclines. Caution with
pre-existing cardiovascular disease, previous treatment with anthracyclines.
LVEF should be evaluated before initiation of treatment. Afterwards, echocardiography before each
cycle when the cumulative dose is 240 mg/m2 .
Internet sources:
USA: http://hiv.net/link.php?id=82 (2.3 MB)
References:
1. Gill PS, Wernz J, Scadden DT, et al. Randomized phase III trial of liposomal daunorubicin versus
doxorubicin, bleomycin, and vincristine in AIDS-related Kaposi's sarcoma. J Clin Oncol 1996; 14:
2353-64. http://amedeo.com/lit.php?id=8708728
2. Fumagalli L, Zucchetti M, Parisi I, et al. The pharmacokinetics of liposomal encapsulated
daunorubicin are not modified by HAART in patients with HIV-associated Kaposi's sarcoma. Cancer
Chemother Pharmacol 2000, 45: 495-501. http://amedeo.com/lit.php?id=10854138
3. Hjortsberg C, Persson U, Lidbrink E, Bennett C. Cost-effectiveness analysis of
pegylated-liposomal doxorubicin and liposomal daunorubicin treatments in patients with Kaposi's
sarcoma. Acta Oncol 1999, 38:1063-7. http://amedeo.com/lit.php?id=10665764
4. Rosenthal E, Poizot-Martin I, Saint-Marc T, Spano JP, Cacoub P. Phase IV study of liposomal
daunorubicin (DaunoXome) in AIDS-related Kaposi sarcoma. Am J Clin Oncol 2002, 25:57-9.
http://amedeo.com/lit.php?id=11823698
DaunoXome™ see Daunorubicin, liposomal
ddC - Zalcitabine
The distribution of ddC (HIVID™) was stopped in 2006 due to the complicated dosing, moderate
efficacy, side effects and cross-resistances.
ddI - Didanosine
ddI was one of the first NRTIs, which today, because of its side effects (pancreatitis 10 %) and
mitochondrial toxicity, is only used in certain resistence situations. The dose has to be adjusted
according to body weight.
Combination with tenofovir and d4T should be avoided.
Trade name: Videx™
Enteric coated capsules: 125 mg, 200 mg, 250 mg, 400 mg.
Powder: 4 g per bottle.
Drug class: NRTI
Manufacturer: Bristol-Myers Squibb
Indications: HIV infection
Oral dose: 400 mg qd (body weight > 60 kg) or 250 mg qd (body weight < 60 kg). ddI must be taken on
an empty stomach, at least 2 hours after or at the latest 1 hour before meals.
Side effects: diarrhea, nausea, headache. ddI specific: pancreatitis, even after longer periods on
treatment! Peripheral polyneuropathy. Rarely: episodes of lactic acidosis, especially in combination
with d4T and ribavirin.
Comments/Warnings: acute and chronic pancreatitis are contraindications, as is treatment with
ribavirin! Caution with d4T, ethambutol, cisplatin, disulfiram, INH, vincristine, etc. (PNP).
Concurrent dosing with tenofovir increases the Cmax and AUC of ddI by 28 % and 44 %, respectively.
The ddI dose should therefore be reduced to 250 mg. Tenofovir is taken two hours before or one hour
after ddI; the two should not be combined at all if possible (see HAART chapter).
With indinavir, dapsone, ketoconazole, itraconazole, or tetracyclines there should be a two-hour
interval.
Initially, monthly monitoring of amylase, blood count, transaminases and bilirubin. Patients should
be informed about the risk and signs of pancreatitis. ddI should be discontinued if there is
clinical suspicion; avoid rechallenge.
Internet sources:
USA: http://hiv.net/link.php?id=86
References:
1. Leon A, Mallolas J, Martinez E, et al. High rate of virological failure in maintenance
antiretroviral therapy with didanosine and tenofovir. AIDS 2005; 19: 1695-7. Abstract:
http://amedeo.com/lit.php?id=16184042
2. Martinez E, Milinkovic A, de Lazzari E, et al. Pancreatic toxic effects associated with
co-administration of didanosine and tenofovir in HIV-infected adults. Lancet 2004; 364: 65-7.
http://amedeo.com/lit.php?id=15234858
3. Moreno A, Quereda C, Moreno L, et al. High rate of didanosine-related mitochondrial toxicity in
HIV/HCV-coinfected patients receiving ribavirin. Antivir Ther 2004; 9: 133-8.
http://amedeo.com/lit.php?id=15040545
4. Murphy MD, O'Hearn M, Chou S. Fatal lactic acidosis and acute renal failure after addition of
tenofovir to an antiretroviral regimen containing Didanosine. Clin Infect Dis 2003; 36: 1082-5.
http://amedeo.com/lit.php?id=12684925
Diflucan™ see Fluconazole
Delavirdine
Delavirdine is rarely used, due to high dosing and drug interactions. Delaviridine is not licensed
in Europe.
Trade name: Rescriptor™; abbr. DLV.
Tablets: 100 mg and 200 mg (can also be dissolved in water!).
Drug class: NNRTI
Manufacturer: Pfizer
Indications: HIV infection.
Oral dose: 400 mg tid
Side effects: rash, usually occurring within the first six weeks of treatment. In mild cases, give
antihistamines; discontinue DLV if systemic effects (fever, conjunctivitis, myalgia and arthralgia)
occur. Nausea, elevated transaminases.
Comments/Warnings: delavirdine is contraindicated for concurrent treatment with rifabutin, rifampin,
carbamazepine, phenytoin, alprazolam, astemizole, phenobarbital, cisapride, midazolam, terfenadine
and triazolam.
Delavirdine interacts with numerous drugs via reduction of CYP3A-activity. It increases the AUC of
some PIs (saquinavir, nelfinavir), sildenafil, dapsone, clarithromycin, quinidine and warfarin.
Delavirdine levels are lowered by ddI, H2 blockers, carbamazepine, phenytoin and antacids.
Internet sources:
USA: http://hiv.net/link.php?id=178
References:
1. Conway B. Initial therapy with protease inhibitor-sparing regimens: evaluation of nevirapine and
delavirdine. Clin Infect Dis 2000, Suppl 2:S130-4. http://amedeo.com/lit.php?id=10860897
2. Harris M, Alexander C, O'Shaughnessy M, Montaner JS. Delavirdine increases drug exposure of
ritonavir-boosted protease inhibitors. AIDS 2002; 16: 798-9.
3. Shelton MJ, Hewitt RG, Adams J, Della-Coletta A, Cox S, Morse GD. Pharmacokinetics of Ritonavir
and Delavirdine in HIV-Infected Patients. Antimicrob Agents Chemother 2003; 47: 1694-1699.
http://amedeo.com/lit.php?id=12709342
Doxorubicin (liposomal)
Trade name: Caelyx™
10 ml (20 mg) and 25 ml (50 mg) vials
Drug class: anthracycline
Manufacturer: Schering-Plough, Ortho Biotech (USA)
Indications: Kaposi's sarcoma in AIDS patients with < 200 CD4 cells/µl and severe mucocutaneous or
visceral involvement.
Dose: 20 mg/m2 i.v. in 250 ml 5 % glucose over 30 minutes every 2-3 weeks.
Side effects: cardiomyopathy, myelosuppression, stomatitis (rarely severe), hand-foot syndrome
(painful erythema). Treatment: cool affected areas. Beware extravascularisation (never s.c. or i.m.,
no bolus administration!).
Comments/Warnings: contraindicated in cardiomyopathy, severe myelosuppression (neutrophils <
1,000/µl, platelets < 50,000/µl).
Contraindicated in cardiomyopathy, previous treatment with anthracyclines above the cumulative dose.
ECG and echocardiography (left ventricular ejection fraction?) before and during treatment and at
periodic intervals during treatment above the cumulative dose of 450 mg/m2 before each cycle.
Hand-foot syndrome is induced by sweating, pressure, friction - therefore no tight gloves, no sun,
or long showers. Cool drinks are beneficial!
This drug is expensive (in Germany, two 20 mg vials cost approximately 1,343 Euro).
References:
1. Martin-Carbonero L, Barrios A, Saballs P, et al. Pegylated liposomal doxorubicin plus highly
active antiretroviral therapy versus highly active antiretroviral therapy alone in HIV patients with
Kaposi's sarcoma. AIDS 2004; 18: 1737-40. http://amedeo.com/lit.php?id=15280789
2. Nunez M, Saballs P, Valencia ME, et al. Response to liposomal doxorubicin and clinical outcome of
HIV-1-infected patients with Kaposi's sarcoma receiving HAART. HIV Clin Trials 2001; 2: 429-37.
http://amedeo.com/lit.php?id=11673818
Efavirenz
Efavirenz is a frequently used NNRTI. Diverse CNS side effects are a substantial problem
(disturbances of sleep architecture, morning dizziness, somnolence). Further disadvantages include
drug interactions and cross-resistance, as with the other members of this drug class.
Efavirenz is also available in the fixed combination Atripla™.
Trade name: Sustiva™, or Stocrin™. Also a component of Atripla™
Sustiva™ tablets: 600 mg. Capsules: 50 mg, 100 mg, 200 mg
Atripla™ tablets (600 mg plus 200 mg emtricitabine + 300 mg tenofovir)
Drug class: NNRTI
Manufacturer: Bristol-Myers Squibb, MSD
Indications: HIV infection
Oral dose: 600 mg daily, at bedtime.
Side effects: CNS symptoms occur frequently: nightmares, confusion, dizziness, somnolence, abnormal
thinking, depression, impaired concentration, insomnia, and depersonalization. These symptoms
usually resolve after a few weeks. A rash (15 %) in the first weeks, usually mild, and further
treatment is normally possible.
Elevation of liver function tests and biliary enzymes (?GT). Dyslipidemia, occasionally very
uncomfortable, painful gynecomastia.
