HIV-Overview of ARVs

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HIV - Overview of Antiretroviral Agents

Authors: Philip Grant, MD, Andrew R. Zolopa, MD (More Info)

Released: 11/17/10

Last Reviewed: 3/4/11 (What's New)

Introduction

Potent combination antiretroviral therapy has dramatically changed the prognosis for patients

with HIV infection, allowing the infection to be effectively managed with medication. Thischapter provides an overview of the HIV viral life cycle, the currently available antiretroviral

agents, the use of antiretroviral agents in combination therapy, and medications currently beinginvestigated in phase III trials. Antiretroviral medications currently approved by the US Food

and Drug Administration (FDA) for the treatment of patients with HIV and those currently inphase III clinical trials are listed in Table 1, and those currently available as coformulations are

itemized in Table 2. The manufacturers of rilpivirine and elvitegravir have also filed for approvalfor use in HIV-infected patients.

Table 1. Antiretroviral Agents Approved by the FDA and in Phase III Clinical Trials

Approved Agents

NRTIs PIs NNRTIsFusion

Inhibitors

Entry

Inhibitors

Integrase

Inhibitors

Zidovudine Saquinavir Nevirapine EnfuvirtideMaraviroc Raltegravir

Didanosine

Ritonavir

Delavirdine

Stavudine Indinavir EfavirenzLamivudine Nelfinavir Etravirine

Abacavir Lopinavir/ritonavirTenofovir Atazanavir

Emtricitabine FosamprenavirTipranavir

Darunavir

Investigational Agents in Phase III Trials

Rilpivirine(TMC 278)

Elvitegravir(GS 9137)

Table 2. Currently Available Coformulated Antiretroviral Agents

Agent Type

Lamivudine/zidovudine Dual NRTIAbacavir/lamivudine/zidovudine Triple NRTI

Abacavir/lamivudine Dual NRTIEmtricitabine/tenofovir Dual NRTI

Efavirenz/emtricitabine/tenofovir NNRTI + dual NRTILopinavir/ritonavir Boosted PI

Investigational Agents in Phase III Trials


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Agent TypeEmtricitabine/tenofovir/rilpivirine Dual NRTI + NNRTI

Emtricitabine/tenofovir/elvitegravir/cobicistat Dual NRTI + INSTI + booster

Figure 1 illustrates the timeline of development of antiretroviral agents and coformulations.

Figure 1. Timeline for development of antiretroviral agents.

*Dates indicate FDA approval.

2003-2011 Clinical Care Options, LLC. All Rights Reserved.

Keywords: Initial Antiretroviral Therapy, Special Populations


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HIV-1 Viral Life Cycle

Improved understanding of the life cycle of HIV has allowed for the development of the 6

currently available classes of antiretroviral therapy. The HIV life cycle can be broadly dividedinto 11 steps: attachment, coreceptor binding, fusion, uncoating, reverse transcription,

integration, transcription, translation, assembly, budding, and maturation (Figure 2).

Figure 2.HIV-1 viral life cycle.

Attachment; Coreceptor Binding; Fusion

Initially, the HIV-1 surface envelope protein gp120 attaches to a CD4 receptor that is located onseveral CD4+ cell types (including CD4+ T cells, macrophages, monocytes, and dendritic cells).

Subsequently, gp120 undergoes a conformational change that unmasks a binding site on gp120that is able to bind to 1 of 2 beta-chemokine coreceptors, CCR5 or CXCR4. The currently

approved CCR5 antagonist, maraviroc, is a small molecule that binds to the CCR5 receptormaking it unavailable for binding by CCR5-tropic viruses.

Once the virus is bound to both CD4 and the chemokine receptor, an additional conformational

change allows the viral envelope and the host cell membrane to be brought directly into contact.The fusion peptide gp41 penetrates the cell membrane, triggering repeat sequences in gp41

(referred to as heptad repeat 1 and 2) to interact. This causes a collapse of the extracellularportion of gp41 and fusion of the viral and cell membranes. The fusion inhibitorenfuvirtide is a

synthetic peptide derived from heptad repeat 2. Enfuvirtide competitively binds to heptad repeat

1, thereby preventing the conformational change in the extracellular portion of gp41 that isrequired for fusion of the viral and cell membranes.

Uncoating and Reverse Transcription

The fusion of the cellular and viral membranes allows the viral core to be delivered into thecytoplasm of the host cell. Once inside the cell, the viral capsid is shed, exposing the single-

stranded viral RNA in a process referred to as uncoating. Following this, the reverse transcriptaseenzyme transcribes the single-stranded viral RNA genome into a single-stranded complementary

DNA molecule. The reverse transcriptase enzyme also has inherent functions other than reversetranscription; ribonuclease activity causes the degradation of the viral RNA after completion of


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reverse transcription, while DNA-dependent DNA polymerase allows the creation of double-stranded viral DNA from the single-stranded cDNA that is generated as a product of reverse

transcription.

NRTIs are analogues of the naturally occurring deoxynucleotides. After phosphorylation bycellular kinases, NRTIs compete for incorporation into the expanding viral DNA chain. Because

the NRTIs lack a 3-hydroxyl group on the deoxyribose moiety, they do not allow for theformation of the 5-3-phosphodiester bond with the incoming deoxynucleotide, resulting in

chain termination. NNRTIs noncompetitively inhibit the reverse transcriptase by binding to a

nonactive site on the enzyme, preventing the normal movement of the protein domains that arerequired for DNA synthesis.

Integration

Once the double-stranded DNA is formed, HIV integrase catalyzes a multistep process thatallows the double-stranded DNA to be irreversibly incorporated within the host DNA. Within the

cytoplasm of the cell, integrase fastens onto specific sequences located on the ends of the HIVviral DNA, recruiting cellular and viral factors to create a preintegration complex. Integrase then

excises 2 nucleotides from each 3' end, exposing reactive ends in preparation for strand transfer.Cellular cofactors allow the preintegration complex to then enter into the nucleus. The

preintegration complex binds to specific regions within the host DNA, where integrase nicksboth strands of host DNA and executes the process of strand transfer, covalently bonding the

primed viral ends to the cleaved host DNA. The hosts cellular DNA repair enzymes seal theHIV viral DNA into the host genome.

The US Food and Drug Administrationapproved integrase inhibitorraltegravirand the

investigational drug elvitegravir inhibit the strand transfer step catalyzed by integrase. Second-generation integrase inhibitors are in development and act against the same step but have been

designed to provide activity against HIV strains resistant to raltegravirand elvitegravir. Forexample, S/GSK1249572 (GSK-572), MK-2048, and GS-9160 are integrase strand transfer

inhibitors with activity against some HIV mutants resistant to raltegravirand

elvitegravir (Capsule Summary).[Wai 2007; Jones 2009; Lalezari 2009] S/GSK1249572 is currently beingtested in phase IIb trials in raltegravir-resistant patients.

