Drugs for HIV infections

Regimens for Post-Exposure Prophylaxis Page 14 Drugs for HIV Infection Antiretroviral therapy is recommended for all HIV-infected patients, both to reduce the risk of disease progressi

Treatment Guidelines

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Treatment Guidelines

Published by The Medical Letter • 145 Huguenot Street, New Rochelle, NY 10801 • A Nonprofi t Publication

Volume 12 (Issue 138) February 2014

1 Regimens for Treatment-Naive Patients Page 7

2 Dosage and Cost of NRTIs and NNRTIs Page 8

3 Adverse Effects and Drug Interactions of NRTIs and Page 9 NNRTIs

4 Dosage and Cost of PIs, INSTIs, and Others Page 11

5 Adverse Effects and Drug Interactions of PIs and INSTIs Page 12

6 Regimens for Post-Exposure Prophylaxis Page 14

Drugs for HIV Infection

Antiretroviral therapy is recommended for all

HIV-infected 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 1 Antiretroviral therapy is often complicated by

adverse effects and interactions with other drugs, some of

which are listed in Tables 3 and 5.

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-fl uorinated derivative of lamivudine, emtricitabine

Table 1 Regimens for Treatment-Naive Patients1

NNRTI-Based Regimens

Preferred Efavirenz2/tenofovir DF3/emtricitabine4 Alternative Efavirenz2 + abacavir5/lamivudine4 Rilpivirine6/tenofovir DF3/emtricitabine4 Rilpivirine6 + abacavir5/lamivudine4

PI-Based Regimens

Preferred Atazanavir/ritonavir7 + tenofovir DF3/emtricitabine4 Darunavir/ritonavir (once daily)

+ tenofovir DF3/emtricitabine4 Alternative 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 Raltegravir + tenofovir DF3/emtricitabine4 Elvitegravir/cobicistat/tenofovir DF/emtricitabine8 Dolutegravir + either abacavir5/lamivudine4 or tenofovir DF3/emtricitabine4

Alternative Raltegravir + abacavir5/lamivudine4

CCR5 Antagonist-Based Regimens 9

Acceptable Maraviroc + either zidovudine/lamivudine4 or tenofovir DF3/emtricitabine4 or

abacavir5/lamivudine4

1 For non-pregnant adults and adolescents An NNRTI-, PI- or INSTI-based 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 effi cacy, favorable tolerability and toxicity profi les, and ease of use “Alternative regimens” are those regimens that are effective but have potential disadvantages when compared with preferred regimens.

2 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.

3 Use with caution in patients with renal insuffi ciency.

4 Emtricitabine can be substituted for lamivudine and vice versa.

5 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.

6 Not recommended if pretreatment viral load is >100,000 copies/mL Use

of proton pump inhibitors is contraindicated.

7 Not recommended for patients who require >20 mg/d omeprazole equivalent.

8 Should not be started in patients with CrCl <70 mL/min and should be changed to an alternative regimen if CrCl <50 mL/min.

9 Should be considered in patients who have only CCR5-tropic virus.

For further information call: 800-211-2769

Related article(s) since publication

Table 2 Dosage and Cost of NRTIs and NNRTIs

Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs)

Didanosine [ddl] – generic* 125, 200, 250, 400 mg 400 mg once/d5,6 1 265.50

Emtricitabine [FTC]

Stavudine [d4T] – generic* 15, 20, 30, 40 mg caps 40 mg bid6,7 2 107.50

Tenofovir DF [TDF]

Viread (Gilead)* 150, 200, 250, 300 mg tabs 300 mg once/d6 1 873.10

Zidovudine [AZT, ZDV] – generic* 100 mg caps, 300 mg tabs 300 mg bid6,8 2 59.53

Fixed-Dose NRTI Combinations

Abacavir3/lamivudine

Emtricitabine/tenofovir DF

Zidovudine/lamivudine/abacavir2 – generic 300/150/300 mg tabs 1 tab bid 2 1390.80

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

(Viiv Healthcare)

Efavirenz [EFV] – Sustiva (BMS) 50, 200 mg caps; 600 mg tabs 600 mg once/d10 1 718.50

Etravirine [ETR] – Intelence (Janssen) 25, 100, 200 mg tabs 200 mg bid 2 867.70

extended-release – Viramune XR 100, 400 mg tabs 400 mg once/d14 1 592.40

Rilpivirine [RPV] – Edurant (Janssen)15 25 mg tabs 25 mg once/d11 1 713.20

Fixed-Dose NNRTI/NRTI Combinations 6

Efavirenz/emtricitabine/tenofovir DF

Rilpivirine/emtricitabine/tenofovir DF15

* Also available in a liquid or oral powder formulation.

1 Approximate wholesale acquisition cost (WAC) of 30 days’ treatment at the lowest recommended dosage 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.

2 For patients who test negative for HLA-B*5701 It should be used with caution in patients with pretreatment viral loads >100,000 copies/mL or in those at high

risk for cardiovascular disease.