Comments/Warnings: contraindicated in pregnancy. Caution in women of child-bearing age; talk about
possible wish to have children.
Contraindicated for concurrent administration with ergotamines, astemizole, cisapride, midazolam,
terfenadine and triazolam. Should not be combined with contraceptive pills.
Increase dose of lopinavir/r with efavirenz (2 x 3 tablets/day (TDM!), atazanavir/r (400/100 mg),
rifabutin (450 mg), methadone (approximately 20-30 %).
Not to be taken with fatty meals (poorer absorption).
Internet sources:
USA: http://hiv.net/link.php?id=88
References:
1. Boffito M, Rossati A, Reynolds HE, et al. Undefined duration of opiate withdrawal induced by
efavirenz in drug users with hiv infection and undergoing chronic methadone treatment. AIDS Res Hum
Retroviruses 2002; 18: 341-2.
2. Clifford DB, Evans S, Yang Y, et al. Impact of efavirenz on neuropsychological performance and
symptoms in HIV-infected individuals. Ann Intern Med 2005; 143: 714-21. Abstract:
http://amedeo.com/lit.php?id=16287792
3. Frampton JE, Croom KF. Efavirenz/emtricitabine/tenofovir disoproxil fumarate: triple combination
tablet. Drugs 2006; 66: 1501-12 Abstract: http://amedeo.com/lit.php?id=16906786
4. Fumaz CR, Munoz-Moreno JA, Molto J, et al. Long-term neuropsychiatric disorders on
efavirenz-based approaches: quality of life, psychologic issues, and adherence. J Acquir Immune
Defic Syndr 2005; 38: 560-5. Abstract: http://amedeo.com/lit.php?id=15793366
5. Fundaro C, Genovese O, Rendeli C, Tamburrini E, Salvaggio E. Myelomeningocele in a child with
intrauterine exposure to efavirenz. AIDS 2002, 16: 299-300.
6. Gallego L, Barreiro P, del Rio R, et al. Analyzing sleep abnormalities in HIV-infected patients
treated with Efavirenz. Clin Infect Dis 2004; 38: 430-2. Epub 2004 Jan 09.
http://amedeo.com/lit.php?id=14727217
7. Mira JA, Lozano F, Santos J, et al. Gynaecomastia in HIV-infected men on highly active
antiretroviral therapy: association with efavirenz and didanosine treatment. Antivir Ther 2004; 9:
511-7. http://amedeo.com/lit.php?id=15456082
8. Staszewski S, Morales-Ramirez J, Tashima KT, et al. Efavirenz plus zidovudine and lamivudine,
efavirenz plus indinavir, and indinavir plus zidovudine and lamivudine in the treatment of HIV-1
infection in adults. N Engl J Med 1999, 341:1865-73. http://amedeo.com/lit.php?id=10601505
9. van Leth F, Phanuphak P, Ruxrungtham K, et al. Comparison of first-line antiretroviral therapy
with regimens including nevirapine, efavirenz, or both drugs, plus stavudine and lamivudine: a
randomised open-label trial, the 2NN Study. Lancet 2004; 363: 1253-63.
http://amedeo.com/lit.php?id=15094269
Emtricitabine (FTC)
Emtricitabine (FTC) is a well-tolerated cytidine analog, comparable to 3TC both biochemically and in
its resistance profile, but has a longer half-life.
Trade name: Emtriva™. Also in Truvada™ and Atripla™.
Emtriva™ hard capsules with 200 mg; solution: 170 ml (1 mg = 10 mg/ml).
Truvada™ (emtricitabine 200 mg + tenofovir 300 mg).
Drug class: NRTI
Manufacturer: Gilead
Indications: HIV infection
Dose: 1 x 200 mg daily (solution: 240 mg = 24 ml).
Use single-drug preparations instead of combination preparations with reduced creatinine clearance
(see respective section for dose). Emtricitabine is adjusted as follows:
CrCl (ml/min) Dose
30-49 200 mg every 2 days
15-29 200 mg every 3 days
Below 14 or dialysis 200 mg every 4 days
Side effects: rare. Most commonly, headache, nausea, diarrhea, rash. Possibly hyperpigmentation.
Comments/Warnings: danger of hepatitis rebound with HBV coinfection after stopping FTC. Do not stop
therapy if possible, check liver function.
Internet sources:
USA: http://hiv.net/link.php?id=223
References:
1. Dando TM, Wagstaff AJ. Emtricitabine/tenofovir disoproxil fumarate. Drugs 2004; 64: 2075-82
http://amedeo.com/lit.php?id=15341498
2. Frampton JE, Croom KF. Efavirenz/emtricitabine/tenofovir disoproxil fumarate: triple combination
tablet. Drugs 2006; 66: 1501-12 Abstract: http://amedeo.com/lit.php?id=16906786
3. Gallant JE, DeJesus E, Arribas JR, et al. Tenofovir DF, emtricitabine, and efavirenz vs.
zidovudine, lamivudine, and efavirenz for HIV. N Engl J Med 2006; 354: 251-60. Abstract:
http://amedeo.com/lit.php?id=16421366
4. Saag MS, Cahn P, Raffi F, et al. Efficacy and safety of emtricitabine vs stavudine in combination
therapy in antiretroviral-naive patients: a randomized trial. JAMA 2004; 292: 180-9.
http://amedeo.com/lit.php?id=15249567
5. Saag MS. Emtricitabine, a new antiretroviral agent with activity against HIV and Hepatitis B
Virus. CID 2006; 42: 126-31. http://amedeo.com/lit.php?id=16323102
Emtriva™ see Emtricitabine
Enfuvirtide see T-20
Epivir™ see 3TC (at the beginning of this chapter)
Epzicom™ see Kivexa
Erypo™ see Erythropoetin
Erythropoietin
Trade name: Erypo™
Including vials with 2,000, 4,000 or 10,000 I.U./ml
Drug class: anti-anemic
Manufacturer: Janssen-Cilag among other companies
Indications: anemia in chronic renal failure, reduction of the need for transfusion in patients with
solid tumours and malignant lymphomas, who are receiving chemotherapy and are at risk of
transfusion. Asymptomatic when hemoglobin is at the earliest below 10-11 g/dl, if endogenous
erythropoietin levels are below 500 mU/ml.
Dose: According to the indication 3 x 50-100 I.U./kg/week s.c. until a hematocrit of 30-35 % is
reached. If there is no response, increase dose; if there is no response after a further 6 weeks:
discontinue. If there is a response, a weekly maintenance dose of 100-200 I.U./kg body weight is
sufficient. At hematocrit values > 40 % or Hb > 13 g/dl: discontinue.
Side effects: in particular at the start, flu-like symptoms, such as headache, arthralgia, asthenia,
dizziness, fatigue.
Comments/Warnings: erythropoietin is contraindicated with uncontrolled hypertension. It is expensive
and should be used sparingly. Before initiating treatment, other causes of anemia should be
excluded. These include:
§ Vitamin B12 or folic acid deficiency, iron deficiency, occult blood loss, hematological disorders
such as thalassemia and myelodysplasia.
§ AIDS-defining illnesses with bone marrow involvement such as MAC infection, tuberculosis, CMV
infection, lymphoma, Kaposi's sarcoma.
Strict monitoring of blood pressure initially!
Subcutaneous administration of Erypo™ is contraindicated in patients with chronic renal
insufficiency due to the risk of antibody-induced erythroblastopenia (Pure Red Cell Aplasia).
Store Erypo™ at 2-8° Celsius in the original package. Do not freeze!
Drug interactions: erythropoietin can diminish the efficacy of concurrently administered
antihypertensives. Concurrent treatment with anticonvulsive drugs may increase seizure
susceptibility.
Ethambutol
Drug class: tuberculostatic
Manufacturer: Ethambutol is manufactured by several different companies.
Indications: tuberculosis, MAC infection
Dose: 15 to 25 mg/kg (maximum 2 g) daily, usually 3 tablets ŕ 400 mg qd. Ethambutol should only be
given as combination therapy.
Dose reduction in renal failure:
CrCl Dose
Above 75 ml/min 25 mg/kg
40-75 ml/min 15 mg/kg
30-40 ml/min 15 mg/kg every second day
<30 ml/min Measurement of serum levels required *
*Serum levels should be within the range of the minimal inhibitory concentration 2-5 µg/ml after 2-4
hours.
Side effects: ethambutol can lead to optical neuritis with impaired vision (decreased acuity,
restricted fields, loss of red-green color discrimination). It is usually reversible if ethambutol
is discontinued immediately.
Other side effects: nausea, vomiting, abdominal pain, headache, dizziness, pruritus, arthralgia,
elevated serum uric acid (acute gout attacks possible!), abnormal liver function tests.
Comments/Warnings: ethambutol is contraindicated with pre-existing optical nerve damage.
Ophthalmologic examination before initiation of treatment and subsequently at 4-week intervals
(color discrimination, field of vision, acuity). Immediate discontinuation to prevent optical
atrophy if drug-related impairment of vision occurs.
Patients should be informed that impairment of vision may occur and to immediately report this to
the treating physician.
Aluminum hydroxide reduces absorption of ethambutol; ethambutol should therefore be taken at least
one hour before antacids.
Monitor liver values and uric acid levels at monthly intervals.
References:
1. Shafran SD, Singer J, Zarowny DP, et al. A comparison of two regimens for the treatment of
Mycobacterium avium complex bacteremia in AIDS: rifabutin, ethambutol, and clarithromycin versus
rifampin, ethambutol, clofazimine, and ciprofloxacin. N Engl J Med 1996, 335:377-83.
http://amedeo.com/lit.php?id=8676931
2. Ward TT, Rimland D, Kauffman C, Huycke M, Evans TG, Heifets L. Randomized, open-label trial of
azithromycin plus ethambutol vs. clarithromycin plus ethambutol as therapy for Mycobacterium avium
complex bacteremia in patients with HIV infection. Clin Infect Dis 1998, 27:1278-85.
http://amedeo.com/lit.php?id=9827282
Etravirin (TMC-125)
Etravirin is a NNRTI, which is also effective against NNRTI-resistant HIV strains. Since February
2007, etravirin has been available in an Expanded Access Program. Requirements for participation
include limited treatment options following previous treatment (NNRTI + NRTI + at least 2 previous
therapy regimes with a PI basis).