[Eron 2010]and in treatment-naive patients

compared with efavirenz.[Rockstroh 2010]

Another class of integrase inhibitors, the quinolones,

inhibit both the 3 processing and strand transfer steps of integrase,[Thibaut 2009]

but have not yetprogressed into clinical studies.

Transcription, Translation, Assembly

Once integrated, the viral DNA may either lie latent or be transcribed into mRNA. Factors such

as the location within the chromosome where the provirus resides, the availability of activatorsof transcription such as nuclear factor kappa-light-chain-enhancer of activated B cells, and

differences in cell type determine whether the viral DNA will be transcribed or lie latent. Cellscontaining transcriptionally latent viral DNA are not susceptible to antiretroviral therapy, thereby

providing an important mechanism for persistence of infection even with antiretroviral therapytreatment.

Once transcription of the viral genome has begun, different splicing patterns result in a variety of

HIV-specific transcripts. Multiply spliced transcripts are transported rapidly to the cytoplasmwhere they encode the regulatory proteins Nef, Tat, and Rev. Singly spliced or unspliced viral

transcripts encode the structural, enzymatic, and accessory proteins and the viral genomic RNAneeded for the assembly of infectious virions. The structural and enzymatic proteins of HIV are


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produced as parts of long polypeptides. Gag proteins are the driving force for viral assembly andrecruit viral and host cellderived products in the process of producing mature viral particles.

HIV protease is critical in the post-translational processing of gag and gag-pol polyproteins into

functional core proteins and viral enzymes. Protease inhibitors bind the catalytic site of HIVprotease, thereby preventing the production of mature virions.

Budding and Maturation

During assembly and budding, gag proteins associate preferentially with cholesterol- andglycolipid-enriched areas of the lipid bilayer, yielding virions with cholesterol-rich membranes.After release from the cell, the virion is not infectious until further processing of the viral capsid

by protease. A final step in the production of an infectious virion is the processing of the capsidprecursor (CA-SP1 or p25) to the mature capsid protein (CA or p24). An investigational

maturation inhibitor, bevirimat, is no longer in active clinical development. Figure 3 provides anoverview of the HIV life cycle and the target steps for the development of antiretroviral agents.

Figure 3. Overview ofHIV viral life cycle: target steps for antiretroviral agents.

Keywords: Initial Antiretroviral Therapy, Special Populations

NRTIs

The reverse transcriptase enzyme was an attractive initial therapeutic target after the discovery

that the cause of AIDS was a retrovirus. As discussed above, NRTIs are analogues of thenaturally occurring deoxynucleotides. The 8 US Food and Drug Administration (FDA)approved

NRTIs and their characteristics are outlined in Table 3; in addition there are 5 available NRTIfixed-dose combinations (Table 4).

Table 3. Currently FDA-Approved NRTIs and Their Characteristics

Drug Dose Adverse EffectsSpecial

MonitoringNotes

Zidovudine300 mgorally

twice daily

Nausea, malaise,

headache,insomnia, anemia,

neutropenia,

lipoatrophy

Blood count

Generally has

been replaced bynewer, less toxic,

once-daily NRTIs


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MonitoringNotes

Didanosine

400 mgorally once

daily(enteric-

coatedcapsules)

for persons

60 kg

Pancreatitis,peripheral

neuropathy, lacticacidosis, dry

mouth, hepatitis,potential increased

risk of MI

Clinicalmonitoring for

neuropathy

Taken on emptystomach; pills

must beswallowed intact

Stavudine

40 mgorally

twice dailyfor persons

60 kg

(although30-mg

dose haslargely

replaced40-mg

dose)

Lipoatrophy,

peripheralneuropathy, lactic

acidosis, hepaticsteatosis

Clinicalmonitoring for

neuropathy

Rarely used in

developed world;no longer

recommended inWHO guidelines

Lamivudine300 mg

orally oncedaily or

150 mgtwice daily

Low incidence ofadverse effects; has

been associatedwith rash

NoneAlso active

against HBV

Abacavir 600 mgorally once

daily or

300 mgtwice daily

Hypersensitivity

reaction (fever,rash, flulike

illness), potentialincreased risk of

MI

HLA B*5701

allele

screeningprior to

initiation of

therapy; do noadminister to

those who testpositive

Controversy overpotential link

between abacavir

and MI andincreased

virologic failure

in patients withbaseline high

viral loads in 1study (ACTG

5202)

Tenofovir300 mg

orally once

daily

Well tolerated but

rarely can lead toacute renal failure,

Fanconissyndrome,

proteinuria, maycontribute to

decrease in bonemineral density

Serum

creatinine,eGFR,

urinalysis

Also active

against HBV;dose adjustment

for modest renalfailure

Emtricitabine200 mg

orally oncedaily

Well tolerated None

Very similar tolamivudine; also

active againstHBV


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DHHS, US Department of Health and Human Services; eGFR, epidermal growth factorreceptor;; HBV, hepatitis B virus; MI, myocardial infarction; WHO, World Health Organization.

Table 4. Coformulations Containing NRTIs

ApprovedAbacavir/lamivudine

Lamivudine/zidovudineAbacavir/lamivudine/zidovudine

Emtricitabine/tenofovir

Efavirenz/emtricitabine/tenofovir

InvestigationalEmtricitabine/tenofovir/rilpivirine

Emtricitabine/tenofovir/elvitegravir/cobicistat

NRTIs as a class have been associated with lactic acidosis and hepatomegaly with steatosis; the

prescribing information for each NRTI contains a black box warning about these events.Treatment with the NRTI in question should be suspended if clinical or laboratory findings

suggestive of lactic acidosis, hyperlactatemia, or pronounced hepatotoxicity occur. Although thiswarning appears in the prescribing information for all NRTIs, these problems are primarily

associated with the thymidine analogues zidovudine and stavudine and with didanosine.

The thymidine analogueassociated mutationsM41L, D67N, K70R, L210W, T215Y/F, andK219Q/Econfer varying degrees of reduced susceptibility to all currently approved NRTIs.

The 69 insertion complex (consisting of a substitution at codon 69 [typically T69S] plus theinsertion of 2 or more amino acids [S-S, S-A, S-G, or others]) is associated with resistance to all

NRTIs when present with 1 or more thymidine analogueassociated mutations at codons 41, 210,or 215. The Q151M complex confers resistance to all NRTIs except tenofovir.

[Johnson 2009]

Zidovudine

Zidovudine became the first US Food and Drug Administrationapproved anti-HIV drug inMarch 1986.

[Zidovudine PI]Originally known as azidothymidine, it was initially synthesized in 1964

as a possible treatment for cancer, but was found to lack activity. The drug resurfaced in 1974

when it was found to have activity against a murine retrovirus. However, because retroviruseswere not thought to cause human disease, the continued development ofzidovudine was halted.