3 Dosage for mild hepatic impairment is 200 mg bid; contraindicated in patients with moderate or severe hepatic impairment.

4 Also available generically in 100-, 150-, and 250-mg tabs for oral suspension.

5 The dose is 250 mg once daily for adults weighing 25 to <60 kg and 200 mg once daily for those weighing 20 to <25 kg When taken with tenofovir, the dose

of didanosine in adults with CrCl >60 mL/min should be reduced to 250 mg/d for those weighing >60 kg and to 200 mg/d for those weighing <60 kg Should

be taken on an empty stomach.

6 Not recommended for use in, or dosage adjustment required for, patients with renal impairment.

7 The dose is 30 mg bid for patients weighing <60 kg

8 Can also be given as 200 mg tid Also available in a parenteral preparation for intrapartum use; the dose during labor and delivery is 2 mg/kg IV over the fi rst

hour, followed by a continuous IV infusion of 1 mg/kg/hour until clamping of the umbilical cord.

9 Patients with achlorhydria should take with an acidic beverage.

10 Without food Taking at bedtime may diminish CNS effects.

11 With food.

12 G DiPerri et al HIV Clin Trials 2013; 14:92.

13 200 mg once/day for the fi rst 2 weeks of treatment to decrease the risk of rash Contraindicated in patients with moderate or severe hepatic impairment.

14 200 mg once/day of immediate-release nevirapine for the fi rst 2 weeks of treatment to decrease risk of rash No 14-day lead-in is necessary if the patient is

already receiving immediate-release nevirapine 200 mg bid.

15 Must be taken with a full meal Not recommended if pretreatment viral load is >100,000 copies/mL Concurrent use with a proton pump inhibitor is

contraindicated.

Table 3 Adverse Effects and Drug Interactions of NRTIs and NNRTIs

Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs)

NRTI Class Lipoatrophy; lactic acidosis with hepatic steatosis2 NRTIs are not metabolized by CYP450 enzymes, but

drug interactions by other mechanisms have been reported Abacavir Hypersensitivity reactions with fever, rash, malaise,

respiratory and/or gastrointestinal symptoms3; possible

increased risk of myocardial infarction4

Didanosine Peripheral neuropathy; pancreatitis; gastrointestinal Pediatric powder formulation interferes with absorption of

disturbances; non-cirrhotic portal hypertension; insulin drugs that require gastric acidity for absorption, including resistance/diabetes; retinal changes; optic neuritis indinavir and atazanavir

Emtricitabine Well tolerated compared to other NRTIs; can cause

hy-perpigmentation of the palms and soles, particularly in

Lamivudine Well tolerated compared to other NRTIs; pancreatitis

has been reported rarely in children

Stavudine Hyperlipidemia; peripheral neuropathy (which may persist Antiviral antagonism when used with zidovudine

even after drug is stopped); increased serum

amino-transferase levels; diabetes; pancreatitis; fatal lactic

acidosis (may occur more frequently with stavudine than

with other NRTIs)

Tenofovir Generally well tolerated; renal toxicity, including a Tenofovir lowers serum concentrations of atazanavir;

com-Fanconi-like syndrome and progression to renal failure; bined use with didanosine has been associated with CD4 decreased bone density and osteomalacia can occur, decline

even in adolescents

Zidovudine Nausea and vomiting (taking the drug with food may de- Hematologic toxicity may increase with coadministration of

crease GI side effects); anemia; neutropenia; headache; ganciclovir, interferon alfa, ribavirin, and other bone marrow fatigue; confusion; malaise; myopathy; hepatitis; hyper- suppressive or cytotoxic agents; coadministration with doxo-pigmentation of the oral mucosa and nail beds; diabetes rubicin or stavudine should be avoided

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Efavirenz Rash5; dizziness; headache; insomnia, diffi culty concen- Induces CYP3A4 and 2B6, decreasing serum concentrations

trating, vivid dreams; nightmares6;suicidality; reductions of 2B6 and 3A4 substrates such as methadone and some

in vitamin D levels; hyperlipidemia; potentially teratogenic protease inhibitors; substrate of 3A4; can also inhibit

CYP3A4, 2C9 and 2C19 Etravirine Generally well tolerated; rash5; nausea; peripheral Substrate of CYP3A4, 2C9 and 2C19; inducer of CYP3A4;

neuropathy; increases in cholesterol and triglycerides inhibitor of CYP2C9 and 2C19; can increase or decrease

used with tipranavir/ritonavir, fosamprenavir/ritonavir, or ataza-navir/ritonavir, with PIs given without ritonavir, or with other

Nevirapine Rash7; fever; nausea; headache; severe hepatotoxicity, Induces CYP3A4 and 2B6, decreasing serum concentrations

hepatic failure, and death 8 of 3A4 and 2B6 substrates

Rilpivirine Depression; insomnia; headache; rash5; higher-than- Drugs that increase gastric pH, such as omeprazole, or

in-recommended doses can prolong the QT interval duce CYP3A4 may signifi cantly reduce rilpivirine

concentra-tions and are contraindicated; CYP3A4 inhibitors can increase

drugs with a known risk of QT prolongation and torsades de

1 Some antiretroviral drugs have complex drug-drug interaction profi les; information on these interactions is available in the drug’s package insert and at www.aidsinfo.nih.gov/contentfi les/lvguidelines/adultandadolescentgl.pdf.