Trade name: not yet known
Drug class: NNRTI
Manufacturer: Tibotec
Dose: 200 mg bid (2 tablets bid)
Side effects: headache, diarrhea, rash.
Interactions: tipranavir/r, nevirapine and efavirenz reduce etravirin exposure and should therefore
not be combined.
Etravirin increases fosamprenavir/r levels (+ 69 %), and the dose may need adjusting. Etravirin can
be used with rifabutin und clarithromycin in most situations without dose adjustments; however, in
MAC treatment, clarithromycin is not recommended.
Etravirin reduces sildenafil levels by 69 %.
Dose adjustment is not necessary with proton pump inhibitors, H2-blockers, methadone and
contraceptives.
Literatur:
1. Andries K, Azijn H, Thielemans T, et al. TMC125, a novel next-generation nonnucleoside reverse
transcriptase inhibitor active against nonnucleoside reverse transcriptase inhibitor-resistant human
immunodeficiency virus type 1. Antimicrob Agents Chemother 2004; 48: 4680-6. Abstract:
http://amedeo.com/lit.php?id=15561844
2. Gruzdev B, Rskhmanova A, Doubovskaya E, et al. A randomized, double-blind, placebo-controlled
trial of TMC125 as 7-day monotherapy in antiretroviral naive, HIV-1 infected subjects. AIDS 2003;
17: 2487-94. http://amedeo.com/lit.php?id14600520
3. Sankatsing SU, Weverling GJ, Peeters M, et al. TMC125 exerts similar initial antiviral potency as
a five-drug, triple class antiretroviral regimen. AIDS 2003; 17:2623-7.
http://amedeo.com/lit.php?id=14685056
Filgrastim see G-CSF
Fluconazole
Fluconazole is an antifungal azole and the drug of choice for treatment of candidiasis in HIV
infection and for secondary prophylaxis of cryptococcosis. It is also a component of acute therapy
for cryptococcosis.
Trade name: Diflucan™, several generics
50 mg, 100 mg and 200 mg capsules
Oral solution with 50 mg per 10 ml. Powder for suspension with 50 mg per 5 ml
Bottles for infusion with 100 mg, 200 mg and 400 mg
Drug class: antimycotic
Manufacturer: Pfizer and several other companies
Indications: Candidiasis, cryptococcal infections, a few rare mycoses.
Dose: for oropharyngeal candidiasis: 100 mg qd po; for Candida esophagitis 200 mg qd for 7-10 days.
Double the dose on the first day. An attempt may be made with a higher dose if there is persistance
after 10 days (up to 800 mg daily).
Cryptococcal meningitis: Initially, 400-800 mg daily, combined with flucytosine and amphotericin B
if possible. After completion of acute therapy - usually after 6 weeks - maintenance therapy with
200 mg fluconazole daily.
Renal insufficiency: halve dose with creatinine clearance of 50 to 10 ml/min; reduce to 25 % below
10 ml/min.
Side effects: rarely gastrointestinal complaints and elevated transaminases. Reversible alopecia in
approximately 10 % of cases with more than 400 mg daily.
Comments/warnings: azole-resistant Candida strains on long-term treatment. No effect on C. krusei or
Aspergillus. In cases of C. glabrata infection, higher doses are required (sensitivity
dose-dependent).
Fluconazole levels are reduced by rifabutin/rifampin. Fluconazole increases serum concentrations of
rifabutin, atovaquone, clarithromycin, theophylline, opiates, coumarins, benzodiazepines, phenytoin,
and anti-convulsive drugs as well as AZT.
The tablets have good absorption, and infusions (2-3 times more expensive) are only required in
cases of non-adherence, mucositis or problems with absorption.
Internet sources:
USA: http://hiv.net/link.php?id=94
References:
1. Chapman TM, Plosker GL, Perry CM. Fosamprenavir: a review of its use in the management of
antiretroviral therapy-naive patients with HIV infection. Drugs 2004; 64: 2101-24.
http://amedeo.com/lit.php?id=15341507
2. Eron J Jr, Yeni P, Gathe J Jr, et al. The KLEAN study of fosamprenavir-ritonavir versus
lopinavir-ritonavir, each in combination with abacavir-lamivudine, for initial treatment of HIV
infection over 48 weeks. Lancet 2006; 368: 476-82. http://amedeo.com/lit.php?id=16890834
3. Gathe JC Jr, Ive P, Wood R, et al. SOLO: 48-week efficacy and safety comparison of once-daily
fosamprenavir/ritonavir versus twice-daily nelfinavir in naive HIV-1-infected patients. AIDS 2004;
18: 1529-37. http://amedeo.com/lit.php?id=15238771
Fosamprenavir
Fosamprenavir is a calcium phosphate ester of amprenavir, which is more soluble and is better
absorbed than amprenavir. Overall tolerability is fairly good. Fosamprenavir has an interesting
resistance profile and a variety of possibilities for dosing (see below).
Trade name: USA: Lexiva™, Europe: Telzir™
Film-coated tablets with 700 mg (60 = N3). Suspension 50 mg/ml (225 ml = N1)
Drug class: protease inhibitor
Manufacturer: GlaxoSmithKline
Indications: HIV infection, both treatment-naďve and -experienced patients
Dose: varies for treatment-naďve patients:
§ 700 mg bid + 100 mg ritonavir bid (2 x 2 pills, is the usual dose).
§ 1,400 mg bid (without ritonavir - not licensed in Europe!).
§ 1,400 mg qd + 200 mg ritonavir qd (4 pills qd, not in Europe).
The once-daily version is not recommended for PI-experienced patients. PI-experienced patients
should therefore only receive the following dose:
§ 700 mg bid + 100 mg ritonavir bid (2 pills bid).
Fosamprenavir may be taken with or without food.
Side effects: most common: diarrhea; less frequent: nausea, vomiting, rash (up to 20 %). Rarely:
Stevens-Johnson syndrome (< 1 %).
Comments/warnings: contraindicated: cisapride, pimozide, midazolam, triazolam, ergotamines.
Flecainide and propafenone are contraindicated when fosamprenavir is boosted with ritonavir. There
may be life-threatening interactions with amiodarone, lidocaine (systemic), tricyclic
anti-depressants and quinidine.
Do not administer together with rifampin (this reduces amprenavir plasma levels by 90 %),
delavirdine or St. John's wort; use cautiously with simvastatin, lovastatin, sildenafil, vardenafil.
Carbamazepine, phenobarbital, phenytoin and dexamethasone can lower plasma levels of amprenavir.
Rifabutin: dose reduction of rifabutin by approximately 50 %; 75% if fosamprenavir is boosted with
ritonavir (instead of 300 mg daily, only 150 mg every other day, or 150 mg 3 x/week).
Efavirenz seems to lower plasma levels significantly (probably to an extent that is clinically
relevant). However, this is not the case if fosamprenavir is boosted. But: on once daily
fosamprenavir/r, the ritonavir dose should be increased to 1 x 300 mg. Caution in combination with
lopinavir (plasma levels of both drugs are reduced)!
Ketoconazole, itraconazole: if dosed > 400 mg daily, possibly dose reduction of
ketoconazole/itraconazole. If fosamprenavir is boosted with ritonavir, ketoconazole and itraconazole
doses above 200 mg daily are not recommended.
Caution in patients with sulfonamide allergy, reduced liver function (possibly dose reduction).
Possibly, an increase in the methadone dose might be required.
Internet sources:
USA: http://hiv.net/link.php?id=222
References:
1. Bicanic T, Harrison T, Niepieklo A, Dyakopu N, Meintjes G. Symptomatic relapse of HIV-associated
cryptococcal meningitis after initial fluconazole monotherapy: the role of fluconazole resistance
and immune reconstitution. Clin Infect Dis 2006; 43: 1069-73. http://amedeo.com/lit.php?id=16983622
2. Friese G, Discher T, Fussle R, Schmalreck A, Lohmeyer J. Development of azole resistance during
fluconazole maintenance therapy for AIDS-associated cryptococcal disease. AIDS 2001, 15:2344-5.
3. Goldman M, Cloud GA, Wade KD, et al. A randomized study of the use of fluconazole in continuous
versus episodic therapy in patients with advanced HIV infection and a history of oropharyngeal
candidiasis. Clin Infect Dis 2005; 41: 1473-80. http://amedeo.com/lit.php?id=16231260
4. Vasquez JA, Peng G, Sobel JD, et al. Evolution of antifungal susceptibility among candida species
isolates recovered from HIV-infected women receiving fluconazole prophylaxis. Clin Infect Dis 2001,
33: 1069-75. http://amedeo.com/lit.php?id=11528582
5. de Wet N, Llanos-Cuentas A, Suleiman J, et al. A randomized, double-blind, parallel-group,
dose-response study of micafungin compared with fluconazole for the treatment of esophageal
candidiasis in HIV-positive patients. Clin Infect Dis 2004; 39: 842-9.
http://amedeo.com/lit.php?id=15472817
6. Wheat LJ, Connolly P, Haddad N, et al. Antigen clearance during treatment of disseminated
histoplasmosis with itraconazole versus fluconazole in patients with AIDS. Antimicrob Agents
Chemother 2002, 46: 248-50. http://amedeo.com/lit.php?id=11751146
Foscarnet
Trade name: Foscavir™
250 ml bottles with 24 mg/ml
Drug class: virostatic
Manufacturer: AstraZeneca
Indications: reserve drug for induction and maintenance therapy of CMV retinitis. Severe
acyclovir-resistant herpes or varicella zoster infections.