In November 1984, scientists in industry, the National Cancer Institute, and Duke Universitycollaborated to evaluate the drug for treatment of HIV. It was initially approved on the basis of a

randomized phase II study, which showed a significant decrease in mortality in patients withsymptomatic HIV disease.

[Fischl 1987]Unfortunately, the benefit ofzidovudine monotherapy was

found to be transient, only delaying and not preventing disease progression and death.Zidovudine was later tested as part of dual NRTI therapy, and was part of the first HAART

regimens studied.

Zidovudine is currently indicated for treatment of HIV infection in combination with otherantiretroviral agents and prevention of mother-to-child transmission of HIV[Zidovudine PI] ; it can be

used in both antiretroviral-naive and treatment-experienced patients. It is administered at an oraldose of 300 mg twice daily. It is also coformulated as a dual NRTI with lamivudine

(lamivudine/zidovudine) and as a triple NRTI with lamivudine and abacavir(abacavir/lamivudine/zidovudine). The use ofzidovudine has diminished in recent years as more

tolerable and potent NRTIs requiring only once-daily administration have become available. Thecoformulation oflamivudine/zidovudine remains an alternative NRTI choice for first-line

therapy regimens in both the US Department of Health and Human Services guidelines

(Management Guidelines)[DHHS 2011]

and the European AIDS Clinical Society guidelines


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(Management Guidelines).[EACS 2009]

Zidovudine is an important part of antiretroviral therapy toprevent mother-to-child transmission based on the results of the PACTG 076 trial (Management

Guidelines).[DHHS 2011; Perinatal Guidelines 2010; Connor 1994]

For additional information from CCO inPractice on prevention of mother-to-child transmissionof HIV, click here.

Approximately 40% of patients experience subjective adverse effects including nausea, malaise,

headache, and insomnia. Anemia and neutropenia are the most frequent dose-limiting adverse

effects; these occur in approximately 3% and 7% of patients, respectively.[Lamivudine-Zidovudine PI]Long-term use ofzidovudine has been associated with lipoatrophy, lactic acidosis, andhepatomegaly with steatosis. Stavudine inhibits the intracellular phosphorylation ofzidovudine;

the 2 agents should not be used in combination.[Stavudine PI]

For additional information from CCO inPractice on metabolic complications associated with

antiretroviral therapy, click here.

The prescribing information forzidovudine contains a black box warning.[Zidovudine PI]

In additionto the warning about lactic acidosis and hepatomegaly with steatosis that applies to all NRTIs,

the warning lists the following:

y Zidovudine is associated with hematologic toxicity including neutropenia and severe anemia,particularly in patients with advanced HIV-1 disease

y Prolonged use ofzidovudine is associated with symptomatic myopathyFor additional information from CCO inPractice on hematologic disorders in HIV-infectedpatients, click here.

For additional information from CCO inPractice on myopathy in HIV-infected patients, click

here.

Failure of a zidovudine-containing regimen can select 1 or more of the thymidine analogueassociated mutationsM41L, D67N, K70R, L210W, T215Y/F, and K219Q/E, which conferresistance to stavudine (the other thymidine NRTI) and to all current NRTIs.[Whitcomb 2003] The

degree to which these mutations confer cross-resistance to other NRTIs depends on preciselywhich mutations are selected and on how many are selected.

[Larder 1989; Kellam 1992; Calvez 2002; Kuritzkes

2004] M184V may delay or prevent the emergence of TAMs,[Kuritzkes 1996] but this protective activitymay be overcome by continuing accumulation of TAMs or other mutations. In virus-harboring

TAMs, E44D and V118I increase resistance to zidovudine and stavudine.[Johnson 2009]

T215Y/Frevertants (T215A/C/D/E/G/H/I/L/N/S/V) may be detected in antiretroviral-naive patients

originally infected with virus harboring T215Y/F. Revertants may quickly evolve back to T215Yduring failure of a zidovudine-containing regimen.

[Garcia-Lerma 2004; Lanier 2002]

Didanosine

Didanosine was approved by the US Food and Drug Administration in 1991. Didanosine is

indicated for use in combination with other antiretroviral agents for the treatment of HIV-1

infection and may be prescribed for both antiretroviral-naive and treatment-experiencedpatients.

[Didanosine-EC PI]Until 2000, didanosine was available either as a tablet, which required

crushing or chewing, or as a powder, which required suspension in water. Currently, the mostconvenient formulation is the enteric-coated capsule. For adults weighing more than 60 kg, this

capsule is given at a once-daily oral dose of 400 mg; for adults weighing between 25 kg and 59kg, the capsule is administered at a dose of 250 mg; and for those who are 20-25 kg, the dose is


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200 mg. Dosing on an empty stomach is required to prevent inactivation by stomach acid.Patients with renal insufficiency should also receive a lower dose (Table 5).

[Didanosine-EC PI]The US

Department of Health and Human Services designate the combination ofdidanosine pluslamivudine oremtricitabine and efavirenz as an acceptable NNRTI-based regimen for first-line

therapy. Acceptable regimens are defined as those that may be selected for some patients butare less satisfactory than preferred or alternative regimens.[DHHS 2011] The European AIDS

Clinical Society guidelines designate the combination ofdidanosine plus lamivudine oremtricitabine as an alternative NRTI combination for first-line therapy.

[EACS 2009]

Table 5. Recommended Dosage of Didanosine-EC in Patients With Renal Impairment by Body Weight

Creatinine

Clearance, mL/minRecommended Dosage ofDidanosine

Body Weight

60 kgBody Weight < 60 kg

60400 mg once

daily250 mg once daily

30-59200 mg once

daily125 mg once daily

10-29125 mg once

daily

125 mg once daily

< 10125 mg once

daily

Not recommended; different formulation

ofdidanosine should be used

The most common characteristic adverse effects associated with didanosine include pancreatitis

(< 1%), peripheral neuropathy, lactic acidosis, and dry mouth.[Didanosine-EC PI]

Didanosine should be

avoided in patients with a history of pancreatitis, who are taking other drugs that can causepancreatitis, or who are actively abusing alcohol. Didanosine may also be associated with

noncirrhotic portal hypertension.[Kovari 2009]

The combination ofdidanosine and stavudine shouldbe avoided because of overlapping toxicity (peripheral neuropathy and hyperlactatemia).

Didanosine + tenofovirhas been associated in 1 report with paradoxical CD4+ cell count decline

despite complete virologic suppression (Capsule Summary).

[Barrios 2005]

The combination ofdidanosine + tenofovir+ efavirenz was associated with high rates of early virologic failure intreatment-naive patients in 3 separate reports (Capsule Summary).