2 Especially with didanosine, stavudine, and zidovudine.

3 Hypersensitivity reactions usually develop early in treatment (median of 9 days), but can occur at any time and are strongly associated with the presence

of the HLA-B*5701 allele Screening for this allele is recommended prior to abacavir use Patients who screen positive for HLA-B*5701 should not receive abacavir Rechallenge after a hypersensitivity reaction to abacavir can be fatal.

4 Some studies have suggested an association between abacavir use and myocardial infarction, but other studies and an FDA meta-analysis have not found an increased risk.

5 Rash is less frequent than with nevirapine, but can be severe; erythema multiforme and Stevens-Johnson syndrome have been reported.

6 CNS effects tend to begin 1-2 days after starting therapy and usually resolve within a few weeks, but can persist for months or years, and may be associated with high efavirenz serum concentrations When the dose is taken at bedtime, CNS effects may still be present in the morning on awakening and may impair driving; this effect generally wanes with time and can be ameliorated by taking the drug earlier in the evening.

7 Common early in treatment and can be more severe than with other NNRTIs; may progress to Stevens-Johnson syndrome or toxic epidermal necrolysis

8 Particularly in patients with previously elevated transaminases or underlying hepatitis B or C; treatment-naive women with CD4 counts >250 cells/mm 3 and men with CD4 counts >400 cells/mm 3 are at increased risk.

EFAVIRENZ (EFV, Sustiva) — Efavirenz plus

emtricitabine/tenofovir DF is the preferred NNRTI-based regimen for treatment-naive patients In such

patients, the combination of efavirenz with 2 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 fi rst trimester.

RILPIVIRINE (RPV, Edurant) — Rilpivirine is the

newest NNRTI.9 FDA approval was based on pooled results from 2 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 fi xed-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 treatment-experienced 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)

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”).

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

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

Co-infected 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 effi cacy of regimens

containing an abacavir/lamivudine backbone have been

confl icting 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 fi nd 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

Lamivudine-resistant strains are cross-Lamivudine-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

fi rst 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.

NON-NUCLEOSIDE REVERSE

TRANSCRIPTASE INHIBITORS (NNRTIs)

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

do not completely suppress viral replication NNRTIs

are metabolized in the liver by CYP450 enzymes and

interact with many other drugs (see Table 3).

Table 4 Dosage and Cost of PIs, INSTIs, and Others

Protease Inhibitors (PIs)

Atazanavir [ATV]

Reyataz (BMS) 150, 200, 300 mg caps 300 mg/100 mg RTV once/d 2 (300 mg caps) $1174.50

or 400 mg once/d2-4 2 (200 mg caps) 1185.70 Darunavir [DRV] 75, 150, 600, 800 mg tabs 800 mg/100 mg RTV once/d 2 1090.80

Fosamprenavir [FPV]

Lexiva (Viiv Healthcare)* 700 mg tabs 1400 mg/100 mg RTV once/d2,4,6 3 870.20 Indinavir [IDV]

or 800 mg/100-200 mg RTV bid2,4,7 6-8 Lopinavir/ritonavir [LPV/RTV]

Kaletra (Abbvie)* 100/25, 200/50 mg tabs 400/100 mg bidor 4 814.40

800/200 mg once/d8 4 Nelfi navir [NFV]

Viracept (Viiv Healthcare)* 250, 625 mg tabs 1250 mg bid or 4 (625 mg tabs) 844.70

Saquinavir [SQV]

Invirase (Genentech) 200 mg caps; 500 mg tabs 1000 mg/100 mg RTV bid2,10,11 6 981.30 Tipranavir [TPV]

Aptivus (Boehringer Ingelheim)* 250 mg caps 500 mg/200 mg RTV bid2,11 8 1179.40

Integrase Strand Transfer Inhibitors (INSTIs)

Dolutegravir

Raltegravir [RAL]

Integrase Strand Transfer Inhibitor Combination

Elvitegravir/cobicistat/emtricitabine/tenofovir DF14

CCR5 Antagonist

Maraviroc [MVC]

Selzentry (Viiv Healthcare) 150, 300 mg tabs 150-300 mg bid15 2 1081.40

Fusion Inhibitor

Enfuvirtide [T20]

* Also available in a liquid or oral powder formulation

1 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.

2 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.

3 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.

4 Dosage adjustment required for use, or use not recommended in, hepatic or renal impairment.

5 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

darunavir-associated substitutions and is 600 mg/100 mg RTV bid for treatment-experienced patients with darunavir-resistance-darunavir-associated substitutions.

6 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.

