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Antiretroviral Therapy

Antiretroviral treatment should be offered to all patients with the acute HIV syndrome, those within six months of seroconversion, and all patients with symptoms ascribed to HIV infection. In asymptomatic patients, treatment should be offered to individuals with fewer than 300 CD4 ⁺ T cells/mm³ or plasma HIV RNA levels exceeding 10,000 copies/mL (bDNA assay) or 20,000 copies/mL (RT-PCR assay). This may be achieved with a potent protease inhibitor (PI) in combination with two nucleoside analogue reverse transcriptase inhibitors (NRTIs).

Plasma HIV RNA levels and CD 4 ⁺ T cell count

Measurement of plasma HIV RNA levels (viral load) should be performed at the time of diagnosis and every 3–4 months thereafter. Plasma HIV RNA levels should also be measured immediately prior to and at 2–8 weeks after initiation.

Once the patient is on therapy, HIV RNA testing should be repeated every 3–4 months. With optimal therapy viral levels in plasma should be undetectable (below 500 copies of HIV RNA per mL of plasma).

Initiating therapy in asymptomatic HIV infection

Any patient with less than 500 CD4 ⁺ T cells/mm³ or greater than 10,000 (bDNA) or 20,000 (RT-PCR) copies of HIV RNA/mL of plasma.

Antiretroviral agents for treatment of HIV infection
Column A	Column B
Indinavir	ZDV + ddI
Nelfinavir	d4T + ddI
Ritonavir	ZDV + ddC
Saquinavir	ZDV + 3TC
Ritonavir + Saquinavir	d4T + 3TC
Efavirenz
Regimen should consist of agents from column A and column B

Initiating therapy in advanced HIV disease. All patients diagnosed with advanced HIV disease (defined as any AIDS-defining condition) should be treated with antiretroviral agents. All patients with symptomatic HIV infection without AIDS, defined as the presence of thrush or unexplained fever, should also be treated. Once therapy is initiated, a maximally suppressive regimen, such as 2 NRTIs and a protease inhibitor.

Indications for changing therapy

Less than a 0.5–0.75 log reduction in plasma HIV RNA by 4 weeks following initiation of therapy, or less than a 1 log reduction.

Failure to suppress plasma HIV RNA to undetectable levels within 4–6 months of initiating therapy.

Repeated detection of virus in plasma after initial suppression to undetectable levels.

Any reproducible significant increase, defined as 3-fold or greater, from the nadir of plasma HIV RNA not attributable to intercurrent infection, vaccination, or test methodology.

Persistently declining CD4 ⁺ T cell numbers, as measured on at least two separate occasions.

Clinical deterioration. A new AIDS-defining diagnosis that was acquired after the time treatment was initiated suggests clinical deterioration.

Characteristics of nucleoside reverse transcriptase inhibitors (NRTIs)
Name	Zidovudine ( Retrovir, AZT, ZDV)	Didanosine (Videx, ddI)	Zalcitabine ( HIVID, ddC)	Stavudine ( Zerit, d4T)	Lamivudine ( Epivir, 3TC)
Dosage	200 mg tid or 300 mg bid or with 3TC as Combivir, 1 bid	>60kg: 200 mg bid <60 kg: 125 mg bid	0.75 mg tid	>60 kg: 40 mg bid < 60 kg: 30 mg bid	150 mg bid <50kg:2mg/kg bid or with ZDV as Combivir 1 bid
Adverse Events	Bone marrow suppression: Anemia and/or neutropenia, GI intolerance, headache, insomnia, asthenia Lactic acidosis with	Pancreatitis, peripheral neuropathy nausea, diarrhea Lactic acidosis with hepatic steatosis rare.	Peripheral neuropathy, stomatitis Lactic acidosis with hepatic steatosis rare.	Peripheral neuropathy Lactic acidosis with hepatic steatosis rare.	Lactic acidosis with hepatic steatosis rare.

Characteristics of protease inhibitors

Name

Indinavir (Crixivan)

Ritonavir (Norvir)

Saquinavir (Fortovase)

Nelfinavir (Viracept)

Form

200, 400 mg caps

100 mg caps

600 mg/7.5ml po solution

200 mg caps

250 mg tablets

50mg/g oral powder

Dosage

800 mg q8h

Take 1 hr before or 2 hrs after meals; may take with skim milk or

600 mg q12h

Take with food if possible

1,200 mg TID

Take with food

750 mg TID

Take with food

Adverse Effects

Nephrolithiasis, GI intolerance, nausea, increased indirect bilirubinemia

Headache, asthenia, blurred vision, dizziness, rash, metallic taste, thrombocytopenia, hyperglycemia, fat redistribution and