[Maitland 2005; Podzamczer 2005; Leon

2005]Early virologic failure was also noted with a first-line regimen ofdidanosine + emtricitabine

+ atazanavirin the PEARLS study (Capsule Summary).[Campbell 2008]

The prescribing information fordidanosine contains a black box warning.[Didanosine-EC PI] In

addition to the warning about lactic acidosis and hepatomegaly with steatosis that applies to allNRTIs, this warning lists the following:

y Fatal and nonfatal pancreatitis has occurred during therapy with didanosine used alone or incombination regimens in both treatment-naive and treatment-experienced patients, regardlessof the degree of immunosuppression

o Didanosine should be suspended in patients with suspected pancreatitis anddiscontinued in patients with confirmed pancreatitis

y Fatal lactic acidosis has been reported in pregnant women who received the combination ofdidanosine and stavudine with other antiretroviral agents

o The combination ofdidanosine and stavudine should be used with caution duringpregnancy and is recommended only if the potential benefit clearly outweighs the

potential risk

For additional information from CCO inPractice on metabolic complications associated withantiretroviral therapy, click here.


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For additional information from CCO inPractice on the management of pregnant HIV-infectedwomen, click here.

K65R and L74V are the primary mutations selected by didanosine.[Johnson 2009]

K65R also confers

resistance to abacavir, didanosine, emtricitabine, lamivudine, and tenofovir, and L74V is aprimary abacavirresistance mutation. Three or more of the following thymidine analogue

associated mutationsM41L, D67N, L210W, T215Y/F, and K219Q/Eare associated withdecreased susceptibility to didanosine.

[Marcelin 2005]

Stavudine

Stavudine in combination with other antiretroviral agents is indicated for the treatment of HIV

infection.[Stavudine PI]

It can be used in both antiretroviral-naive and treatment-experienced patients.Approved by the US Food and Drug Administration in 1994, stavudine is recommended to be

dosed orally at 40 mg twice daily for individuals weighing 60 kg and at 30 mg twice daily forthose weighing < 60 kg. However, in an effort to decrease toxicity, stavudine is most commonly

currently prescribed at a dose of 30-mg twice daily for adults, regardless of weight.

Although stavudine has been shown to have good activity as an antiretroviral drug, its adverseeffect profile has limited its use in the developed world. Lipoatrophy is a common adverse effect

associated with stavudine. Lipoatrophy most noticeably results in facial thinning but also resultsin the thinning of the extremities and buttocks. Increased duration of use of an offending drug

and low body mass index are the most important risk factors for lipoatrophy.[Heath 2001; Thibaut 2000]

Stavudine can also lead to peripheral neuropathy (8% to 21% of patients in clinical trials)[Stavudine

PI]and to other manifestations of mitochondrial toxicity such as lactic acidosis or hyperlactemia

and hepatic steatosis. Given the range of adverse effects associated with stavudine, the drug

should not be used in developed countries, except in very rare cases where no other suitablealternative exists. Until recently, stavudine was an integral part of first-line therapy in resource-

limited nations, but the most recent World Health Organization guidelines have removedstavudine-based regimens from the list of preferred first-line regimens and have suggested

limiting the use ofstavudine when possible (Management Guidelines).[WHO 2010] As described

above, the combination ofstavudine and didanosine should be avoided because of overlappingtoxicity. Stavudine inhibits the intracellular phosphorylation ofzidovudine (and vice versa); the2 agents should not be used in combination.

[Stavudine PI]

For additional information from CCO inPractice on lipoatrophy, click here.

For additional information from CCO inPractice on management of patients in resource-limitedsettings, click here.

The prescribing information forstavudine contains a black box warning.[Stavudine PI]

In addition to

the warning about lactic acidosis and hepatomegaly with steatosis that applies to all NRTIs, this

warning lists the following:

y Fatal lactic acidosis has been reported in pregnant women who received the combination ofstavudine and didanosine with other antiretroviral agents

o The combination ofstavudine and didanosine should be used with caution duringpregnancy and is recommended only if the potential benefit clearly outweighs the

potential risk

y Fatal and nonfatal pancreatitis have occurred during therapy when stavudine was part of acombination regimen that included didanosine in both treatment-naive and treatment-

experienced patients, regardless of the degree of immunosuppression


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Stavudine can select the thymidine analogueassociated mutations M41L, D67N, K70R, L210W,T215Y/F, and K219Q/E.

[Johnson 2009]Thymidine analogue mutations confer resistance not only to

the other thymidine NRTI, zidovudine, but also to other currently licensed NRTIs.[Whitcomb 2003]

M184V, the mutation usually selected first upon failure of a regimen containing emtricitabine or

lamivudine, delays or prevents emergence of thymidine analogueassociated mutations,[Kuritzkes

1996] although accumulation of these and other mutations may negate this effect. E44D and V118I

make HIV more resistant to stavudine and zidovudine in virus already carrying thymidineanalogueassociated mutations.

[Johnson 2009]T215Y/F revertants (T215A/C/D/E/G/H/I/L/N/S/V)

represent virus evolving back to wild-type from T215Y/F transmitted during primary HIV

infection. Revertants may rapidly evolve to resistance-conferring T215Y upon failure of aregimen containing stavudine orzidovudine.

[Garcia-Lerma 2004; Lanier 2002]In addition, in HIV-1 clade

C virus, failure ofstavudine-based therapy has also been associated with the development the

K65R mutation,[Orrell 2009]

which can also confer resistance to abacavir, didanosine, emtricitabine,lamivudine, and tenofovir.

Lamivudine

Approved by the FDA in 1995, lamivudine is indicated in combination with other antiretroviral

agents for the treatment of HIV-1 infection.[Lamivudine PI]

It can be used in both antiretroviral-naiveand treatment-experienced patients. Eitherlamivudine oremtricitabine is an integral part of most

first-line antiretroviral regimens. Lamivudine is administered at an oral dose of either 300 mgonce daily or 150 mg twice daily and is part of several NRTI coformulations:

abacavir/lamivudine, abacavir/lamivudine/zidovudine, and lamivudine/zidovudine.The dose oflamivudine should be adjusted in patients with renal insufficiency (Table 6).

[Lamivudine PI]

Table 6. Adjustment of Dosage of Lamivudine in Adults and Adolescents ( 30 kg) Is Based on Creatinine

Clearance Rates

Creatinine Clearance, mL/min Recommended Dosage ofLamivudine

50 150 mg twice daily or 300 mg once daily30-49 150 mg once daily

15-29 150 mg first dose, then 100 mg once daily5-14 150 mg first dose, then 50 mg once daily

< 5 50 mg first dose, then 25 mg once daily

Lamivudine is well tolerated and not associated with any significant adverse effects. In addition

to HIV, lamivudine also has activity against the hepatitis B virus. When used to treat hepatitis B

monoinfection in a patient who is not infected with HIV, however, the dose is different.