7 With water or other liquids, 1 hour before or 2 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.

8 GI effects are reduced when taken with food The recommended dose is 500 mg/125 mg bid when taken with efavirenz, nevirapine, fosamprenavir, or nelfi navir Once-daily dosing can be used for patients with <3 resistance-associated substitutions Once-daily dosing is not recommended for pregnant women.

9 With food

10 Within 2 hours after a full meal Dosage is 1000 mg bid (without RTV) when taken with lopinavir/ritonavir.

11 Must be coadministered with RTV

12 Must be taken 2 hours before or 6 hours after drugs containing polyvalent cations (such as sucralfate, buffered medications, and calcium, magnesium, and iron supplements).

13 Dose is 50 mg bid for INSTI-resistant patients or when coadministered with UGT1A/CYP3A inducers such as efavirenz, fosamprenavir/RTV, tipranavir/RTV, or rifampin.

14 Should not be started in patients with CrCl <70 mL/min and should be changed to an alternative regimen if CrCl <50 mL/min.

15 Dose is 150 mg bid when given with strong CYP3A4 inhibitors, including PIs (except tipranavir/RTV) and delavirdine Dose is 600 mg bid when given with strong CYP3A4 inducers including efavirenz A dose of 300 mg bid can be used with other concomitant medications including nevirapine, tipranavir/RTV, all NRTIs, raltegravir, and enfuvirtide.

16 Cost of one 90-mg vial.

Table 5 Adverse Effects and Drug Interactions of PIs and INSTIs

Protease Inhibitors (PIs)

PI Class2 Gastrointestinal distress, including stool urgency and diarrhea; PIs interact with a continuously growing list of

increased bleeding in hemophiliacs; hyperglycemia; insulin re- drugs All PIs are metabolized by and are sistance; altered fat distribution; hyperlipidemia; serum trans- inhibitors of hepatic CYP3A4; drug interactions aminase elevations; an increased risk of myocardial infarction; are common and can be severe

hepatotoxicity (occasionally severe)3 Atazanavir Asymptomatic indirect hyperbilirubinemia4; rash5; nephrolithiasis6; Concurrent use of drugs that increase gastric

cholelithiasis; PR interval prolongation; fewer adverse effects pH, such as proton pump inhibitors,

H2-anti-on lipid profi les than many other PIs (unboosted atazanavir) histamines, and antacids, may decrease

absorption of atazanavir Darunavir Rash7; contains a sulfonamide moiety (use with caution in patients

with sulfonamide allergy) Fosamprenavir Perioral paresthesias; nephrolithiasis; rash8; contains a

sulfona-mide moiety (use with caution in patients with sulfonasulfona-mide allergy) Indinavir Asymptomatic elevation of indirect bilirubin; nephrolithiasis9;

cholelithiasis; dermatologic changes including alopecia, dry skin and mucous membranes, and paronychia and ingrown toenails Lopinavir/ritonavir Generally well tolerated; headache; asthenia; pancreatitis; PR

and QT interval prolongation Nelfi navir Generally well tolerated; diarrhea is common (may resolve

with continued use) Ritonavir Hypertriglyceridemia; altered taste; circumoral and peripheral

paresthesias (rarely); adverse reactions are less common with the low doses used for boosting other PIs

Saquinavir Usually well tolerated; rarely causes rash and hyperprolactinemia Prolonged QT and PR intervals when combined

with ritonavir Tipranavir Abdominal pain; intracranial hemorrhage; severe hepatitis,

in-cluding some fatalities10; contains a sulfonamide moiety (use with caution in patients with sulfonamide allergy)

Integrase Strand Transfer Inhibitors (INSTIs)

Dolutegravir Generally well tolerated; hypersensitivity reactions including rash Inhibits renal organic cation transporter OCT2

and sometimes organ dysfunction have been reported in <1% tubular secretion of serum creatinine and drugs

of patients in clinical trials11; elevations in liver transaminases eliminated by OCT2, such as metformin and were reported in patients co-infected with hepatitis B or C the antiarrhythmic drug dofetilide12; polyvalent

cations can decrease the absorption of dolute-gravir13; inducers of UGT1A/CYP3A, such as rif-ampin, efavirenz, and fosamprenavir/RTV, can reduce serum concentrations of dolutegravir Raltegravir Generally well tolerated; rash, insomnia, diarrhea, nausea, and Metabolized by uridine diphosphate

glucuro-headache have been reported, but have been comparable in nosyltransferase (UGT) 1A1; caution should incidence to placebo; increases in creatinine phosphokinase; be used with strong inducers of this enzyme myopathy and rhabdomyolysis such as rifampin or inhibitors such as

ataza-navir; coadministration with aluminum or mag-nesium-containing antacids is not recommended Elvitegravir14 Nausea; diarrhea; new or worsening renal impairment; Fanconi Cobicistat is an inhibitor of CYP3A4 and 2D6

syndrome; cobicistat inhibits tubular creatinine secretion, and the P-glycoprotein (P-gp) transporter; resulting in an increase in serum creatinine and a correspond- coadministration of Stribild with drugs that are

ing decrease in the estimated creatinine clearance, but actual metabolized by these pathways or are sub-glomerular fi ltration rate is not affected strates of P-gp may increase serum

concen-trations of those drugs; elvitegravir is a CYP3A4 and UGT1A1/3 substrate; concurrent use of antacids reduces elvitegravir concentrations

1 Some antiretroviral drugs have complex drug-drug interaction profi les; information on these interactions is available in the drug’s package insert and at www.aidsinfo.nih.gov/contentfi les/lvguidelines/adultandadolescentgl.pdf.