Dose: 90 mg/kg iv over at least 2 hours twice daily for induction therapy (2-3 weeks) of CMV
retinitis. 90-120 mg/kg over 2 hours once daily for maintenance therapy. HSV and VZV: 60 mg/kg iv
bid for 2 weeks.
Side effects: nephrotoxicity! Usually reversible after discontinuation of foscarnet. Electrolyte
changes (hypocalcemia, hypokalemia) are also common. More rarely: anemia, neutropenia, fever, rash,
headache, nausea, vomiting, diarrhea. Often painful penile ulcers (wash after every urination!).
Comments/Warnings: good hydration! At least 2.5 l fluids daily. To prevent hypocalcemia give one
ampule of 10 % calcium solution in 100 ml 5 % glucose immediately prior to infusion of foscarnet.
Give 500-1,000 ml 5 % glucose before or after foscarnet dose. Do not mix infusions.
Initial monitoring of Na, K, Ca, creatinine, blood count 3x/week.
No concurrent treatment with other nephrotoxic drugs.
Adjust dose in renal insufficiency. See prescribing information.
References:
1. Breton G, Fillet AM, Katlama C, Bricaire F, Caumes E. Acyclovir-resistant herpes zoster in
HIV-infected patients: results of foscarnet therapy. Clin Infect Dis 1998, 27: 1525-7.
http://amedeo.com/lit.php?id=9868672
2. Cheung TW, Jayaweera DT, Pearce D, et al. Safety of oral versus intravenous hydration during
induction therapy with intravenous foscarnet in AIDS patients with cytomegalovirus infections. Int J
STD AIDS 2000, 11: 640-7. http://amedeo.com/lit.php?id=11057934
3. Salmon-Ceron D, Fillet AM, Aboulker JP, et al. Effect of a 14-day course of foscarnet on
cytomegalovirus (CMV) blood markers in a randomized study of HIV-infected patients with persistent
CMV viremia. Clin Infect Dis 1999, 28: 901-5. http://amedeo.com/lit.php?id=10825058
4. Weinberg A, Jabs DA, Chou S, et al. mutations conferring foscarnet resistance in a cohort of
patients with acquired immunodeficiency syndrome and cytomegalovirus retinitis. J Infect Dis 2003;
187: 777-784. http://amedeo.com/lit.php?id=12599051
5. Zanetta G, Maurice-Estepa L, Mousson C, et al. Foscarnet-induced crystalline glomerulonephritis
with nephrotic syndrome and acute renal failure after kidney transplantation. Transplantation 1999.
67: 1376-8. http://amedeo.com/lit.php?id=10360595
Foscavir™ see Foscarnet
Fuzeon™ see T-20
Ganciclovir
Trade name: Cymeven™
Bottles for injection with 500 mg. Orally, valganciclovir should be used instead of ganciclovir (see
Valganciclovir).
Drug class: virostatic
Manufacturer: Hoffmann-La Roche
Indications: CMV retinitis. Since the approval of valganciclovir: only for use in patients for whom
oral treatment is not possible.
Dose: initial treatment with normal renal function: 5 mg/kg bid as an iv infusion over one hour, for
at least 14-21 days. Maintenance: 6 mg/kg iv qd, 5 x/week.
Side effects: leukopenia, anemia and thrombocytopenia are dose limiting. Less frequent: nausea,
vomiting, diarrhea or CNS symptoms such as confusion or headache.
Comments/Warnings: monitor blood count every two days. Reduce dose by 30 % to 50 % for neutrophil
counts between 500 and 800/µl; discontinue drug when below 500/µl (G-CSF if necessary!).
Contraindicated in neutropenia < 500/µl, thrombocytopenia < 25,000/µl and concurrent chemotherapy.
Caution if administering with AZT and ddI (increased toxicity!).
Ganciclovir is a potential teratogen and carcinogen. Dose adjustment is necessary in renal
insufficiency (see link below).
Internet sources:
USA: http://hiv.net/link.php?id=97
References:
1. Casper C, Nichols WG, Huang ML, Corey L, Wald A. Remission of HHV-8 and HIV-associated
multicentric Castleman's disease with ganciclovir treatment. Blood 2003; : Blood 2003 Nov 13
http://amedeo.com/lit.php?id=14615380
2. Czock D, Scholle C, Rasche FM, Schaarschmidt D, Keller F. Pharmacokinetics of valganciclovir and
ganciclovir in renal impairment. Clin Pharmacol Ther 2002, 72: 142-50.
http://amedeo.com/lit.php?id=12189361
3. Imai Y, Shum C, Martin DF, Kuppermann BD, Drew WL, Margolis TP. Emergence of drug-resistant
cytomegalovirus retinitis in the contralateral eyes of patients with AIDS treated with ganciclovir.
J Infect Dis 2004; 189: 611-5. Epub 2004 Jan 28. http://amedeo.com/lit.php?id=14767813
G-CSF
Trade names: Neupogen™ (Filgrastim), Granocyte™ (Lenograstim)
Granocyte™: Vials with 13.4 million I.U. and 33.6 million I.U.
Neupogen™: prefilled syringes with 300 µg and 480 µg
Neupogen™: vials with 300 µg in 1 ml and 480 µg in 1.6 ml
Drug class: cytokine
Manufacturer: Amgen, Chugai Pharma
Indications: neutropenia, especially drug-induced (AZT, ganciclovir, interferon, myelosuppressive
chemotherapy), rarely HIV-related.
Dose: with chemotherapy, usually approx. 5 µg/kg Neupogen™ daily on fixed days. Outside of
chemotherapy protocols, 1-5 µg/kg Neupogen™ 1-3x/week, titrate dose down. The goal is usually at
least 1,000 neutrophil granulocytes/µl. For Granocyte™ doses see product information.
Side effects: bone, back or muscle pain in 10 to 20 % of patients, sometimes severe (requiring
generous analgesia). Irritation at the injection site.
Comments/Warnings: G-CSF is expensive. Long-term treatment should be avoided (change the drug
causing neutropenia if possible). Remainders of individual ampules should be kept refrigerated in a
syringe.
Monitoring: blood count twice weekly.
Internet sources:
USA, Neupogen™: http://hiv.net/link.php?id=100
References:
1. Campbell TB, Rapaport E, Schooley RT, Kuritzkes DR. Increased replication of HIV-1 minor variants
during hematopoietic stem-cell mobilization with filgrastim. J Infect Dis 2004; 190: 257-66. Epub
2004 Jun 22. http://amedeo.com/lit.php?id=15216459
2. Davidson M, Min YI, Holbrook JT, et al. Use of filgrastim as adjuvant therapy in patients with
AIDS-related cytomegalovirus retinitis. AIDS 2002, 16:757-65. http://amedeo.com/lit.php?id=11964532
3. Davidson M, Min YI, Holbrook JT, et al. Influence of filgrastim (granulocyte colony-stimulating
factor) on HIV type 1 RNA in patients with cytomegalovirus retinitis. J Infect Dis 2002, 186:
1013-8. http://amedeo.com/lit.php?id=12232843
Hivid™ see ddC - no longer on the market.
Indinavir
Indinavir was, in 1996, one of the first PIs. Today, however, its use is limited due to side
effects, especially skin and renal problems. Ritonavir boosting is recommended.
Trade name: Crixivan™.
Hard capsules of 200 mg, 333 mg and 400 mg
Drug class: protease inhibitor
Manufacturer: Merck/MSD
Indications: HIV infection
Dose: two current dosing regimens:
Boosted: 800 mg bid (two 400 mg capsules bid) plus 100 mg ritonavir bid (one 100 mg capsule bid).
400 mg bid (one 400 mg capsule bid) plus 400 mg ritonavir bid (four 100 mg capsules bid). Dose
reduction often possible on TDM.
Unboosted dose (uncommon!): 800 mg tid (two 400 mg capsules tid) one hour before/two hours after
eating.
Side effects: nephrolithiasis (in up to 25 %); less frequently: nephrotoxicity with elevated serum
creatinine. Diarrhea, nausea/vomiting, hyperbilirubinemia.
Frequently: sicca syndrome (dry skin, dry mouth, dry eyes); alopecia, ingrown toenails and
paronychia; rarely hair loss.
Lipodystrophy ("Crixbelly"), dyslipidemia, disorders of glucose metabolism.
Comments/Warnings: At least 1.5 l of fluid should be consumed daily to prevent nephrolithiasis.
Nephrolithiasis and also probably skin problems, correlate with plasma levels. No concurrent
administration of ddI.
In combination with ritonavir, indinavir can be taken twice daily and with meals.
Concurrent use of rifampin, astemizole, terfenadine, cisapride, triazolam, ergotamines, simvastatin,
lovastatin, or St. John's wort is contraindicated.
The following dose adjustments are necessary:
§ Rifabutin: boosting with ritonavir: 150 mg rifabutin every 2 days or three times a week.
§ Ketoconazole and itraconazole: 600 mg indinavir tid.
§ Sildenafil: maximum 25 mg sildenafil/48h.