The prescribing information forlamivudine contains a black box warning.[Lamivudine PI]

In addition

to the warning about lactic acidosis and hepatomegaly with steatosis that applies to all NRTIs,this warning lists the following:

y Severe acute exacerbations of hepatitis B virus have been reported in patients who arecoinfected with hepatitis B virus and HIV and have discontinued lamivudine

o Monitor hepatic function closely in these patients and, if appropriate, initiate anti-hepatitis B treatment

y Patients with HIV infection should receive only dosage forms oflamivudine appropriate for thetreatment of HIV

For additional information from CCO inPractice on hepatitis B coinfection, click here.

M184V and M184I are the hallmarklamivudine mutations, emerging rapidly upon failure of a

regimen containing lamivudine (oremtricitabine).[Johnson 2009]

Lamivudine exhibits extensive


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cross-resistance with emtricitabine. M184V may also add to resistance to abacavirin virusharboring 2 or more thymidine analogueassociated mutations (M41L, D67N, K70R, L210W,

T215Y/F, K219Q/E).[Lanier 2004]

K65R, the second majorlamivudine mutation, also confersresistance to abacavir, didanosine, emtricitabine, and tenofovir.

[Johnson 2009]

Abacavir

Abacavirwas approved by the US Food and Drug Administration in 1998 and is indicated in

combination with other antiretroviral agents for the treatment of HIV infection as a result of the

CNA30024 trial in which noninferiority ofabacavirplus lamivudine and efavirenz wasestablished to lamivudine/zidovudine and efavirenz.

[DeJesus 2004]It can be administered to both

treatment-naive and treatment-experienced patients.[Abacavir PI] Abacaviris administered orally at adose of 300 mg twice daily or 600 mg once daily, and is part of 2 NRTI coformulations:

abacavir/lamivudine and abacavir/lamivudine/zidovudine.

Abacaviris generally well tolerated, but a hypersensitivity reaction can occur during the first 6

weeks of therapy.[Abacavir PI]

This is a multiorgan clinical syndrome usually characterized by a signor symptom in 2 or more of the following groups: 1) fever, 2) rash, 3) gastrointestinal (including

nausea, vomiting, diarrhea, or abdominal pain), 4) constitutional (including generalized malaise,fatigue, or achiness), and 5) respiratory (including dyspnea, cough, or pharyngitis). Individuals

with these symptoms should discontinue abacaviras soon as a hypersensitivity reaction issuspected; in addition they should not be rechallenged as subsequent reactions can be fatal.

Patients who carry the HLA-B*5701 allele are at high risk for experiencing a hypersensitivityreaction to abacavir.

[Mallal 2002]Prior to initiating therapy with abacavir, screening for the HLA-

B*5701 allele is recommended; this approach has been found to decrease the risk ofhypersensitivity reaction.

[Mallal 2008]The abacavirhypersensitivity reaction is diagnosed based on

clinical criteria in 5% to 8% of unscreened individuals.

Screening is also recommended prior to reinitiation ofabacavirin patients of unknown HLA-B*5701 status who have previously tolerated abacavir.

[Abacavir PI]HLA-B*5701-negative patients

may develop a suspected hypersensitivity reaction to abacavir; however, this occurs rarely. A

black box warning about hypersensitivity reactions appears in the prescribing information forabacavir.

There has been considerable attention focused on a possible relationship between abacaviruseand increased risk of myocardial infarction. A large prospective cohort study found an

association between current abacaviruse (and also didanosine use) and myocardialinfarction.

[DAD 2008]A re-evaluation of this data set demonstrated that cumulative abacaviruse

was also associated with myocardial infarction.[Worm 2010]

The association between abacaviruseand myocardial infarction risk has also been observed in 3 additional observational

studies,[Lundgren 2008; Martin 2010; Durand 2009]

but has not been observed in several other studies,including several clinical trial populations (Capsule Summary).

[Lang 2010; Cutrell 2008; Benson 2009; Triant

2010; Cruciani 2010; Bedimo 2009] Based on the evidence at this time, it seems reasonable to avoid abacavirin patients at high risk for coronary heart disease if a reasonable alternative agent is available.

For additional information from CCO inPractice on abacavirand cardiovascular risk, click here.

The US Department of Health and Human Services guidelines[DHHS 2011]

has categorizedabacavir/lamivudine as part of alternative and acceptable regimens rather than a component of

preferred first-line regimens based on the reports of the association ofabacavirwith myocardialinfarction and the results of ACTG 5202, which described a shorter time to virologic failure with

abacavir-containing vs tenofovir-containing first-line regimens in patients with baseline HIV-1RNA 100,000 copies/mL,

[Sax 2009]although the time to virologic failure was similar among the


13/31

stratum of patients with baseline HIV-1 RNA < 100,000 copies/mL (Capsule Summary).[Daar 2010]

In the most recent revision, the International AIDS Society-USA guidelines also listed

abacavir/lamivudine as an alternative NRTI combination for first-line therapy.[Thompson 2010]

Onthe other hand, the European AIDS Clinical Society lists abacavir/lamivudine as a recommended

NRTI combination for first-line therapy.[EACS 2009]

For additional information from CCO inPractice on the choice of NRTIs in first-line therapy,click here.

The main mutations in reverse transcriptase conferring resistance to abacavirare K65R, L74V,Y115F, and M184V.[Johnson 2009] The M184V mutation emerges rapidly when a regimencontaining emtricitabine orlamivudine is not fully suppressive. By itself, M184V appears not to

confer resistance to abacavirin patients,[Harrigan 2000; Lanier 2004]

but it can add to resistance when thevirus also carries 2 or more thymidine analogueassociated mutations (M41L, D67N, K70R,

L210W, T215Y/F, K219Q/E).[Lanier 2004]

K65R also confers resistance to didanosine,emtricitabine, lamivudine, and tenofovir.

Tenofovir

Tenofovirin combination with other antiretroviral agents is indicated for the treatment of HIV

infection.[Tenofovir PI] It was approved by the US Food and Drug Administration in 2001. Tenofoviris administered once daily at a dose of 300 mg and is part of a coformulated NRTI pair with

emtricitabine (emtricitabine/tenofovir) and with emtricitabine and efavirenz as a 1-pill once-dailyregimen (efavirenz/emtricitabine/tenofovir). Tenofovircombined with emtricitabine or

lamivudine is recommended as the first-line NRTI to be used in combination with other agents inthe US Department of Health and Human Services, the International AIDS Society-USA panel

guidelines and the European AIDS Clinical Society guidelines.[DHHS 2011; Thompson 2010; EACS 2009]

The

efficacy of this combination was demonstrated in the GS934 study.[Gallant 2006] Currently, tenofovir

is the only nucleotide analogue approved by the US Food and Drug Administration for thetreatment of HIV-1 infection.

Tenofoviris generally well tolerated, but can rarely cause acute renal failure, Fanconissyndrome, proteinuria, and tubular necrosis. Patients with renal insufficiency may require a doseadjustment (Table 7).