2 Especially tipranavir; more common in patients who are co-infected with hepatitis B or C.

3 Not all of these occur with every protease inhibitor.

4 Sometimes with jaundice; it is reversible when the drug is stopped.

5 Mostly mild or moderate; occurred in about 20% of patients in clinical trials.

6 Greater risk than with other PIs (Y Hamada et al Clin Infect Dis 2012); can occur after years of treatment.

7 Can be severe; erythema multiforme and Stevens-Johnson syndrome have been reported.

8 Many patients with rash can continue or restart fosamprenavir if the rash is mild or moderate; about 1% of patients have developed severe rash, including Stevens-Johnson syndrome.

9 Nephrolithiasis can lead to renal insuffi ciency Ritonavir boosting increases the risk Patients should drink at least 1.5-2 liters of water daily to minimize renal adverse effects

10 Careful monitoring of liver function is recommended, especially in patients with chronic HBV or HCV infection.

11 Dolutegravir should be discontinued permanently if hypersensitivity reactions occur.

12 Concurrent use of dolutegravir and dofetilide is contraindicated.

13 Dolutegravir should be taken 2 hours before or 6 hours after polyvalent cations such as sucralfate, buffered medications and calcium, magnesium, and iron supplements.

RALTEGRAVIR (RAL, Isentress) — Raltegravir is

FDA-approved for use in naive and treatment-experienced adults In two studies in treatment-naive patients, raltegravir based-therapy was similar in effi cacy to an efavirenz-based regimen.21,22

Randomized trials have evaluated replacing a boosted PI with raltegravir in treatment-experienced, virologically suppressed patients with the goal of regimen simplifi cation.23-25 Overall, the switch to raltegravir was associated with continued virologic suppression, but patients with pre-existing NRTI resistance were more likely to experience virologic failure.

ELVITEGRAVIR (EVG, Stribild) — Elvitegravir is

only available in a fi xed-dose combination (Stribild)

with the pharmacokinetic enhancer cobicistat and the NRTIs emtricitabine and tenofovir Cobicistat is

a CYP3A inhibitor; it increases systemic exposure

to elvitegravir, a CYP3A substrate, allowing once-daily administration.26 FDA approval was based on 2 randomized 48-week trials in treatment-naive patients

that demonstrated that Stribild was as effective as

efavirenz and ritonavir-boosted atazanavir.27,28

DOLUTEGRAVIR (Tivicay) — Dolutegravir is the

newest INSTI to be approved by the FDA.29Approval was based on three 48-week trials in treatment-naive patients that demonstrated that dolutegravir-containing regimens were as effective as raltegravir and more effective than efavirenz- and darunavir- containing regimens.7,30,31 Treatment-emergent INSTI resistance appears to be less likely with dolutegravir than with raltegravir Dolutegravir may retain activity

in some patients with resistance to raltegravir.32

CCR5 ANTAGONIST

MARAVIROC (MVC, Selzentry) — Maraviroc binds

to the CCR5 co-receptor, preventing entry of CCR5-tropic viruses into CD4 host cells It is approved for use in both treatment-naive and treatment-experienced adults with CCR5-tropic (R5) strains Patients should

be screened for CCR5 tropism before starting the drug Maraviroc is active against HIV strains resistant to other classes of drugs, but viral resistance to maraviroc has been reported.33

Adverse Effects – Pyrexia, rash, cough,

musculo-skeletal symptoms, abdominal pain, and postural dizziness have been reported with maraviroc use Hepatotoxicity can occur, sometimes associated with a rash and eosinophilia Cardiovascular events have also been reported.

Drug Interactions – Maraviroc is a substrate of CYP3A4

and P-glycoprotein; signifi cant drug-drug interactions could occur

ATAZANAVIR (ATV, Reyataz) —

Ritonavir-boosted atazanavir and ritonavir-Ritonavir-boosted darunavir

are the preferred PIs for treatment-naive patients.1,15

Atazanavir/ritonavir or lopinavir/ritonavir is

recom-mended for treatment-naive pregnant women.16

Atazanavir requires the presence of food and an acidic

gastric pH for absorption.

