Treatment Guidelines from The Medical Letter® Published by The Medical Letter • 145 Huguenot Street, New Rochelle, NY 10801 • A Nonprofit Publication IN THIS ISSUE (starts on next page) Drugs for HIV Infections p The Medical Letter ® publications are protected by US and international copyright laws Forwarding, copying or any distribution of this material is prohibited Sharing a password with a non-subscriber or otherwise making the contents of this site available to third parties is strictly prohibited By accessing and reading the attached content I agree to comply with US and international copyright laws and these terms and conditions of The Medical Letter, Inc For further information click: Subscriptions, Site Licenses, Reprints or call customer service at: 800-211-2769 FORWARDING OR COPYING IS A VIOLATION OF US AND INTERNATIONAL COPYRIGHT LAWS The Medical Letter publications are protected by US and international copyright laws Forwarding, copying or any other distribution of this material is strictly prohibited For further information call: 800-211-2769 Treatment Guidelines from The Medical Letter® Published by The Medical Letter • 145 Huguenot Street, New Rochelle, NY 10801 • A Nonprofit Publication Volume 12 (Issue 138) February 2014 www.medicalletter.org Drugs for HIV Infection Tables Regimens for Treatment-Naive Patients Dosage and Cost of NRTIs and NNRTIs Adverse Effects and Drug Interactions of NRTIs and NNRTIs Dosage and Cost of PIs, INSTIs, and Others Adverse Effects and Drug Interactions of PIs and INSTIs Regimens for Post-Exposure Prophylaxis Page Page Page Page 11 Page 12 Page 14 Related article(s) since publication Antiretroviral therapy is recommended for all HIVinfected patients, both to reduce the risk of disease progression and to prevent transmission of the virus to others.Various guidelines for treatment of HIV infection are available.1-4 Antiretroviral treatment most often includes a “backbone” of two nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) and a third drug, which can be a non-nucleoside reverse transcriptase inhibitor (NNRTI), a protease inhibitor (PI), an integrase strand transfer inhibitor (INSTI), or a CCR5 antagonist Preferred and alternative regimens for treatment-naive patients are listed in Table Antiretroviral therapy is often complicated by adverse effects and interactions with other drugs, some of which are listed in Tables and Drug-resistance testing is recommended before antiretroviral drugs are started.1 While on therapy, an increase in HIV RNA levels (“viral load”) after an initial reduction or complete virologic suppression may indicate development of drug resistance In such patients, an assessment of adherence, further resistance testing, and a change in the treatment regimen should be considered NUCLEOSIDE/NUCLEOTIDE REVERSE TRANSCRIPTASE INHIBITORS (NRTIs) NRTIs inhibit HIV-1 reverse transcriptase and decrease or prevent HIV replication in infected cells They are not metabolized by CYP450 enzymes, but drug interactions by other mechanisms have been reported (see Table 3) NRTIs (especially didanosine, stavudine, and zidovudine) can cause a potentially fatal syndrome of lactic acidosis with hepatic steatosis EMTRICITABINE (FTC, Emtriva) — Emtricitabine combined with tenofovir DF is the preferred NRTI backbone for treatment-naive patients The 5-fluorinated derivative of lamivudine, emtricitabine Table Regimens for Treatment-Naive Patients1 NNRTI-Based Regimens Preferred Alternative Efavirenz2/tenofovir DF3/emtricitabine4 Efavirenz2 + abacavir5/lamivudine4 Rilpivirine6/tenofovir DF3/emtricitabine4 Rilpivirine6 + abacavir5/lamivudine4 PI-Based Regimens Preferred Alternative Atazanavir/ritonavir7 + tenofovir DF3/emtricitabine4 Darunavir/ritonavir (once