GI intolerance, nausea, vomiting, diarrhea

Paresthesias - circumoral and extremities

Hepatitis, asthenia, triglycerides increase >200%, transaminase elevation, elevated CPK and uric acid; hyperglycemia, fat redistribution and lipid abnormalities

GI intolerance, nausea, diarrhea, abdominal pain and dyspepsia

Headache, elevated transaminase enzymes, hyperglycemia

Fat redistribution and lipid abnormalities

Diarrhea, hyperglycemia

Fat redistribution and lipid abnormalities

Drug Interactions

Inhibits cytochrome P450

Not recommended for concurrent use: rifampin, astemizole, cisapride, triazolam, midazolam, ergot alkaloids

Levels increased by: ketoconazole, delavirdine, nelfinavir

Levels reduced by: rifampin, rifabutin, grapefruit juice, nevirapine

Didanosine: reduces indinavir absorption unless taken >2 hrs apart

Inhibits cytochrome P450

Increases levels of amiodarone, astemizole, bepridil, bupropion, cisapride, clorazepate, clozapine, diazepam, encainide, estazolam, flecainide, flurazepam, meperidine, midazolam, piroxicam, propoxyphene, propafenone, quinidine, rifabutin, triazolam, zolpidem, ergot alkaloids.

Didanosine may cause reduced absorption; take >2 hours apart

Decreases levels of ethinyl estradiol, theophylline, ZDV

Increases levels of clarithromycin, desipramine

Inhibits cytochrome P450

Levels increased by: ritonavir, ketoconazole, grapefruit juice, nelfinavir, delavirdine

Levels reduced by rifampin, rifabutin, phenobarbital, phenytoin, dexamethasone and carbamazepine, nevirapine

Not recommended for concurrent use: rifampin, rifabutin, astemizole, cisapride, ergot alkaloids, triazolam, midazolam

Inhibits cytochrome P450

Levels reduced by rifampin, rifabutin

Contraindicated: triazolam, midazolam, ergot alkaloids, astemizole, cisapride

Nelfinavir decreases levels of ethinyl estradiol and norethindrone

Nelfinavir increases levels of rifabutin, saquinavir and indinavir

Not recommended for concurrent use: rifampin

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Name	Nevirapine (Viramune)	Delavirdine (Rescriptor)	Efavirenz (Sustiva)
Form	200 mg tabs	100 mg tabs	50, 100, 200 mg capsules
Dosage	200 mg po qd x 14 days, then 200 mg po bid	400 mg po tid (four 100 mg tablets in >3 oz. water to produce slurry)	600 mg po qHS
Drug interactions	Induces cytochrome p450 enzymes The following drugs have suspected interactions that require careful monitoring if co-administered with nevirapine: rifampin, rifabutin, oral contraceptives, protease inhibitors, triazolam and midazolam	Inhibits cytochrome p450 enzymes Not recommended for concurrent use: astemizole, alprazolam, midazolam, cisapride, rifabutin, rifampin, triazolam, ergot derivatives, amphetamines, nifedipine, anticonvulsants (phenytoin, carbamazepine, phenobarbital) Delavirdine increases levels of clarithromycin, dapsone, quinidine, warfarin, indinavir, saquinavir Antacids or didanosine: separate delavirdine administration by >1 hr	Mixed inducer/inhibitor of cytochrome p450 A4 enzymes. Contraindications: astemizole, midazolam, triazolam, cisapride, ergot alkaloids. Efavirenz decreases indinavir, saquinavir, and increases levels of nelfinavir, ritonavir. Potentially significant interactions: warfarin, clarithromycin, rifabutin, rifampin, ethinyl estradiol. Enzyme inducers such as rifampin, rifabutin, phenobarbital, and phenytoin decrease efavirenz concentrations.
Adverse Events	Rash Increased transaminase levels Hepatitis	Rash Headaches	Rash Central nervous systems symptoms Increased transaminase levels False positive cannabinoid test Teratogenic in monkeys

Drugs Available Through Treatment Investigational New Drug Protocols
Drug	Adefovir ( Preveon)	Abacavir ( 1592-U89)	Amprenavir ( Agenerase; 141W94)
Class	Nucleotide RT Inhibitor	Nucleotide RT Inhibitor	Protease Inhibitor
Usual Dose	60 mg po qd or 120 mg po qd + L-carnitine 500 mg po qd	300 mg po bid	1200 mg po bid
Comments	Activity vs. HBV, CMV, HSV	Good CNS penetration; non CY450-mediated metabolism	Unique resistance profile

Therapeutic options when changing antiretroviral therapy

A change in regimen because of treatment failure should involve complete replacement of the regimen with different drugs to which the patient is naive and to which cross-resistance is not anticipated. The new regimen may include the use of 2 new NRTIs and one new PI or NNRTI, two PIs with one or two new NRTIs, or a PI combined.