DARUNAVIR (DRV, Prezista) — Darunavir/ritonavir

or atazanavir/ritonavir is the PI of choice for

treatment-naive patients.1,17 In treatment-experienced

lopinavir-naive patients, virologic response rates with darunavir/

ritonavir were superior to those with lopinavir/ritonavir,

with less emergence of new resistance.18

FOSAMPRENAVIR CALCIUM (FPV, Lexiva) —

Fosamprenavir calcium is a prodrug of amprenavir,

which is no longer available in the US In

treatment-naive patients, fosamprenavir/ritonavir was as effective

and as well tolerated as lopinavir/ritonavir, each in

combination with abacavir/lamivudine.19

LOPINAVIR/RITONAVIR (LPV/RTV, Kaletra) —

Lopinavir is available only in a fi xed-dose combination

with ritonavir It is a PI of choice in treatment-naive

pregnant women because of a history of effi cacy and

safe use.16 Kaletra oral solution contains propylene

glycol, which newborns may not be able to eliminate;

it should not be used in newborns <2 weeks old.

TIPRANAVIR (TPV, Aptivus) — In clinical studies

of patients with extensive treatment experience and

drug resistance, tipranavir-containing regimens

were more effective than regimens based on some

other ritonavir-boosted PIs, including lopinavir/

ritonavir, indinavir/ritonavir, and saquinavir/ritonavir,

but darunavir/ritonavir may be better tolerated for the

same indications.

OTHERS — In treatment-naive patients,

ritonavir-boosted saquinavir (SQV, Invirase) was non-inferior

to lopinavir/ritonavir,20 but saquinavir is not commonly

used due to its toxicity and high pill burden Indinavir

(IDV, Crixivan) is uncommonly used because of its

toxicity Nelf navir (NFV, Viracept) is less potent than

lopinavir/ritonavir, cannot be boosted, and is no longer

recommended

INTEGRASE STRAND TRANSFER

INHIBITORS (INSTIs)

HIV-1 integrase catalyzes the process that results in viral

DNA insertion into the host genome INSTIs block the

enzyme’s activity, preventing viral DNA from integrating

with cellular DNA Cross-resistance is common between

raltegravir and elvitegravir Dolutegravir may retain

activity in HIV-1 strains that have become resistant to

either raltegravir or elvitegravir

Drugs Not To Be Used in Pr egnancy – Efavirenz

should be avoided in pregnancy, especially during the

fi rst trimester, because of its potential teratogenicity The risk of neural tube defects is restricted to the fi rst 5-6 weeks of pregnancy, a time when pregnancy is rarely recognized; women who present for antenatal care after this time and are already taking efavirenz and have optimal viral suppression can stay on it.16

Initiation of nevirapine in pregnancy should be avoided

in women with CD4 counts >250 cells/mm3 because of

an increased risk of hepatotoxicity.

PRE- AND POST-EXPOSURE PROPHYLAXIS Pre-Exposure Prophylaxis (PrEP) – Truvada,

the fi xed dose combination of tenofovir DF and emtricitabine, is the only drug approved by the FDA for PrEP to reduce the risk of sexually acquired

HIV-1 in adults at high risk.37 Approval for this indication was based on two randomized placebo-controlled trials (one in men who have sex with men [or transgender women] and the other in heterosexual couples in whom one partner was infected and the other was not) which demonstrated that the rate of infection was reduced by 44% and 75%, respectively.38,39

PrEP with Truvada should be considered only for

persons who are at high-risk for HIV-1 acquisition, are confi rmed to be HIV-negative, and are willing to take the drug regularly Although FDA approval is only for patients at high risk for sexual transmission, the

CDC recommends use of Truvada for PrEP among

intravenous drug users who are also at high risk for

HIV-1 acquisition.40 Follow-up HIV-1 antibody testing (every 2-3 months) is recommended while taking the drug to ensure early diagnosis of newly-acquired HIV infection;

resistance can develop if Truvada is continued for PrEP

after HIV infection has occurred.

FUSION INHIBITOR

ENFUVIRTIDE (T20, Fuzeon) — After HIV binds

to the host cell surface, a conformational change occurs

in the transmembrane glycoprotein subunit (gp41) of

the viral envelope, facilitating fusion of the viral and

host cell membranes and entry of the virus into the cell

Enfuvirtide, an HIV fusion inhibitor, binds to gp41 and

prevents this conformational change It is indicated

for treatment-experienced patients with ongoing HIV

replication despite current antiretroviral use.

Adverse Effects – Almost all patients develop local

injection site reactions to enfuvirtide, with mild or

moderate pain, erythema, induration, nodules, and

cysts Other adverse effects include eosinophilia,

hypersensitivity reactions, and possibly an increased

incidence of bacterial pneumonia.

Drug Interactions – Enfurvitide does not appear to

have any clinically signifi cant drug interactions.

PREGNANCY AND PERINATAL

TRANSMISSION

All HIV-infected pregnant women should receive

combination antiretroviral therapy during pregnancy

to prevent progression of their own disease and to

reduce the risk of perinatal transmission In

treatment-naive women, zidovudine and lamivudine plus either

lopinavir/ritonavir or atazanavir/ritonavir are the

preferred regimens throughout pregnancy.16 Most

perinatal transmission of HIV occurs close to the time

of, or during, labor and delivery Oral antiretroviral

therapy should be continued during labor If maternal

HIV RNA is >400 copies/mL near delivery, zidovudine

administration (preferably IV) is recommended during

the intrapartum period regardless of the antepartum

antiretroviral regimen All newborns born to

HIV-infected mothers should receive zidovudine for 6 weeks.

