(HIVPlus) Standard of Care :

SEPTEMBER 1998

NUMBER ONE

STANDARD OF CARE

Anti-HIV Drugs
There's a combo built for you.

The success-and failure-of combination therapy using protease and other HIV drugs has ushered in a race among drug companies to provide new drugs to stop HIV and target dormant cells harboring virus particles. There are 15 anti-HIV drugs being used in combination regimens, including three drugs available through broadened expanded access programs, indicated by an asterisk (*) in the table below. These drugs target different HIV enzymes or proteins that the virus uses to reproduce inside a cell.

Reverse transcriptase inhibitors (RTIs) include nucleoside analog reverse transcriptase inhibitor drugs (NRTIs), or "nukes," like Retrovir and the new Ziagen; non-nucleoside analog reverse transcriptase inhibitors (NNRTIs) like Sustiva; the new nucleotide analog drug, Preveon; and protease inhibitors (PIs) such as Crixivan. An anticancer drug, Hydrea, is also potent against HIV. Drug companies are also reformulating some drugs to make them easier to take--and hopefully cheaper. First out of the starting gate is Combivir (Glaxo Wellcome), a combination of AZT and 3TC in a single, once-a-day tablet (see "Wanted: Simpler Regimens"). Treatment guidelines are constantly evolving (see Tables), but experts recommend a potent three-drug protease regimen as a first-line therapy (one PI plus two nukes) or, as an alternative, a non-protease regimen (one NNRTI plus two nukes). Non-protease combinations may be a first-line option for healthy individuals with high, stable T-cell counts and low viral loads who want to save protease drugs for later, or for those responding poorly or developing resistance to HIV.

Remember--HIV can develop resistance to all drugs, so it's important to choose your initial regimen carefully. The selective table below is designed to note the main features of each drug. Read the drug package insert and consult your doctor or AIDS-treatment group for updates. More drugs are coming that target other HIV-proteins, including zinc finger inhibitors, integrase inhibitors, and fusion inhibitors (see "What's in the Pipeline").

There are also new approaches being taken to modulate immune responses that represent a complementary strategy to anti-HIV therapy. Included below are specific side effects and recommendations for each drug. Consult your doctor or treatment groups for updates.

Nucleoside analog reverse transcriptase inhibitors are potent in combination with other drugs; used alone, they lead to HIV resistance. AZT, d4T, 3TC, and Ziagen penetrate the blood-brain barrier.