daily) + tenofovir DF3/emtricitabine4 Atazanavir/ritonavir7 + abacavir5/lamivudine4 Darunavir/ritonavir + abacavir5/lamivudine4 Fosamprenavir/ritonavir (once or twice daily) + either abacavir5/lamivudine4 or tenofovir DF3/emtricitabine4 Lopinavir/ritonavir (once or twice daily) + either abacavir5/lamivudine4 or tenofovir DF3/emtricitabine4 INSTI-Based Regimens Preferred Alternative Raltegravir + tenofovir DF3/emtricitabine4 Elvitegravir/cobicistat/tenofovir DF/emtricitabine8 Dolutegravir + either abacavir5/lamivudine4 or tenofovir DF3/emtricitabine4 Raltegravir + abacavir5/lamivudine4 CCR5 Antagonist-Based Regimens9 Acceptable Maraviroc + either zidovudine/lamivudine4 or tenofovir DF3/emtricitabine4 or abacavir5/lamivudine4 For non-pregnant adults and adolescents An NNRTI-, PI- or INSTIbased regimen is preferred for initial therapy Adapted from HHS guidelines available at www.aidsinfo.nih.gov/guidelines Accessed January 15, 2014 “Preferred regimens” are those regimens studied in randomized controlled trials and shown to have optimal and durable virologic efficacy, favorable tolerability and toxicity profiles, and ease of use “Alternative regimens” are those regimens that are effective but have potential disadvantages when compared with preferred regimens Except in pregnant women or women who might become pregnant; efavirenz is contraindicated in pregnant women initiating therapy Pregnant women with optimal viral suppression with efavirenz can continue taking it Use with caution in patients with renal insufficiency Emtricitabine can be substituted for lamivudine and vice versa For patients who test negative for HLA-B*5701 Abacavir should be used with caution in patients with a pretreatment viral load >100,000 copies/ mL or in those who are at high risk for cardiovascular disease Not recommended if pretreatment viral load is >100,000 copies/mL Use of proton pump inhibitors is contraindicated Not recommended for patients who require >20 mg/d omeprazole equivalent Should not be started in patients with CrCl 400 cells/mm3 are at increased risk Treatment Guidelines from The Medical Letter • Vol 12 (Issue 138) • February 2014 Drugs for HIV Infection is similar to lamivudine in spectrum of activity, potency, safety, and resistance patterns Resistance to emtricitabine is conferred by the M184V/I mutation, which is also the main cause of resistance to lamivudine, so cross-resistance between the two drugs is complete Emtricitabine is also active against hepatitis B TENOFOVIR DF (TDF, Viread) — Tenofovir disoproxil fumarate, the prodrug of tenofovir, is the only nucleotide reverse transcriptase inhibitor available for treatment of HIV Combined with emtricitabine, it is the preferred NRTI backbone for treatment-naive patients Tenofovir DF is also approved for treatment of chronic hepatitis B Coinfected patients being treated for hepatitis B should also be treated for HIV ABACAVIR (ABC, Ziagen) — Abacavir combined with lamivudine is a recommended NRTI backbone for treatment-naive patients Data on efficacy of regimens containing an abacavir/lamivudine backbone have been conflicting One trial found an increased incidence of virologic failure in treatment-naive patients with pretreatment HIV RNA ≥100,000 copies/mL treated with an abacavir/lamivudine backbone compared to treatment with tenofovir/emtricitabine; the patients in this trial received efavirenz or ritonavir-boosted atazanavir as their third drug.5 Other trials in patients taking ritonavir-boosted lopinavir or dolutegravir as their third drug did not find the abacavir/lamivudine backbone less effective in those with a viral load ≥100,000 copies/mL.6,7 LAMIVUDINE (3TC, Epivir) — Lamivudine combined with abacavir is a recommended NRTI backbone for treatment-naive