Already in Labor – Women who are already in labor

and have had no antiretroviral therapy should receive

IV zidovudine as a continuous infusion to decrease the

risk of HIV transmission to the fetus Infants born to

such mothers should receive 6 weeks of zidovudine

and three doses of nevirapine during the fi rst week of

life, started as close to birth as possible.

Pregnancy Adverse Effects – PI therapy may

contribute to development of hyperglycemia in pregnant

women Studies suggest that antenatal combination

antiretroviral therapy, particularly those regimens

that include a PI, may be associated with premature

birth.34-36 Mitochondrial dysfunction has been reported

in uninfected children with perinatal exposure to NRTIs

Most clinicians, however, believe that the benefi t of a

potent antiretroviral regimen taken during pregnancy

greatly outweighs the risk.

Table 6 Regimens for Post-Exposure Prophylaxis

Preferred Raltegravir + tenofovir DF1/emtricitabine Acceptable Raltegravir + tenofovir DF1/lamivudine

or zidovudine/lamivudine2 Darunavir/ritonavir + tenofovir DF1/emtricitabine2

or zidovudine/lamivudine2 Etravirine + tenofovir DF1/emtricitabine2

or zidovudine/lamivudine2 Rilpivirine + tenofovir DF1/emtricitabine2

or zidovudine/lamivudine2 Atazanavir/ritonavir3 + tenofovir DF1/emtricitabine2

or zidovudine/lamivudine2 Lopinavir/ritonavir + tenofovir DF1/emtricitabine2

or zidovudine/lamivudine2 Elvitegravir/cobicistat/tenofovir DF/emtricitabine4

*Adapted from DT Kuhar et al Infect Control Hosp Epidemiol 2013; 34:875.

1 Use with caution in patients with renal impairment.

2 Emtricitabine can be substituted for lamivudine and vice versa.

3 Not recommended for patients who require >20 mg/d omeprazole equivalent.

4 Should not be started in patients with CrCl <70 mL/min and should be changed to an alternative regimen if CrCl <50 mL/min.

of perinatal transmission Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV transmission in the United States Available at www.aidsinfo.nih.gov/contentfi les/lvguidelines/ PerinatalGL.pdf Accessed January 5, 2014

17 AM Mills et al Once-daily darunavir/ritonavir vs lopinavir/ritonavir in treatment-naive, HIV-1-infected patients: 96-week analysis: AIDS 2009; 23:1679

18 D Bánhegyi et al Week 96 effi cacy, virology and safety of darunavir/r

versus lopinavir/r in treatment-experienced patients in TITAN Curr HIV Res 2012; 10:171

19 J Eron 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

20 S Walmsley et al Gemini: a noninferiority study of saquinavir/ritonavir versus lopinavir/ritonavir as initial HIV-1 therapy in adults J Acquir Immune Defi c Syndr 2009; 50:367

21 M Markowitz et al Rapid and durable antiretroviral effect of the HIV-1 integrase inhibitor raltegravir as part of combination therapy

in treatment-naive patients with HIV-1 infection: results of a 48-week controlled study J Acquir Immune Defi c Syndr 2007; 46:125

22 JL Lennox et al STARTMRK Investigators Safety and effi cacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial Lancet 2009; 374:796

23 JJ Eron et al Switch to a raltegravir-based regimen versus continuation

of a lopinavir-ritonavir-based regimen in stable HIV-infected patients with suppressed viraemia (SWITCHMRK 1 and 2): two multicentre, double-blind, randomised controlled trials Lancet 2010; 375:396

24 E Vispo et al Simplifi cation from protease inhibitors to once- or twice-daily raltegravir: the ODIS Trial HIV Clin Trials 2010; 11:197

25 E Martínez et al Substitution of raltegravir for ritonavir-boosted protease inhibitors in HIV-infected patients: the SPIRAL study AIDS 2010; 24:1697

26 A 4 drug combination (Stribild) for HIV Med Lett Drugs Ther 2012; 54:95

27 PE Sax et al Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus co-formulated efavirenz, emtricitabine, and tenofovir for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3 trial, analysis of results after 48 weeks Lancet 2012; 379:2439

28 E DeJesus et al Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate versus ritonavir-boosted atazanavir plus co-formulated emtricitabine and tenofovir disoproxil fumarate for initial treatment of HIV-1 infection: a randomised, double-blind, phase

3, non-inferiority trial Lancet 2012; 379:2429

29 Dolutegravir (Tivicay) for HIV Med Lett Drugs Ther 2013; 55:77

30 F Raffi et al Once-daily dolutegravir versus raltegravir in antiretroviral-naive adults with HIV-1 infection: 48 week results from the randomised, double-blind, non-inferiority SPRING-2 study Lancet 2013; 381:735