Drug/Dosage	Side Effects	Drug Interactions	Recommendations
Retrovir (AZT/ zidovudine) Glaxo Wellcome Dose: 300-600 mg/day Approved for pediatric use.	Nausea, vomiting, anemia, low white-blood-cell counts, bone-marrow damage, headaches, rash, itching, weakness, loss of appetite, muscle loss.	Serious: d4T, toxic bone-marrow drugs (e.g. ganciclovir, chemotherapies, antineoplastics). Possible: Methadone, Dilantin, fluconazole (Diflucan), Depakene, ongoing use of Tylenol, dapsone, pentamidine, probenecid, fencytosine, alpha-interferon, Biaxin, rifabutin, rifampin, ribavirin.	Best on empty stomach; take AZT with food if you have stomach irritation. Take vitamin E, erythropoieitin alpha (EPO), or G-CSF to prevent possible blood-cell damage; B vitamins and manganese. Warning: A structural flaw in AZT may lead to HIV resistance.
Combivir (3TC 150 mg/AZT 300 mg)	See 3TC and AZT.
Epivir (3TC, lamivudine) Glaxo Wellcome 300 mg/day (Two 150 mg/day) Liquid solution for pediatric use.	Headache, nausea, fatigue, low white-blood-cell count, rare hair loss, neuropathy.	Serious: ddC. Possible: Bactrim may increase 3TC levels.	Watch for anemia and neutropenia. Monitor triglycerides for pancreatitis, especially in children. Take with or without food.
Videx (ddI/didanosine) Bristol-Myers Squibb 400 mg/day Approved for pediatric use.	Stomach pain, diarrhea, pancreatitis; neuropathy with high doses; hepatitis, seizures, headaches.	Serious: pentamidine, ethambutol. Possible: antineoplastics, alcohol, ganciclovir,ciprofloxacin, cimetidine (Tagamet). Coated pill causes poor absorption of indinavir (Crixivan), ketoconazole (Nizoral), dapsone, tetracycline (all should be taken two hours apart from ddI.)	Avoid alcohol, which increases risk of pancreatitis. Take on empty stomach at least 30 minutes before meal.
Hivid (ddC/zalcitabine) Hoffmann-La Roche Three 0.75 mg doses/day Approved for pediatric use.	Skin rashes, canker sores, inflammation of mouth, nausea, neuropathy, upset stomach, pancreatitis, liver damage.	Serious: pentamidine, ddI, 3TC. Avoid other neuropathy-causing drugs (chloramphenicol, Antabuse, dapsone, isoniazid). Possible: Radiation therapy, amphotericin B, pyrimethamine, sulfadiazine, intravenous TMP/SMX (Bactrim), ganciclovir, acyclovir, foscarnet, probenecid.	Watch for neuropathy and pancreatitis. Avoid taking with food if possible.
Zerit (d4T/stavudine) Bristol-Myers Squibb Two 40-mg doses/day Liquid solution for pediatric use.	Neuropathy, pancreatitis, insomnia, hyperactivity; elevated liver enzymes and anemia at high doses.	Serious: AZT. Possible: Ganciclovir, pentamidine, other drugs that cause neuropathy.	Watch for neuropathy and pancreatitis. Take with or without food.
* Ziagen (abacavir, 1592U89) Glaxo Wellcome 300 mg twice a day Under study for pediatric use.	Headache, fatigue; rare allergy (fever, rash, nausea,dizziness, vomiting); abdominal pain, GI and liver problems. Warning: Stop drug immediately and don't try again if any sign of allergy.	Alcohol increases blood level of Ziagen.	Very potent. Expanded access for patients failing standard regimens. Compassionate use: adults with HIV dementia and pediatric HIV. Crosses blood-brain barrier.

Non-nucleoside analog reverse transcriptase inhibitors (NNRTIs, or non-nukes) may interact with other cytochrome p450-processed drugs: protease inhibitors, oral contraceptives, etc. NNRTIs have a mixed ability to penetrate the blood-brain barrier. Common side effect: mild rash. Some doctors build up drug doses slowly to avoid rash; others worry that dose building increases risk of drug resistance.

Drug/Dosage	Side Effects	Drug Interactions	Recommendations
Viramune (nevirapine) Roxane Laboratories. One 200-mg/day dose for 14 days then two 200-mg doses/day. Expanded access for pediatric use.	Fever, muscle soreness, elevated liver function, rash (possibly indicating life-threatening Stevens-Johnson syndrome in rare cases).	Possible: rifampin, rifabutin, oral contraceptives, protease inhibitors, triazolam and midazolam. Use with fluconazole increases risk of rash.	If rash develops, call your doctor; Benadryl or topical corticosteroids may relieve rash symptoms. Drug crosses the placenta. Take with or without food.
Rescriptor (delavirdine) Pharmacia & Upjohn. 400 mg three times a day. Under study for pediatric use.	Rash (possibly indicating life-threatening Stevens-Johnson syndrome in rare cases).	Serious: terfenadine, astemizole, alprazolam, midazolam, cisapride, rifabutin, rifampin, triazolam, ergot derivatives, amphetamines, nifedipine, anticonvulsants. Possible: Delavirdine increases levels of Biaxin, dapsone, quinidine, warfarin, indinavir, saquinavir. Take an hour apart from ddI and antacids (Tagamet).	Take with or without food. Take with cranberry or orange juice if you have low stomach acid. If rash develops, call your doctor; Benadryl or topical corticosteroids may relieve rash symptoms. One study shows women may have higher blood levels of Rescriptor.
*Sustiva (efavirenz, DMP-266) DuPont Merck. 600 mg once a day. Under study for pediatric use.	Light-headedness, dizziness, body ache, rash, sinusitis, uppper repiratory-tract infection, diarrhea, nausea, flu-like symptoms.	Serious: saquinavir (Fortovase); rifampin (until dosing is clarified). Potential: Drug may slightly increase ritonavir levels and decrease Crixivan levels.	Take before bedtime to avoid light-headedness. New data supports Sustiva for first line HIV therapy. Warning: Not for use in early pregnancy (caused birth defects in some newborn monkeys). Take with or without food.