[Tenofovir PI]Tenofovirshould be avoided if patients are taking other

nephrotoxic drugs. The contribution of long-term tenofoviruse to renal dysfunction is unclear. Ina combined analysis of safety data from clinical trials GS903 and GS934, long-term tenofovir

use (through 144 weeks) did not lead to a diminution in kidney function compared withstavudine.

[Gallant 2008]However, recent cohort data showed that cumulative use oftenofovirwas

independently associated with increased rates of chronic kidney disease (estimated glomerularfiltration rate 60 mL/min/1.73 m2).[Kirk 2010; Schaefer 2010; Deti 2010] Particular risk factors for renal

impairment with tenofovirincluded older age, hypertension, hepatitis C coinfection, lowerbaseline estimated glomerular filtration rate, low CD4+ count, and concomitant use of a PI.

[Kirk

2010; Gallant 2009]

Table 7. Dosage Adjustment of Tenofovir for Patients With Reduced Creatinine Clearance

Creatinine Clearance, mL/min*

50 30-49 10-29 < 10Hemodialysis

Patients

Recommendedtenofovir300-mg

dosing interval

Every24

hrs

Every48

hrs

Every72-96

hrs

Tenofovirnot

recommended

Every 7 days or

after a total ofapproximately 12

hrs of

dialysis


14/31

*Calculated using ideal (lean) body weight.Tenofovir not studied in these patients.

Generally once weekly assuming 3 hemodialysis sessions per week of approximately 4-hour

duration.

Tenofovir should be administered following completion of dialysis.

For additional information from CCO inPractice on renal disease in HIV-infected patients, clickhere.

During the first year oftenofoviruse, bone mineral density declines to a slightly greater extentthan with comparator NRTIs, but the magnitude of the reduction is likely not clinicallysignificant, and this loss later usually appears to stabilize.

[Gallant 2004]Like lamivudine and

emtricitabine, tenofovirhas activity against the hepatitis B virus and is more potent and has ahigher barrier to resistance against the hepatitis B virus than lamivudine oremtricitabine.

[Matthews

2008]

For additional information from CCO inPractice on bone disease in HIV-infected patients, click

here.

The prescribing information fortenofovircontains a black box warning.[Tenofovir PI]

In addition to

the warning about lactic acidosis and hepatomegaly with steatosis that applies to all NRTIs (butis very unlikely with tenofovir), this warning lists the following:

y Severe acute exacerbations of hepatitis have been reported in hepatitis B virusinfectedpatients who have discontinued anti-hepatitis B therapy, including tenofovir. Hepatic function

should be monitored closely in these patients. If appropriate, resumption of anti-hepatitis B

therapy may be warranted


K65R and K70E (not the thymidine analogue mutation K70R) are the principal mutations that

emerge upon failure of a tenofovir-containing combination.[Johnson 2009]

A reduced virologicresponse to tenofoviralso occurs in virus carrying 3 or more thymidine analogueassociatedmutations including M41L or L210W.

[Miller 2004]M184V may slightly enhance virologic response

to tenofovir.[Miller 2004]

Emtricitabine

Emtricitabine was approved by the US Food and Drug Administration in 2003 based on the

results of the FTC-301A trial in which emtricitabine was found to be noninferior to stavudine in

regimens that also contained didanosine and efavirenz.[Saag 2004]

It is indicated in combinationwith other antiretroviral agents for the treatment of HIV infection.

[Emtricitabine PI]It shares many

properties with lamivudine; eitheremtricitabine orlamivudine is included in many antiretroviralregimens. It is administered orally at a dose of 200 mg once daily and is part of a coformulated

NRTI pair with tenofovir(emtricitabine/tenofovir) and with tenofovirand efavirenz as a 1-pillonce-daily regimen (efavirenz/emtricitabine/tenofovir). Emtricitabine combined with tenofoviris

the recommended NRTI component of all of the preferred first-line therapy regimens in the USDepartment of Health and Human Services guidelines

[DHHS 2011]and in the guidelines issued by

the International AIDS Society-USA panel[Thompson 2010] and the European AIDS ClinicalSociety.

[EACS 2009]

Emtricitabine is well tolerated, but like lamivudine, requires a dose adjustment in patients withrenal insufficiency (Table 8). This agent also has activity against the hepatitis B virus.


15/31

Table 8. Dose Adjustment of Emtricitabine in Patients With Reduced Renal Function

Formulation Creatinine Clearance, mL/min

50 30-49 15-29< 15 or on

Hemodialysis

200-mgcapsule

Every 24 hrs Every 48 hrsEvery 72

hrsEvery 96 hrs

Oral solution

(10 mg/mL)

240 mg every 24

hrs (24 mL)

120 mg every 24

hrs (12 mL)

80 mgevery

24 hrs (8

mL)

60 mg every

24 hrs (6 mL)

The prescribing information foremtricitabine contains a black box warning.[Emtricitabine PI]

In

addition to the warning about lactic acidosis and hepatomegaly with steatosis that applies to allNRTIs, this warning lists the following:

y Emtricitabine is not approved for the treatment of chronic hepatitis B virus infection and thesafety and efficacy ofemtricitabine have not been established in patients coinfected with

hepatitis B virus and HIV

y Severe acute exacerbations of hepatitis B virus have been reported in patients who havediscontinued emtricitabine

o Hepatic function should be monitored closely with both clinical and laboratory follow-upfor at least several months in patients who are coinfected with HIV and hepatitis B virus

and discontinue emtricitabine. If appropriate, initiation of anti-hepatitis B therapy may

be warranted


The M184V/I mutations emerge rapidly when an emtricitabine-containing regimen is not fullysuppressive, often as the first mutation in this regimen.

[Johnson 2009]M184V also confers resistance

to lamivudine and can make HIV more resistant to abacavirin the presence of 2 or 3 TAMs(M41L, D67N, K70R, L210W, T215Y/F, K219Q/E).[Lanier 2004] K65R is also a major

emtricitabine mutation and is associated with resistance to abacavir, didanosine, lamivudine, andtenofovir.

[Johnson 2009]


Keywords: Cardiovascular Disease, Hematologic Complications, Initial Antiretroviral Therapy,

Mitochondrial Disorders, Neurologic Complications, Special Populations, Viral Hepatitis Coinfection


16/31

PIs

The US Food and Drug Administration (FDA) approval of the first PI in late 1995 changed the

paradigm of HIV therapy. Although the first generation PIs had inconvenient dosing schedules,high pill burdens, and frequent gastrointestinal and metabolic adverse effects, they were life-

saving agents for many patients when combined with NRTIs. In general, newer PIs have theadvantage of improved tolerance, a more favorable dosing schedule, and increased activity

against PI-resistant strains of HIV. Because of their metabolism by cytochrome P450 3A4

enzymes, PIs (except nelfinavir) can be pharmacologically boosted with low-dose ritonavir.Boosting results in higher trough concentrations and/or longer half-lives, lower pill burden, andimproved efficacy. In addition, virologic failure of boosted PIs in first-line therapy is not

associated with the emergence of major PI mutations.[Eron 2006; Molina 2008; Ortiz 2008; Walmsley 2008]

Thereare 10 FDA-approved PIs (Table 9); currently, there are no new PIs in the later stages of clinical

development.