31 J Feinberg et al Once-daily dolutegravir (DTG) is superior to darunavir/ ritonavir (DRV/r) in antiretroviral naive adults: 48 week results from FLAMINGO Presented at 53rd Interscience Con ference on Antimicrobial Agents and Chemotherapy Denver, CO;

September 10-13, 2013 Available at http://www.icaaconline.com/php/ icaac2013abstracts/data/papers/2013/late/2013_H-1464a.htm Accessed January 5, 2014

32 JJ Eron et al Safety and effi cacy of dolutegravir in treatment-experienced subjects with raltegravir-resistant HIV type 1 infection: 24-week results

of the VIKING Study J Infect Dis 2013; 207:740

33 M Westby et al Emergence of CXCR4-using human immunodefi ciency 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

34 AM Cotter et al Is antiretroviral therapy during pregnancy associated with an increased risk of preterm delivery, low birth weight, or stillbirth?

J Infect Dis 2006; 193:1195

35 DH Watts et al Combination antiretroviral use and preterm birth J Infect Dis 2013; 207:612

Post-Exposure Prophylaxis – Prophylaxis in this setting

can be categorized as either occupational post-exposure

prophylaxis (PEP) or non-occupational post-exposure

prophylaxis (nPEP) Three or more active drugs should

be used for all occupational exposures, regardless of

severity, and for non-occupational exposures (sexual,

injection-drug use, etc.) in which the source patient

is known to be HIV-infected or if the exposure event

presents a substantial risk for HIV transmission (e.g.,

sexual assault).41,42 Treatment should be started within

72 hours of exposure, but delayed treatment may still

provide a benefi t, particularly in high-risk exposure

settings, and should be continued for 4 weeks

Follow-up HIV-1 antibody testing is recommended for at least

4-6 months after the exposure.

1 Panel on Antiretroviral Guidelines for Adults and Adolescents

Guidelines for the use of antiretroviral agents in HIV-1-infected

adults and adolescents Department of Health and Human Services

Available at www.aidsinfo.nih.gov/contentfi les/lvguidelines/Adultand

AdolescentGL.pdf Accessed January 15, 2014

2 MA Thompson et al Antiretroviral treatment of adult HIV infection:

2012 recommendations of the International Antiviral Society-USA

panel JAMA 2012; 308:387

3 MS Cohen et al Prevention of HIV-1 infection with early retroviral

therapy N Engl J Med 2011; 365:493

4 JA Aberg et al Primary care guidelines for the management of persons

infected with HIV: 2013 update by the HIV Medicine Association of the

Infectious Diseases Society of America Clin Infect Dis 2014; 58:e1

5 PE Sax et al Abacavir/lamivudine versus tenofovir DF/emtricitabine as

part of combination regimens for initial treatment of HIV: fi nal results J

Infect Dis 2011; 204:1191

6 KY Smith et al Randomized, double-blind, placebo-matched,

multicenter trial of abacavir/lamivudine or tenofovir/emtricitabine with

lopinavir/ritonavir for initial HIV treatment AIDS 2009; 23:1547

7 SL Walmsley et al Dolutegravir plus abacavir-lamivudine for the

treatment of HIV-1 infection N Engl J Med 2013; 369:1807

8 ES Daar et al Atazanavir plus ritonavir or efavirenz as part of a 3-drug

regimen for initial treatment of HIV-1 Ann Intern Med 2011; 154:445

9 Rilpivirine (Edurant) – a new drug for HIV infection Med Lett Drugs

Ther 2011;53:67

10 CJ Cohen et al Rilpivirine versus efavirenz with two background

nucleoside or nucleotide reverse transcriptase inhibitors in

treatment-naive adults infected with HIV-1 (THRIVE): a phase 3, randomised,

non-inferiority trial Lancet 2011; 378:229

11 JM Molina et al Rilpivirine versus efavirenz with tenofovir and

emtricitabine in treatment-naive adults infected with HIV-1 (ECHO): a

phase 3 randomised double-blind active-controlled trial Lancet 2011;

378:238

12 P Tebas et al SPIRIT study: switching boosted PI to rilpivirine

in-combination with Truvada as a single-tablet regimen week 24 results

14th International Workshop on Co-morbidities and Adverse Drug

Reaction in HIV.; Washington DC, July 20 2012 Available at: http://

www.natap.org/2012/AdverseReactComor/AdverseReactComor_02

htm

13 R Schrijvers et al Rilpivirine: a step forward in tailored HIV treatment

Lancet 2011; 378:201

14 E Poveda et al Phenotypic impact of resistance mutations on etravirine

susceptibility in HIV patients with prior failure to nonnucleoside

analogues AIDS 2008; 22:2395

15 JM Molina et al Once-daily atazanavir/ritonavir compared with

twice-daily lopinavir/ritonavir, each in combination with tenofovir and

emtricitabine, for management of antiretroviral-naive HIV-1-infected

patients: 96-week effi cacy and safety results of the CASTLE study J

Acquir Immune Defi c Syndr 2010; 53:323

16 Panel on treatment of HIV-infected pregnant women and prevention