Nucleoside analog reverse transcriptase inhibitors appear potent against HIV.

Drug/Dosage	Side Effects	Drug Interactions	Recommendations
* Preveon (adefovir dipivoxil, bis-POM PMEA) Gilead. 120 mg/day. In Phase II/III trials.	Nausea, diarrhea, elevated liver enzymes. Preveon depletes the body of a natural substance called L-carnitine.	Serious: drugs toxic to kidney (e.g. foscarnet.)	Expanded access for those failing standard regimens. Check liver function; take with L-carnitine supplement. Good against herpes viruses. Take with or without food.

Protease inhibitors (PIs) are very potent and may interact with other drugs using cytochrome p450 metabolic pathways. Potentially life-threatening if taken with Seldane, Hismanal, Propulsid, Halcion, or Versed. Avoid rifabutin, Nizoral, rifampin. Poor absorption may affect potency. Common side effects: liver toxicity, hypoglycemia, flatulence, bloating, lipodystrophy (fat distribution). Monitor liver and glucose levels.

Drug/Dosage	Side Effects	Drug Interactions	Recommendations
Fortovase (saquinavir) Hoffmann-La Roche 1,200 mg three times a day. Invirase: old formula. Under study for pediatric use.	Diarrhea, gas, nausea, stomach cramps, heartburn, fatigue, numbness, rash; elevated liver enzymes. Poor absorption affects potency.	Serious: Sustiva reduces Fortovase in early studies and possibly phenobarbital, phenytoin, dexamethasone, carbamezapine. Potential: ritonavir,nevirapine.	Take with food or within two hours of eating. Fortovase is more potent than Invirase. Invirase not recommended as first-line therapy due to poor absorption and resistance issues.
Norvir (ritonavir) Abbott Laboratories. Six 100 mg. twice a day. Liquid solution for children.	Nausea, vomiting, weakness, diarrhea, rash, fatigue, numbness around mouth, changed taste in mouth, elevated liver enzymes.	Serious: A long list. Read package insert carefully. Poor interaction with common antihistamines and antidepressants like Prozac.	Build up to optimal dose over a few days. Take with a full, high-protein meal. Yogurt may reduce side effects.
Crixivan (indinavir) Merck & Company. Three 800-mg doses/day. Under study for pediatric use.	Kidney stones, anemia, lipodystrophy (body fat changes; facial or truncal wasting).	Serious: grapefruit juice. Potential: Viramune, saquinavir (poor interaction in test-tube studies).	Take on empty stomach with water one hour before or two hours after eating. Drink at least six glasses of water daily to avoid kidney stones. Alternative liquids: juice, skim milk, coffee, tea. Eat with fat free snacks.
Viracept (nelfinavir) Agouron Pharmaceuticals Three 750 mg doses/day. Approved for pediatric use: dose 20-30 mg/kg.	Fatigue, rash, nausea, stomach cramps, diarrhea, elevated liver enzymes.	Potential: Increases Fortovase (under study as combo) and Crixivan in preliminary studies.	Take with food. Use Imodium, Lomotil to control diarrhea. Women should consult with their doctors prior to use. Monitor glucose levels to avoid risk of diabetes.

Other Drugs

Drug/Dosage	Side Effects	Drug Interactions	Recommendations
Hydrea (Hydroxyurea/HO) Bristol-Myers Squibb. Two 500-mg doses/day. A chemotherapy drug; probably penetrates blood- brain barrier. Available for pediatric use.	Mild nausea, bone-marrow suppression, hair loss, rare dry mouth. Reduces CD8+ cell activation.	Increases efficacy of ddI, even against ddI-resistant HIV. In vitro synergy with AZT, but risk of bone-marrow suppression.	Animal studies suggest possible toxicity for pregnant women. Monitor bone-marrow suppression, liver and kidney function. Drug attacks a cell enzyme (ribonucleotide reductase); may work against proviral HIV in resting T-cells and macrophages (latent infection).