Internet sources:
USA: http://hiv.net/link.php?id=102
References:
1. Acosta EP, Wu H, Hammer SM, et al. comparison of two indinavir/ritonavir regimens in the
treatment of HIV-infected individuals. J Acquir Immune Defic Syndr 2004; 37: 1358-1366.
http://amedeo.com/lit.php?id=15483465
2. Elzi L, Hirsch HH, Battegay M. Once-daily directly observed therapy lopinavir/ritonavir plus
indinavir as a protease inhibitor-only salvage therapy in heavily pretreated HIV-1-infected
patients: a pilot study. AIDS 2006; 20: 129-31. Abstract: http://amedeo.com/lit.php?id=16327333
3. Ghosn J, Lamotte C, Ait-Mohand H, et al. Efficacy of a twice-daily antiretroviral regimen
containing 100 mg ritonavir/400 mg indinavir in HIV-infected patients. AIDS 2003; 17: 209-14.
http://amedeo.com/lit.php?id=12545081
4. Gulick RM, Meibohm A, Havlir D, et al. Six-year follow-up of HIV-1-infected adults in a clinical
trial of antiretroviral therapy with indinavir, zidovudine, and lamivudine. AIDS 2003; 17:
2345-2349. http://amedeo.com/lit.php?id=14571186
5. Hammer SM, Squires KE, Hughes MD, et al. A controlled trial of two nucleoside analogues plus
indinavir in persons with HIV infection and CD4 cell counts of 200 per cubic millimeter or less. N
Engl J Med 1997, 337:725-33. http://amedeo.com/lit.php?id=9287227
6. Wasmuth JC, la Porte CJ, Schneider K, Burger DM, Rockstroh JK. Comparison of two reduced-dose
regimens of indinavir (600 mg vs 400 mg twice daily) and ritonavir (100 mg twice daily) in healthy
volunteers (COREDIR). Antivir Ther 2004; 9: 213-20. http://amedeo.com/lit.php?id=15134183
Interferon alfa 2a/2b
Trade names: 2a: Roferon™, Pegasys™; 2b: Intron A™, PegIntron™
Pegasys™ (pegylated interferon a-2a): vials with 135 and 180 µg
PegIntron™ (pegylated interferon a-2b): vials with 50, 80, 100, 120 and 150 µg
Roferon-A™: prefilled syringes with 3, 4.5, 6 or 9 mill I.U. Alternatively, vials with 3 or 18 mill
I.U. or cartridges with 18 mill I.U.
Intron A™ (Interferon alfa-2b): either in pen devices with 18, 30 or 60 mill I.U. or in vials with
corresponding syringes and cannulas with 18 or 25 mill I.U.
Drug class: cytokine
Manufacturer: Roche (Roferon™, Pegasys™); Schering-Plough (Intron A™, Peg-Intron™)
Indications: severe Kaposi's sarcoma in patients with good immune status (> 300 CD4 cells/µl; always
try HAART first). Chronic hepatitis C, possibly also for hepatitis B.
Dose: Peg-Intron™: 1.5 µg/kg 1 x/week
Pegasys™: 180 µg 1 x/week
Standard interferons: 6 mil I.U. 3 x/week
Duration is dependent on success of treatment of KS, on HCV genotype and success of treatment for
hepatitis C. Interferon is injected subcutaneously.
Side effects: Frequent influenza-like symptoms such as fever, and myalgia. Depression (even
suicidality), fatigue, sleeping disorders, personality changes. Anemia, thrombocytopenia and
leukopenia. Autoimmune thyroiditis. Reversible hair loss. Possibly also impaired vision.
Comments/Warnings: influenza-like symptoms usually occur a few hours after dosing and can be reduced
with Paracetamol (1,000 mg in advance!).
All side effects are usually reversible.
Contraindications are severe heart, liver or renal dysfunction, bone marrow disorders, CNS disorders
(e.g. epilepsy, severe depression), uncompensated thyroid disorders.
Monitor blood count every two weeks initially, later monthly. TSH every three months.
Interferons must be kept refrigerated.
References:
1. Chung RT, Andersen J, Volberding P, et al. Peginterferon Alfa-2a plus ribavirin versus interferon
alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons. N Engl J Med 2004; 351:
451-9. http://amedeo.com/lit.php?id=15282352
2. Farel C, Suzman DL, McLaughlin M, et al. Serious ophthalmic pathology compromising vision in
HCV/HIV co-infected patients treated with peginterferon alpha-2b and ribavirin. AIDS 2004; 18:
1805-9. http://amedeo.com/lit.php?id=15316341
3. Plosker GL, Keating GM. Peginterferon-alpha-2a (40kD) plus ribavirin: A review of its use in
hepatitis C virus and HIV co-infection. Drugs 2004; 64: 2823-43.
http://amedeo.com/lit.php?id=15563253
4. Torriani FJ, Rodriguez-Torres M, Rockstroh JK, et al. Peginterferon Alfa-2a plus ribavirin for
chronic hepatitis C virus infection in HIV-infected patients. N Engl J Med 2004; 351: 438-50.
http://amedeo.com/lit.php?id=15282351
Interleukin-2
Interleukin-2 is not licensed for HIV; justified as a therapy attempt in individual cases (contact
health insurance) with failed immune reconstitution (< 100 CD4 cells despite several months of viral
suppression). Otherwise only in studies.
Trade name: Proleukin™ (Aldesleukin). Bottles for injection with 18 × 106 I.E.
Drug class: cytokine
Manufacturer: Chiron
Dose: 4.5-9 Mill I.E. sc bid for 5 days, every 6-8 weeks.
Side effects: almost obligatory fever, chills. Fatigue, malaise, nausea/vomiting, myalgia. Rarely
hypotension (caution with antihypertensives).
Comments/warnings: counseling! The clinician must be experienced! Generous administration of
paracetamol. Side effects usually subside 1-2 days after the last dose. Contraindicated in
individuals with severe coronary disease, infections or pO2 < 60 mm; it is also contraindicated in
pregnancy.
Internet sources:
USA: http://hiv.net/link.php?id=112
References:
1. Levy Y, Gahery-Segard H, Durier C, et al. Immunological and virological efficacy of a therapeutic
immunization combined with interleukin-2 in chronically HIV-1 infected patients. AIDS 2005; 19:
279-86. Abstract: http://amedeo.com/lit.php?id=15718838
2. Marchetti G, Meroni L, Varchetta S, et al. Low-dose prolonged intermittent interleukin-2 adjuvant
therapy: results of a randomized trial among HIV-positive patients with advanced immune impairment.
J Infect Dis 2002, 186: 606-616. http://amedeo.com/lit.php?id=12195347
3. Stellbrink HJ, Van Lunzen J, Westby M, et al. Effects of interleukin-2 plus highly active
antiretroviral therapy on HIV-1 replication and proviral DNA (COSMIC trial). AIDS 2002, 16:
1479-1487. http://amedeo.com/lit.php?id=12131185
Intron A™ see Interferon
Invirase™ see Saquinavir
Isoniazid (INH)
Drug class: tuberculostatic
Manufacturer: isoniazid is offered by different manufacturers
Indications: combination therapy of tuberculosis.
Prophylactic treatment after tuberculin conversion.
Dose: 200 to 300 mg qd (4 to 5 mg/kg, maximum 300 mg) po, iv only in severe cases during the first
two weeks of therapy. For prophylaxis of neuropathy, INH should always be combined with 100 mg
pyridoxine po qd.
Pediatric dose: 6 (to 10) mg/kg qd, maximum 300 mg.
Side effects: toxic hepatitis, more frequent in older patients, with liver disease and alcohol
abuse.
Peripheral neuropathy! Discontinue INH in severe cases and treat for several weeks with pyridoxine
and vitamin B12. Psychosis, CNS symptoms. Fever, rash, nausea, vomiting, anemia, leukopenia,
thrombocytopenia.
Comments/Warnings: contraindications are acute hepatitis and history of INH-associated hepatopathy
or severe febrile reactions, peripheral neuropathy, macrohematuria.
Patients on treatment with carbamazepine or an hydantoin derivative might require dose adjustment of
these drugs.
Interactions with barbiturates, cycloserine, theophylline, phenytoin and rifampin; doses of these
drugs should be reduced due to CNS disorders.
Reduced absorption if taken concurrently with aluminum-based antacids.
Do not combine with d4T, ddI (PNP risk), and caution with alcohol.
Initially, biweekly monitoring of blood count, transaminases, bilirubin, and renal function.
Discontinue INH with elevated transaminases to more than 3-fold initial levels and symptoms; or with
a 5-fold elevation even in the absence of symptoms.
References:
1. Benator D, Bhattacharya M, Bozeman L, et al. Rifapentine and isoniazid once a week versus
rifampicin and isoniazid twice a week for treatment of drug-susceptible pulmonary tuberculosis in
HIV-negative patients: a randomised clinical trial. Lancet 2002, 360: 528.
http://amedeo.com/lit.php?id=12241657
2. Casado JL, Moreno S, Fortun J, et al. Risk factors for development of tuberculosis after
isoniazid chemoprophylaxis in HIV-infected patients. Clin Infect Dis 2002, 34:386-389.
http://amedeo.com/lit.php?id=11753825
3. Gurumurthy P, Ramachandran G, Hemanth Kumar AK, Rajasekaran S, Padmapriyadarsini C, Swaminathan S
et al. Malabsorption of rifampin and isoniazid in HIV-infected patients with and without
tuberculosis. Clin Infect Dis 2004; 38: 280-3. http://amedeo.com/lit.php?id=14699462
4. Scholten JN, Driver CR, Munsiff SS, Kaye K, Rubino MA, Gourevitch MN et al. Effectiveness of
isoniazid treatment for latent tuberculosis infection among human immunodeficiency virus
(HIV)-infected and HIV-uninfected injection drug users in methadone programs. Clin Infect Dis 2003;
37: 1686-92. Epub 2003 Nov 17. http://amedeo.com/lit.php?id=14689352
Itraconazole
Trade name: Sempera™
100 mg capsules
Oral solution (Sempera Liquid™) with 10 mg/ml (150 ml)
Drug class: antimycotic
Manufacturer: Janssen-Cilag / GlaxoSmithKline
Indications: histoplasmosis, aspergillosis, treatment-resistant Candida infections (second choice).
Dose: histoplasmosis, aspergillosis 200 mg bid.
Fluconazole-resistant Candida infections: 100 mg qd to 100 mg bid (up to 200 mg bid), ideally as
itraconazole oral solution.