Lipohypertrophy, manifested as an increase in abdominal girth, breast size, and the dorsocervicalfat pad, emerged as a potential important complication, associated with PI agents, especially

indinavir.[Galli 2002]

However, the pathophysiology and risk factors for this condition are not aswell defined as for lipoatrophy, and more recent data have not shown an association between PI-

based therapy and lipohypertrophy.[Haubrich 2009]

PIs are associated with increased total cholesteroland triglycerides and gastrointestinal adverse effects, particularly nausea and diarrhea. The

widespread use ofritonavir-boosted PIs has highlighted these adverse events.

For additional information from CCO inPractice on metabolic complications of HIV and

antiretroviral therapy, click here.

Table 9. Currently Available PIs and Their Characteristics


MonitoringNotes

Saquinavir

1000 mg with

ritonavir100mg orally

twice daily

Diarrhea, nausea,dyspepsia,

abdominal pain,dyslipidemia,

QT and PR intervalprolongation

Cholesterol,

triglycerides,EKG

Taken with

food. Tabletsor HGC

available

Ritonavir

100-400 mggiven once or

twice daily aspharmacologic

booster

Dyslipidemia and

GI adverse effects

Cholesterol,triglycerides,

fastingglucose

Therapeuticdose (600 mg

BID) no longerused

Indinavir

800 mg orally3 times daily

or 2 times

dailycoadministered

with ritonavir100 mg

Kidney stones,indirecthyperbilirubinemia,

GI adverse effects,potential increased

MI risk, insulinresistance,

dyslipidemia

Cholesterol,triglycerides,

bilirubinlevel, fasting

glucose

Taken with

food and 48ounces of fluid

daily

Nelfinavir1250 mg orally

twice dailyGI adverse effects

Cholesterol,triglycerides

Taken with

food. Noteffectively

boosted by


17/31


MonitoringNotes

ritonavir

Lopinavir/ritonavir

400/100 mg

twice daily or800/200 mg

once daily (ininitial therapy

and for

experiencedpatients with< 3 lopinavir

resistancemutations)

GI adverse effects,hypertriglyceri-

demia, potentialincreased MI risk

Cholesterol,

triglycerides,

glucose

Long durationdata available,

but adverseeffects and pill

burden have

made other PIsmore attractive

for first-line

therapy

Atazanavir

400 mg once

daily or 300mg with

ritonavir100mg once daily

Indirect

hyperbilirubinemiasometimes causing

jaundice or scleralicterus

Cholesterol,

triglyceridesif boosted,

jaundice,sclera icterus

Taken withlight meal.

Avoid withproton pump

inhibitors.Requires

dosingseparation

with H2blockers,

antacids

Fosamprenavir

PI naive: 1400

mg twice dailyor 1400 mg

with ritonavir100-200 mg

once daily

PIexperienced:

700 mg withritonavir100

mg twice daily

GI adverse effects,hyperlipidemia,

rash, potentialincreased MI risk

Cholesterol,

triglycerides

Prodrug ofamprenavir.

Potential forrash

Tipranavir

500 mg with

ritonavir200mg twice daily

GI adverse effects,hepatitis,

intracranialhemorrhage,

dyslipidemia

Cholesterol,

triglycerides,liver

enzymes

Cannot be

coadministeredwith etravirine.

Potential forrash.. Must be

administeredwith ritonavir

Darunavir

Treatmentnaive: 800 mg

with ritonavir100 mg once

daily

Treatment

experienced:600 mg with

ritonavir100

Occasional rashCholesterol,

triglycerides

Potential forrash. Must be

administeredwith ritonavir


18/31


MonitoringNotes

mg twice daily

BID, twice daily; EKG, electrocardiogram; GI, gastrointestinal; HGC, hard-gel capsule; H2,

histamine 2; MI, myocardial infarction.

Saquinavir

Saquinavirwas the first PI and was approved by the US Food and Drug Administration in 1995.It is currently indicated in combination with ritonavirand other antiretroviral agents for thetreatment of HIV infection.[Saquinavir PI] It may be used in both treatment-naive and treatment-

experienced patients. It is currently available as hard-gel capsules (200 mg) and tablets (500 mg).Because of poor pharmacokinetics and tolerability, a previously available soft-gel capsule

formulation was discontinued. Saquinavirshould be dosed with ritonavir(1000 mg ofsaquinavirplus 100 mg ofritonavirtwice daily) and taken within 2 hours after a meal. Saquinavir/ritonavir

1000/100 mg twice daily is a recommended boosted PI and saquinavir/ritonavir2000/100 mgonce daily is an alternative boosted PI in the European AIDS Clinical Society guidelines

(Management Guidelines).[EACS 2009]

On the other hand, saquinavir/ritonaviris not currentlyincluded among recommended or alternative first-line agents in the International AIDS Society-

USA Guidelines (Management Guidelines).[Thompson 2010] Similarly, in the January 2011 edition ofthe US Department of Health and Human Services (DHHS) guidelines, the status of

saquinavir/ritonavir-based regimens was changed from the alternative category to regimensthat may be acceptable but should be used with caution in response to a study in healthy

volunteers that demonstrated an increase in the PR and QT interval with saquinavir/ritonavir(Management Guidelines).

[DHHS 2011]The DHHS guidelines recommend that all patients who are

initiating therapy with saquinavir/ritonavirhave a pretherapy electrocardiogram. They alsorecommend that saquinavir/ritonavirnot be used in patients with a pretreatment QT interval >

450 msec, refractory hypokalemia or hypomagnesemia, concomitant therapy with other drugsthat prolong the QT interval, complete atrioventricular block without implanted pacemaker, or

risk of complete atrioventricular block.

Other common adverse effects ofsaquinavirinclude diarrhea, nausea, dyspepsia, and abdominalpain.

Saquinavirhas 2 primary resistance mutations, G48V and L90M.[Johnson 2009]

Secondary or

accessory mutations may evolve at protease positions 10, 24, 54, 62, 71, 73, 77, 82, and 84.

Ritonavir

Ritonavirin combination with other antiretroviral agents is indicated for the treatment of HIVinfection and may be used in both treatment-naive and treatment-experienced patients.