patients Lamivudineresistant strains are cross-resistant to emtricitabine, and may have a modest decrease in susceptibility to abacavir A lower-dose formulation of lamivudine (Epivir-HBV) is approved for treatment of chronic hepatitis B in patients not infected with HIV OTHERS — Zidovudine (AZT, ZDV, Retrovir) was the first antiretroviral approved for treatment of HIV It can be effective when used as part of the backbone of an initial regimen, but it is generally not recommended because of its adverse effects Didanosine (ddI, Videx) and stavudine (d4T, Zerit) are not recommended for initial therapy and are rarely used because of their adverse effects EFAVIRENZ (EFV, Sustiva) — Efavirenz plus emtricitabine/tenofovir DF is the preferred NNRTIbased regimen for treatment-naive patients In such patients, the combination of efavirenz with NRTIs has been at least as effective in lowering HIV RNA levels as an atazanavir- or lopinavir-based regimen.8 Efavirenz is potentially teratogenic and should not be used during pregnancy, especially during the first trimester RILPIVIRINE (RPV, Edurant) — Rilpivirine is the newest NNRTI.9 FDA approval was based on pooled results from double-blind non-inferiority studies in previously untreated patients that found that rilpivirine was as effective as efavirenz.10,11 Virologic failure is more common in patients with a pretreatment viral load >100,000 copies/mL; rilpivirine is not recommended for use in such patients Rilpivirine is a more convenient, less toxic alternative (“switch option”) for patients who have virologic suppression with a PI-based regimen.12 The fixed-dose combination of rilpivirine, emtricitabine, and tenofovir (Complera) has been approved by the FDA for such use The pretreatment baseline viral load restriction is not applicable for such patients Resistance to rilpivirine is likely to confer cross-resistance to all other NNRTIs, including etravirine.13 ETRAVIRINE (ETR, Intelence) — Use of etravirine in combination with other antiretroviral drugs has been effective in achieving virologic suppression in treatmentexperienced patients with documented resistance to both PIs and other NNRTIs Etravirine may be active against some HIV-1 strains resistant to efavirenz and nevirapine.14 OTHERS — Nevirapine (NVP, Viramune) has been comparable to efavirenz in effectiveness, but it is rarely used because of its toxicity Delavirdine (DLV, Rescriptor) is the least potent NNRTI and is rarely used PROTEASE INHIBITORS (PIs) NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NNRTIs) PIs prevent cleavage of protein precursors essential for HIV maturation, infection of new cells, and viral replication Use of a PI in combination with other drugs has led to marked clinical improvement and prolonged survival, even in patients with advanced HIV infection Coadministration of a low (non-therapeutic) dose of ritonavir is required for most PIs; it inhibits their metabolism, increasing their serum concentrations to therapeutic levels (“ritonavir boosting”) NNRTIs are direct non-nucleoside inhibitors of HIV-1 reverse transcriptase Resistance to NNRTIs develops rapidly if they are used alone or in combinations that not completely suppress viral replication NNRTIs are metabolized in the liver by CYP450 enzymes and interact with many other drugs (see Table 3) RITONAVIR (RTV, Norvir) — Ritonavir is well absorbed from the gastrointestinal tract, but is poorly tolerated at the doses required to inhibit HIV Ritonavir is a potent inhibitor of CYP3A4 and is now used in lower doses (100-200 mg once or twice daily) to “boost” serum concentrations of other PIs 10 Treatment Guidelines from The Medical Letter • Vol 12 (Issue 138) • February 2014 Drugs for HIV Infection Table Dosage and Cost of PIs, INSTIs, and