Side effects: nausea, vomiting, rash, dizziness. Toxic hepatitis.
Comments/Warnings: due to numerous interactions and unreliable plasma levels, oral dosing of
itraconazole is problematic. However, in contrast to fluconazole, it is effective for many
non-albicans strains, aspergillosis, and histoplasmosis.
No concurrent administration of itraconazole capsules with ddI, H2 blockers, omeprazole, antacids.
No concurrent administration (of capsules or oral solution) with rifampin, rifabutin, carbamazepine,
phenytoin, phenobarbital, simvastatin, lovastatin and isoniazid (these lower the bioavailability of
itraconazole).
Itraconazole increases serum levels of cyclosporine, calcium antagonists, digoxin, lovastatin,
simvastatin and indinavir. Dose adjustment of indinavir: 600 mg tid.
Itraconazole has a negative inotropic effect and should not be given to patients with heart failure.
To achieve maximum absorption:
· the capsules should be taken immediately after a full meal. Acidic drinks such as coke and orange
juice may increase absorption;
· the oral solution should be taken between meals, and not together with grapefruit juice.
Internet sources:
USA: http://hiv.net/link.php?id=114
References:
1. Caillot D, Bassaris H, McGeer A, et al. Intravenous itraconazole followed by oral itraconazole in
the treatment of invasive pulmonary aspergillosis in patients with hematologic malignancies, chronic
granulomatous disease, or AIDS. Clin Infect Dis 2001, 33: e83-90.
http://amedeo.com/lit.php?id=11550120
2. Chariyalertsak S, Supparatpinyo K, Sirisanthana T, Nelson KE. A controlled trial of itraconazole
as primary prophylaxis for systemic fungal infections in patients with advanced HIV infection in
thailand. Clin Infect Dis 2002, 34: 277-284. http://amedeo.com/lit.php?id=11740718
3. Crommentuyn KM, Mulder JW, Sparidans RW, Huitema AD, Schellens JH, Beijnen JH. Drug-drug
interaction between itraconazole and the antiretroviral drug lopinavir/ritonavir in an
HIV-1-infected patient with disseminated histoplasmosis. Clin Infect Dis 2004; 38: e73-5.
http://amedeo.com/lit.php?id=15095234
4. Wheat LJ, Connolly P, Haddad N, et al. Antigen clearance during treatment of disseminated
histoplasmosis with itraconazole versus fluconazole in patients with AIDS. Antimicrob Agents
Chemother 2002, 46: 248-50. http://amedeo.com/lit.php?id=11751146
Kaletra™ see Lopinavir
Kivexa™ (USA: Epzicom™)
Tablets: with 3TC (300 mg) and abacavir (600 mg).
As with Ziagen™, watch for hypersensitivity syndrome.
Drug class: nucleoside reverse transcriptase inhibitors (NRTI)
Manufacturer: GlaxoSmithKline
Indications: HIV infection
Dose: 1 tablet daily. Replace Kivexa™ with the individual drugs if kidney function is impaired
(creatinine clearance below 50 ml/min), in order to adjust the 3TC dose.
Side effects: hypersensitivity syndrome with abacavir (see abacavir section!).
Comments/Warnings: abacavir hypersensitivity syndrome (2-6 %) can be life-threatening. For further
information, see 3TC and abacavir.
Internet sources:
http://hiv.net/link.php?id=240
Reference:
1. DeJesus E, Herrera G, Teofilo E, et al. Abacavir versus zidovudine combined with lamivudine and
efavirenz, for the treatment of antiretroviral-naive HIV-infected adults. Clin Infect Dis 2004; 39
:1038-46. http://amedeo.com/lit.php?id=15472858
Klacid™ see Clarithromycin
Lamivudine see 3TC (at the beginning of this chapter)
Lexiva™ see Fosamprenavir
Lopinavir
Effective PI in treatment-naďve as well as treatment-experienced patients. Disadvantages include
gastrointestinal side effects (diarrhea) and the often significant dyslipidemia, which is more
extreme than with some other PIs. As with all PIs, lipodystrophy and various drug interactions
should be considered.
Trade name: Kaletra™
Tablets with 200 mg lopinavir + 50 mg ritonavir.
Solution with 80 mg lopinavir + 20 mg ritonavir per ml; bottles of 160 ml.
Keep the solution refrigerated, maximum of 4-6 weeks at up to 25°C.
Drug class: protease inhibitor (PI)
Manufacturer: Abbott
Indications: HIV infection
Oral dose: 2 tablets bid or 5 ml solution bid with meals. In the USA: 4 tablets qd.
In combination with efavirenz or nevirapine, the lopinavir dose should probably be increased to 3
tablets bid or 6.5 ml solution bid. Measure plasma levels!
Side effects: mainly diarrhea, nausea, dyslipidemia, and lipodystrophy. Also: headaches, and
elevated transaminases.
Comments/Warnings: drug interactions are numerous. All drugs metabolized by the CYP3A or CYP2D6
enzyme systems are contraindicated: flecainide, propafenone, astemizole, terfenadine, ergotamines,
cisapride, pimozide, midazolam, triazolam. Rifampin and St. John's wort reduce the efficacy of
lopinavir.
Caution with: lovastatin, simvastatin (myopathy, rhabdomyolysis), carbamazepine, phenobarbital,
phenytoin or sildenafil (hypotension), amiodarone, warfarin, lidocaine, tricyclic antidepressants,
quinidine, cyclosporine, tacrolimus. Measure plasma levels in patients with reduced liver function
tests.
If lopinavir is combined with ddI, ddI must be taken one hour before or two hours after lopinavir.
Lopinavir solution contains alcohol, therefore no comedication with disulfiram or metronidazole.
Caution with the pill (contraception not safe).
When used with rifabutin, the rifabutin dose should be reduced by 75 %, i.e. to 150 mg qd every two
days. Increasing the methadone dose may be necessary.
Capsules (not tablets) should be kept refrigerated for a maximum of 4-6 weeks at a maximum
temperature of 25°C.
Internet sources:
USA: http://hiv.net/link.php?id=116
References:
1. Eron JJ, Feinberg J, Kessler HA, et al. Once-daily versus twice-daily lopinavir/ritonavir in
antiretroviral-naive HIV-positive patients: a 48-week randomized clinical trial. J Infect Dis 2004;
189: 265-72. http://amedeo.com/lit.php?id=14722892
2. Eyer-Silva WA, Neves-Motta R, Pinto JF, Morais-De-Sa CA. Inflammatory oedema associated with
lopinavir-including HAART regimens in advanced HIV-1 infection: report of 3 cases. AIDS 2002, 16:
673-4.
3. Hicks C, King MS, Gulick RM, et al. Long-term safety and durable antiretroviral activity of
lopinavir/ritonavir in treatment-naive patients: 4 year follow-up study. AIDS 2004; 18: 775-9.
http://amedeo.com/lit.php?id=15075512
4. Kempf DJ, King MS, Bernstein B, et al. Incidence of resistance in a double-blind study comparing
lopinavir/ritonavir plus stavudine and lamivudine to nelfinavir plus stavudine and lamivudine. J
Infect Dis 2004; 189: 51-60. http://amedeo.com/lit.php?id=14702153
5. Martinez E, Domingo P, Galindo MJ, et al. Risk of metabolic abnormalities in patients infected
with HIV receiving antiretroviral therapy that contains lopinavir-ritonavir. Clin Infect Dis 2004;
38: 1017-23. http://amedeo.com/lit.php?id=15034836
6. Walsmley S, Bernstein B, King M, et al. Lopinavir-ritonavir versus nelfinavir for the initial
treatment of HIV infection. N Engl J Med 2002, 346: 2039-46. http://amedeo.com/lit.php?id=12087139
7. Johnson MA, Gathe JC Jr, Podzamczer D, et al. A once-daily lopinavir/ritonavir-based regimen
provides noninferior antiviral activity compared with a twice-daily regimen. J Acquir Immune Defic
Syndr 2006; 43: 153-60. Abstract: http://amedeo.com/lit.php?id=16951643
8. Eron J Jr, Yeni P, Gathe J Jr, et al. The KLEAN study of fosamprenavir-ritonavir versus
lopinavir-ritonavir, each in combination with abacavir-lamivudine, for initial treatment of HIV
infection over 48 weeks: a randomised non-inferiority trial. Lancet 2006; 368: 476-82. Abstract:
http://amedeo.com/lit.php?id=16890834
9. van der Lee M, Verweel G, de Groot R, Burger D. Pharmacokinetics of a once-daily regimen of
lopinavir/ritonavir in HIV-1-infected children. Antivir Ther 2006; 11: 439-45. Abstract:
http://amedeo.com/lit.php?id=16856617
10. Oldfield V, Plosker GL. Lopinavir/ritonavir: a review of its use in the management of HIV
infection. Drugs 2006; 66: 1275-99. Abstract: http://amedeo.com/lit.php?id=16827606
11. Johnson M, Grinsztejn B, Rodriguez C, et al. 96-week comparison of once-daily
atazanavir/ritonavir and twice-daily lopinavir/ritonavir in patients with multiple virologic
failures. AIDS 2006; 20: 711-8. Abstract: http://amedeo.com/lit.php?id=16514301
Maraviroc
Maraviroc (abbr.: MVC; earlier UK-427,857) is the first and currently the most promising
CCR5-antagonist.
Because maraviroc only inhibits R5-trope viruses, the recpeptor tropism has to be determined before
treatment with maraviroc is started.
The studies conducted so far have shown excellent tolerability. Since April 2007, maraviroc has
been available in several countries through an expanded access program for treatment-experienced
patients with R5-trope viruses and limited therapy options.
Trade name: Celsentri®, Selzentry®.
Tablets with 150 mg and 300 mg.
Drug class: CCR5 inhibitor.
Manufacturer: Pfizer.
Indication: treatment-experienced adult patients with CCR5-trope HIV strains.
Dose: 300 mg bid, before or after a meal.
Dose adjustment with concurrent administration of the following drugs:
Drug Maraviroc Dose (recommended)
Protease inhibitor
(exception: Tipranavir) 2 x 150 mg
Itraconazole, Ketoconazole 2 x 150 mg
Clarithromycin, Telithromycin 2 x 150 mg
Efavirenz 2 x 600 mg
Rifampin, Rifabutin 2 x 600 mg
Interactions: In combination with some PIs such as lopinavir, saquinavir or atazanavir, the
maraviroc dose probably has to be halved; possibly raised in combination with efavirenz (Abel 2005).
Interactions with tipranavir seem to be irrelevant (Abel 2006).
Halve the dose in combination mit PIs (except tipranavir), ketoconazole, itraconazole.
Double the dose in combination mit efavirenz, rifampin, carbamazepine, phenobarbital und phenytoin.
Simultaneous administration of INH is contraindicated (hepatotoxicity).
Side effects: well-tolerated so far; rarely headache, dizziness, fatigue, loss of appetite, nausea,
muscle pain. Data on long-term effects are not available.
Literatur:
1. Abel S, Russell D, Ridgway C, Muirhead G. Overview of the drug-drug interaction data for
maraviroc. Abstract 76, 7th IWCPHT 2005, Quebec.
2. Abel S, Taylor-Worth R, Ridgway C, Weissgerber G, Kraft M. Effect of boosted tipranavir on the
pharmacokinetics of maraviroc (UK427,857) in healthy volunteers. Abstract 77, 7th IWCPHT 2006,
Lissabon, Portugal.
3. Castagna A, Biswas P, Beretta A, Lazzarin A. The appealing story of HIV entry inhibitors : from
discovery of biological mechanisms to drug development. Drugs 2005; 65: 879-904. Abstract:
http://amedeo.com/lit.php?id=15892586
4. Coakley E, Petropoulos CJ, Whitcomb JM. Assessing chemokine co-receptor usage in HIV. Curr Opin
Infect Dis 2005; 18: 9-15. Abstract: http://amedeo.com/lit.php?id=15647694
5. Dorr P, Westby M, Dobbs S, et al. Maraviroc (UK-427,857), a potent, orally bioavailable, and
selective small-molecule inhibitor of chemokine receptor CCR5 with broad-spectrum anti-human
immunodeficiency virus type 1 activity. Antimicrob Agents Chemother 2005; 49: 4721-32. Abstract:
http://amedeo.com/lit.php?id=16251317
6. Fatkenheuer G, Pozniak AL, Johnson MA, et al. Efficacy of short-term monotherapy with maraviroc,
a new CCR5 antagonist, in patients infected with HIV-1. Nat Med 2005; 11: 1170-2.
http://amedeo.com/lit.php?id=16205738
7. Lalezari J, Goodrich J, DeJesus E, Lampiris H, Gulick R, Saag M, Ridgway C, McHale M, van der
Ryst E, Mayer H. Efficacy and Safety of Maraviroc plus Optimized Background Therapy in Viremic
ART-experienced Patients Infected with CCR5-tropic HIV-1: 24-Week Results of a Phase 2b/3 Study in
the US and Canada. CROI 2007; Abstract 104bLB
8. Mayer H, van der Ryst E, Saag M, Clotet, Fätkenheuer G, Clumek N, Turner K, Goodrich JM. Safety
and efficacy of maraviroc, a novel CCR5 antagonist, when used in combination with optimized
background therapy (OBT) for the treatment of antiretriviral-experienced subjects infected with
dual/mixed-tropic HIV-1:24-week results of a phase 2b exploratory trial. Abstract THLB0215, 16th IAS
2006, Toronto, Canada.
9. Nelson M, Fätkenheuer G, Konourina I, Lazzarin A, Clumeck N, Horban A, Tawadrous M, Sullivan J,
Mayer H, van der Ryst E. Efficacy and Safety of Maraviroc plus Optimized Background Therapy in
Viremic, ART-experienced Patients Infected with CCR5-tropic HIV-1 in Europe, Australia, and North
America: 24-Week Results. CROI 2007; Abstract 104aLB
10. Rosario MC, Poland B, Sullivan J, Westby M, van der Ryst E. A pharmacokinetic-pharmacodynamic
model to optimize the phase IIa development program of maraviroc. J Acquir Immune Defic Syndr 2006;
42: 183-91. Abstract: http://amedeo.com/lit.php?id=16639345
11. Westby M, Lewis M, Whitcomb J, et al. Emergence of CXCR4-using human immunodeficiency virus type
1 (HIV-1) variants in a minority of HIV-1-infected patients following treatment with the CCR5
antagonist maraviroc is from a pretreatment CXCR4-using virus reservoir. J Virol 2006; 80: 4909-20.
Abstract: http://amedeo.com/lit.php?id=16641282
Mavid™ see Clarithromycin
Mycobutin™ see Rifabutin
Nelfinavir
Nelfinavir is a well-tolerated PI, but is slightly less potent than boosted PIs or NNRTIs. The main
problems include frequent diarrhea and the high pill burden. Administration was simplified with the
introduction of the 625 mg capsule (dose: 2 capsules bid).
Trade name: Viracept™, abbr. NFV
250 mg film-coated tablets (N2: 270); 50 mg/g oral powder (N1: 144 g). Film-coated tablets with 625
mg, in Europe not available.
Drug class: protease inhibitor
Manufacturer: Hoffmann-La Roche, Pfizer
Indications: HIV infection
Oral dose: 1,250 mg bid or 750 mg tid with meals. Boosting with ritonavir is not useful.
Side effects: diarrhea! Meteorism, and nausea also occur. Lipodystrophy, dyslipidemia, reduced
glucose tolerance.
Comments/Warnings: contraindicated for comedication with rifampin, the "pill", astemizole,
terfenadine, cisapride, triazolam, ergotamines, simvastatin, lovastatin, and St. John's wort.
In combination with rifabutin: 150 mg rifabutin qd and increase nelfinavir dose to 1,250 mg bid or
1,000 mg tid.
Methadone: possibly increase dose.
Sildenafil: maximum 25 mg/48 h.
Diarrhea can often be controlled with loperamide (maximum 16 mg/day).
Internet sources:
USA: http://hiv.net/link.php?id=118
References:
1. Dube MP, Parker RA, Tebas P, et al. Glucose metabolism, lipid, and body fat changes in
antiretroviral-naive subjects randomized to nelfinavir or efavirenz plus dual nucleosides. AIDS
2005; 19: 1807-18. Abstract: http://amedeo.com/lit.php?id=16227788
2. Grossman Z, Paxinos EE, Averbuch D, et al. Mutation D30N is not preferentially selected by human
immunodeficiency virus type 1 subtype C in the development of resistance to nelfinavir. Antimicrob
Agents Chemother 2004; 48: 2159-65. http://amedeo.com/lit.php?id=15155216
3. Regazzi M, Maserati R, Villani P, et al. Clinical pharmacokinetics of nelfinavir and its
metabolite M8 in human immunodeficiency virus (HIV)-positive and HIV-hepatitis C virus-coinfected
subjects. Antimicrob Agents Chemother 2005; 49: 643-9. http://amedeo.com/lit.php?id=15673746
4. Timmermans S, Tempelman C, Godfried MH, et al. Nelfinavir and nevirapine side effects during
pregnancy. AIDS 2005; 19: 795-9. http://amedeo.com/lit.php?id=15867493
5. Walsmley S, Bernstein B, King M, et al. Lopinavir-ritonavir versus nelfinavir for the initial
treatment of HIV infection. N Engl J Med 2002, 346: 2039-46. http://amedeo.com/lit.php?id=12087139
Neupogen™ see G-CSF
Nevirapine
Nevirapine is a frequently prescribed NNRTI, which is also used successfully for the prevention of
mother-to-child transmission. As with all NNRTIs, a single point mutation is sufficient to develop
high-level resistance. With very good long-term tolerability (favorable lipid profile!),
hepatotoxicity within the first months of treatment (see below) is a problem. Dose should always be
increased gradually.
Trade name: Viramune™, abbr. NVP
Tablets: 200 mg.
Suspension: 10 mg/ml
Drug class: NNRTI
Manufacturer: Boehringer Ingelheim
Indications: HIV infection. According to the FDA, patients with a good immune status (women > 250,
men > 400 CD cells/µl) should not receive nevirapine as a component of primary therapy due to the
increased risk of hepatotoxicity.
Oral dose: 1 tablet bid with or without meals. Always start with lead-in dosing! The initial lead-in
dose (1 tablet/day over two weeks) reduces the frequency of rash. For resumption of treatment after
treatment interruption, lead-in dosing is generally not necessary if the drug was well tolerated.
Side effects: hepatotoxicity, rash. Less frequently: fever, nausea, drowsiness, headache, myalgia.
These side effects may occur with or without hepatotoxicity and/or rash. ?GT elevation on nevirapine
is almost the rule.
To detect hepatotoxicity (up to 15 %; defined as an increase in transaminases to at least three
times the upper limit of normal), liver function tests should be monitored biweekly for the first
two months. Thereafter, monthly tests are necessary, as more than half of the hepatotoxic episodes
occur after the first quarter of treatment. In such cases, treatment must be interrupted until liver
function tests have returned to initial levels. Treatment is restarted with 200 mg qd. The dose may
be increased to 200 mg bid only after a prolonged period of observation. If liver enzymes increase
again, nevirapine should be permanently discontinued. The website of the EMEA provides detailed
guidelines: Fehler! Hyperlink-Referenz ungültig.. The risk is greater with a good immune status
(women > 250 CD4 cells/µl: 12-fold ; men > 400 CD4 cells/µl: 5-fold).