Others Some Available Formulations Drug Usual Adult Dosage Total Tablets or Capsules/day Cost1 Protease Inhibitors (PIs) Atazanavir [ATV] Reyataz (BMS) 300 mg/100 mg RTV once/d or 400 mg once/d2-4 800 mg/100 mg RTV once/d or 600 mg/100 mg RTV bid2,5 (300 mg caps) (200 mg caps) 700 mg tabs 1400 mg/100 mg RTV once/d2,4,6 870.20 200, 400 mg caps 800 mg q8h or 800 mg/100-200 mg RTV bid2,4,7 6-8 456.80 Lopinavir/ritonavir [LPV/RTV] Kaletra (Abbvie)* 100/25, 200/50 mg tabs 400/100 mg bid or 800/200 mg once/d8 4 814.40 Nelfinavir [NFV] Viracept (Viiv Healthcare)* 250, 625 mg tabs 1250 mg bid or 750 mg tid9 (625 mg tabs) (250 mg tabs) 844.70 759.60 1000 mg/100 mg RTV bid2,10,11 981.30 500 mg/200 mg RTV bid2,11 1179.40 50 mg tabs 50 mg once/d12,13 $1175.40 400 mg tabs 400 mg bid 1126.70 tab once/d 2457.30 150, 300 mg tabs 150-300 mg bid15 1081.40 90 mg vials 90 mg SC bid — 2927.9016 Darunavir [DRV] Prezista (Janssen)* Fosamprenavir [FPV] Lexiva (Viiv Healthcare)* Indinavir [IDV] Crixivan (Merck) 150, 200, 300 mg caps 75, 150, 600, 800 mg tabs Saquinavir [SQV] Invirase (Genentech) 200 mg caps; 500 mg tabs Tipranavir [TPV] Aptivus (Boehringer Ingelheim)* 250 mg caps $1174.50 1185.70 1090.80 1090.80 Integrase Strand Transfer Inhibitors (INSTIs) Dolutegravir Tivicay (Viiv Healthcare) Raltegravir [RAL] Isentress (Merck)* Integrase Strand Transfer Inhibitor Combination Elvitegravir/cobicistat/emtricitabine/tenofovir DF14 Stribild (Gilead) 150/150/200/300 mg tabs CCR5 Antagonist Maraviroc [MVC] Selzentry (Viiv Healthcare) Fusion Inhibitor Enfuvirtide [T20] Fuzeon (Genentech) * Also available in a liquid or oral powder formulation Approximate wholesale acquisition cost (WAC) of 30 days’ treatment with the lowest recommended dosage of the primary therapy (not including RTV) Source: Analy$ource® Monthly (Selected from FDB MedKnowledge™) January 5, 2014 Reprinted with permission by FDB, Inc All rights reserved ©2014 www.fdbhealth.com/policies/drug-pricing-policy Actual retail prices may be higher RTV = ritonavir (Norvir – Abbvie) Available as 100-mg tablets and soft-gelatin capsules The soft-gelatin capsules must be refrigerated The liquid formulation of ritonavir has an unpleasant taste; the manufacturer suggests taking it with chocolate milk or a liquid nutritional supplement WAC of one Norvir tablet is $8.57 With food For treatment-experienced patients, the FDA-approved dose is 300 mg/100 mg RTV once/d For treatment-naive patients, the FDA-approved dose is 300 mg/100 mg RTV once/d or 400 mg once/d for patients unable to tolerate RTV The dose with tenofovir DF is 300 mg/100 mg RTV and with efavirenz is 400 mg/100 mg RTV In pregnant patients, the dose with tenofovir DF is 400 mg/100 mg RTV Dosage adjustment required for use, or use not recommended in, hepatic or renal impairment With food Must be coadministered with RTV Dose is 800 mg/100 mg RTV once/d for treatment-experienced or treatment-naive patients with no darunavirassociated substitutions and is 600 mg/100 mg RTV bid for treatment-experienced patients with darunavir-resistance-associated substitutions Can also be given as 1400 mg bid, 1400 mg/200 mg RTV once/day or 700 mg/100 mg RTV bid in treatment-naive patients and 700 mg/100 mg RTV bid in protease inhibitor-experienced patients When taken once daily with efavirenz, the recommended dose is 1400 mg/300 mg RTV once/day With water or other liquids, hour before or hours after a meal, or with a light meal Dosage is 600 mg q8h when taken with delavirdine Patients should drink at least 48 ounces (1.5 L) of water daily GI effects are reduced when taken with food The recommended dose is 500 mg/125 mg bid when taken with efavirenz, nevirapine, fosamprenavir, or nelfinavir Once-daily dosing can be used for patients with