A rash, often pruritic and usually occurring within the first six weeks, can generally be treated
with antihistamines if mucous membranes are not involved and transaminases are normal. Topical
formulations are effective against pruritus. Nevirapine must be discontinued if a severe rash
occurs; in these cases, steroids may be used (e.g. prednisolone 1 mg/kg for 3-5 days). Nevirapine
should also be discontinued if other symptoms occur (such as fever, conjunctivitis, myalgia,
arthralgia, malaise). If the rash occurs during the first two weeks, the dose should not be
increased until the rash has resolved completely. Prophylactic treatment with steroids or
antihistamines is not advised.
Comments/Warnings: cautious use in hepatic dysfunction (TDM).
Contraindicated for comedication with rifampin, ketoconazole, St. John's wort and the "pill".
Azole derivatives: fluconazole should be used for antimycotic treatment.
Dose adjustment in combination with
§ Lopinavir: possibly increase Kaletra™ (measure plasma levels!)
§ Indinavir: increase indinavir dose to 1,000 mg tid.
§ Methadone: if withdrawal symptoms occur, dose may need to be increased.
Nevirapine has a favorable long-term profile. In particular, lipid levels are usually positively
influenced. ?GT is almost always increased during long-term treatment. Values of up to 150 U/l can
be tolerated. Nevirapine should not be given for post-exposure prophylaxis.
Internet sources:
USA: http://hiv.net/link.php?id=121
References:
1. Back D, Gibbons S, Khoo S. Pharmacokinetic drug interactions with nevirapine. J Acquir Immune
Defic Syndr 2003; 34 Suppl 1: S8-14. http://amedeo.com/lit.php?id=14562853
2. Chi BH, Wang L, Read JS, et al. Timing of maternal and neonatal dosing of nevirapine and the risk
of mother-to-child transmission of HIV-1: HIVNET 024. AIDS 2005; 19: 1857-64. Abstract:
http://amedeo.com/lit.php?id=16227794
3. Clarke SM, Mulcahy FM, Tjia J, et al. Pharmacokinetic interactions of nevirapine and methadone
and guidelines for use of nevirapine to treat Injection drug users. Clin Infect Dis 2001, 33.
http://amedeo.com/lit.php?id=11568856
4. De Maat MM, Ter Heine R, Van Gorp EC, et al. Case series of acute hepatitis in a non-selected
group of HIV-infected patients on nevirapine-containing antiretroviral treatment. AIDS 2003; 17:
2209-14. http://amedeo.com/lit.php?id=14523278
5. Gonzalez de Requena D, Nunez M, Jimenez-Nacher I, Soriano V. Liver toxicity caused by nevirapine.
AIDS 2002, 16: 290-1. http://amedeo.com/lit.php?id=11807315
6. Johnson JA, Li JF, Morris L, et al. Emergence of drug-resistant HIV-1 after intrapartum
administration of single-dose nevirapine is substantially underestimated. J Infect Dis 2005; 192:
16-23. http://amedeo.com/lit.php?id=15942889
7. Lallemant M, Jourdain G, Le Coeur S, et al. Single-dose perinatal nevirapine plus standard
zidovudine to prevent mother-to-child transmission of HIV-1 in Thailand. N Engl J Med 2004; 351:
217-28. http://amedeo.com/lit.php?id=15247338
8. Martinez E, Blanco JL, Arnaiz JA, et al. Hepatotoxicity in HIV-1-infected patients receiving
nevirapine-containing antiretroviral therapy. AIDS 2001, 15: 1261-1268.
http://amedeo.com/lit.php?id=11426070
9. Sanne I, Mommeja-Marin H, Hinkle J, et al. Severe hepatotoxicity associated with nevirapine use
in HIV-infected subjects. J Infect Dis 2005; 191: 825-9. Abstract:
http://amedeo.com/lit.php?id=15717255
10. van Leth F, Phanuphak P, Ruxrungtham K, et al. Comparison of first-line antiretroviral therapy
with regimens including nevirapine, efavirenz, or both drugs, plus stavudine and lamivudine: a
randomised open-label trial, the 2NN Study. Lancet 2004; 363: 1253-63.
http://amedeo.com/lit.php?id=15094269
11. Wit FW, Wood R, Horban A, et al. Prednisolone does not prevent hypersensitivity reactions in
antiretroviral drug regimens containing abacavir with or without nevirapine. AIDS 2001, 15:
2423-2429. http://amedeo.com/lit.php?id=11740193
Norvir™ see Ritonavir
Pegasys™ see Interferon
PegIntron™ see Interferon
Pentacarinat™ see Pentamidine
Pentamidine
Trade name: Pentacarinat™
Vials: 300 mg
Drug class: antibiotic
Manufacturer: Aventis, GlaxoSmithKline
Indications: treatment and secondary prophylaxis of Pneumocystis pneumonia if co-trimoxazole is
contraindicated (hypersensitivity, resistance to treatment).
Dose: treatment: 200-300 mg Pentacarinat™ iv for five days (4 mg/kg), then halve the dose. In very
mild cases, daily inhalations with 300 mg.
In renal failure and creatinine clearance of 50-10 ml/min: 4 mg/kg q 24-36 h; < 10 ml/min: 4 mg/kg q
48 h.
Prophylaxis: inhalation of 300 mg 1-2 x/month.
Side effects: frequent with intravenous dosing! Nausea, vomiting, metallic taste; nephrotoxicity
(increased creatinine in the second week of treatment) up to renal failure. Hypo- or hyperglycemia
(possible even months after end of treatment), hypotension, arrhythmia, pancreatitis.
Leukopenia and thrombocytopenia. Inhalation may induce cough, rarely asthma attacks.
Comments/Warnings:
Inhalation: pentamidine as an aerosol is contraindicated in asthma and treatment with beta-blockers.
Inhalation may be ineffective with pulmonary disease. Prior inhalation of a ß-mimetic may be
desirable.
Infusions: caution in liver or renal failure, hyper- or hypotension, hyperglycemia, cytopenia.
Always ensure sufficient intake of electrolytes and fluids. No concurrent administration of other
nephrotoxic drugs (e.g. aminoglycosides, amphotericin B, foscarnet). Patient should remain in supine
position before, during and after infusions of pentamidine (caution: hypotension!). Pentamidine
should be infused slowly over at least 2 hours! Daily monitoring of BUN, serum creatinine, blood
count, fasting blood glucose, urinalysis and serum electrolytes, weekly monitoring of bilirubin,
alkaline phosphatase, transaminases.
References:
1. Cardoso JS, Mota-Miranda A, Conde C, et al. Inhalatory pentamidine therapy and the duration of
the QT interval in HIV-infected patients. Int J Cardiol 1997, 59: 285-9.
http://amedeo.com/lit.php?id=9183045
2. Chan M, Lee-Pack LR, Favell K, Chan CK. Acute pulmonary effects of three nebulizers for
administering aerosol pentamidine: comparison of Parineb to Fisoneb and Respirgard II. J Aerosol Med
1996, 9: 521-6. http://amedeo.com/lit.php?id=10163666
3. Girgis I, Gualberti J, Langan L, et al. A prospective study of the effect of I.V. pentamidine
therapy on ventricular arrhythmias and QTc prolongation in HIV-infected patients. Chest 1997, 112:
646-53. http://amedeo.com/lit.php?id=9315796
4. O'Brien JG, Dong BJ, Coleman RL, Gee L, Balano KB. A 5-year retrospective review of adverse drug
reactions and their risk factors in HIV-infected patients who were receiving intravenous pentamidine
therapy for Pneumocystis carinii pneumonia. Clin Infect Dis 1997, 24: 854-9.
http://amedeo.com/lit.php?id=9142782
5. Tabet SR, Krone MR, Hooton TM, Koutsky LA, Holmes KK. Bacterial infections in adult patients
hospitalized with AIDS: case-control study of prophylactic efficacy of trimethoprim-sulfamethoxazole
versus aerosolized pentamidine. Int J STD AIDS 1997, 8: 563-9. http://amedeo.com/lit.php?id=9292345
6. Warnock AC, Rimland D. Comparison of trimethoprim-sulfamethoxazole, dapsone, and pentamidine in
the prophylaxis of Pneumocystis carinii pneumonia. Pharmacotherapy 1996, 16: 1030-8.
http://amedeo.com/lit.php?id=8947975
7. Wei CC, Pack LL, Chan CK. Effects of long-term aerosol pentamidine for Pneumocystis carinii
prophylaxis on pulmonary function. Chest 1998, 114: 742-7. http://amedeo.com/lit.php?id=9743160
Prezista™ see Darunavir
Proleukin™ see Interleukin-2
Pyrimethamine
Trade name: Daraprim™
Tablets: 25 mg
Manufacturer: GlaxoSmithKline
Indications: prophylaxis and treatment of cerebral toxoplasmosis. Prophylaxis of pneumocystis
pneumonia.
Dose: treatment of toxoplasmosis: Daraprim™ 2 tbl. ŕ 25 mg bid (for 3 days, then halve the dose)
plus Leucovorin™ 1 tbl. ŕ 15 mg every other day plus either sulfadiazine or clindamycin.
PCP prophylaxis in combination with dapsone: Daraprim™ 2 tbl. ŕ 25 mg per week plus Dapsone™ 1 tbl.
ŕ 50 mg qd plus Leucovorin™ 2 tbl. ŕ 15 mg per week.
Side effects: Myelosuppressive! Most important side effect is anemia. Thrombocytopenia and
leukopenia. Nausea, colics, vomiting, diarrhea. Rarely seizures, tremor or ataxia.
Comments/Warnings: pyrimethamine is contraindicated in megaloblastic anemia resulting from folic
acid deficiency. Caution in patients with seizures, renal failure, asthma or G6PD deficiency. All
patients on pyrimethamine should receive folinic acid to decrease myelosuppression. In |