[Ritonavir PI]

Although approved by the US Food and Drug Administration in 1996 for use as a PI incombination with NRTIs as a complete regimen, use ofritonavirat full dose (600 mg twice

daily) resulted in fatigue, nausea, diarrhea, lipid abnormalities, and paresthesias; therefore, thisdosage is no longer used in current therapy. However, as a pharmacologic booster at daily doses

of 100-400 mg ritonaviris generally well tolerated with occasional gastrointestinal adverseeffects and mild effects on cholesterol and triglycerides. Use ofritonavir200 mg daily is usually

accompanied by larger increases in triglycerides and total cholesterol when compared withritonavir100 mg daily.[Molina 2008; Ortiz 2008] The doses ofritonavirused with different boosted-PI

regimens are outlined in Table 10.

Table 10. Ritonavir Doses Used for Boosting Other PIs


19/31

Boosted PI RegimenDaily Dose

ofRitonavir

Currently Approved Patient

Population

Atazanavir/ritonavir300/100mg QD

100 mgTreatment-naive and treatment-

experienced patients

Darunavir/ritonavir800/100mg QD

100 mg Treatment-naive patients only

Darunavir/ritonavir600/100mg BID

200 mg Treatment-experienced patients

Fosamprenavir/ritonavir

1400/100 mg QD100 mg Treatment-naive patients only

Fosamprenavir/ritonavir1400/200 mg QD

200 mg Treatment-naive patients only

Fosamprenavir/ritonavir700/100 mg BID



Indinavir/ritonavir800/100 mgBID



Lopinavir/ritonavir400/100mg BID



Lopinavir/ritonavir800/200

mg QD200 mg

Treatment-naive patients andtreatment-experienced patients

with < 3 lopinavirresistancemutations

Saquinavir/ritonavir1000/100mg BID



Tipranavir/ritonavir500/200mg BID

400 mgTreatment-experienced patients

only

BID, twice daily; QD, once daily.

A tablet formulation of ritonavir 100 mg was approved by the US Food and Drug Administration

in February 2010 as an alternative to the soft-gel capsule formulation. Unlike the capsule

formulation, the tablet does not require refrigeration. Also unlike the previous preparation, thetablet should be taken with food.

A black box warning in the ritonavirprescribing information warns that coadministration of

ritonavirwith certain nonsedating antihistamines, sedative hypnotics, antiarrhythmics, or ergotalkaloid preparations may result in serious or potentially life-threatening adverse events because

of the possible effect ofritonaviron the hepatic metabolism of these drugs.[Ritonavir PI]

Thepotential for drug-drug interactions is an important consideration with the use ofritonavir.

Used today virtually exclusively as a pharmacokinetic booster of PIs, ritonavirhelps thwart

emergence of resistance to PIseven when a PI regimen begins to failby raising the critical

trough concentration of these drugs.

For additional information from CCO inPractice on key pharmacologic principles in HIV patientcare, click here.

Indinavir

Indinavirin combination with antiretroviral agents is indicated for the treatment of HIV

infection.[Indinavir PI]

It was approved by the US Food and Drug Administration in 1996; however,

given its adverse effects profile and dosing schedule, and the availability of other more tolerable


20/31

choices, indinaviris rarely used. Indinaviris dosed with food at 800 mg either 3 times daily ortwice daily if coadministered with ritonavir100 mg.

Potential adverse effects ofindinavirinclude lipohypertrophy, kidney stones (3% to 9% of

patients in clinical trial), renal failure, nausea, indirect hyperbilirubinemia (6% to 12% ofpatients in clinical trial), and headache.

[Indinavir PI]Patients taking indinavirare instructed to

consume 48 ounces of fluid daily to reduce the development of kidney stones. The D:A:D cohortfound an association with cumulative PI use and myocardial infarction.

[DAD Study Group 2007]When

evaluating the effects of specific PIs, even after controlling for lipid abnormalities,

lopinavir/ritonavirand indinavir(boosted or unboosted) were associated with increased rates ofmyocardial infarction, while nelfinavirand saquinavirwere not.

[Worm 2010]

The principal mutations arising upon indinavirfailure are M46I/L, V82A/F/T, and I84V.[Johnson

2009]Secondary or accessory mutations may occur at protease positions 10, 20, 24, 32, 36, 54, 71,

73, 76, 77, and 90. The International AIDS Society-USA panel that regularly updatesantiretroviral resistance mutations notes that this list cannot be considered comprehensive

because little research has addressed resistance to indinavirin recent years.[Johnson 2009]

Nelfinavir

Nelfinavirin combination with other antiretroviral agents is indicated for the treatment of HIVinfection; it may be used for both treatment-naive and treatment-experienced patients,

[Nelfinavir PI]

and was approved by the US Food and Drug Administration in 1997. Nelfinaviris dosed at 1250mg twice daily with food. Because nelfinaviris not effectively boosted by ritonavirand results in

poorer virologic outcomes than ritonavir-boosted PIs,[Walmsley 2002]

it is rarely used.The most

common adverse effect associated with nelfinaviris diarrhea.

D30N is 1 of 2 primary resistance mutations fornelfinavir, and this mutation is not involved in

resistance to any other PI.[Johnson 2009]

The other primary nelfinavirresistance mutation is L90M,which is also a primary saquinavirmutation and a secondary mutation with several other PIs.

Secondary or accessory nelfinavirresistance mutations arise at codons 10, 36, 46, 71, 77, 82, 84,

and 88. In its listing of antiretroviral resistance mutations, the International AIDS Society-USApanel issues a disclaimer on the comprehensiveness of the mutation list fornelfinavirbecauselittle recent research has addressed resistance to this PI.

[Johnson 2009]Nelfinavir, which is not

boosted by ritonavir, was the comparator PI in the clinical trial that established the high barrier toresistance with boosted PIs.

[Walmsley 2002]

Lopinavir/Ritonavir

Lopinavir/ritonaviris the only boosted PI that is coformulated with low-dose ritonavir, and is

indicated in combination with other antiretroviral medications for the treatment of HIV infection;it can be administered to both treatment-naive and treatment-experienced patients.

[Lopinavir/Ritonavir

PI] The coformulated product was approved by the US Food and Drug Administration in 2000.The original soft-gel capsule formulation has been phased out and has been replaced with tablets

consisting oflopinavir200 mg and ritonavir50 mg. The dose is lopinavir/ritonavir400/100 mgtwice daily; when coadministered with efavirenz, nevirapine, fosamprenavir, ornelfinavir, the

lopinavir/ritonavirdose must be increased to lopinavir/ritonavir500/125 mg twice daily. Fortreatment-naive and experienced patients with < 3 lopinavirresistance mutations,

lopinavir/ritonavircan also be administered once daily at 800/200 mg but for other treatment-experienced patients, twice-daily dosing is recommended.

For many years, lopinavir/ritonavirwas the only preferred PI in US treatment guidelines. The

clinical trial data of experience with lopinavir/ritonavirin first-line therapy extend over 7


21/31

years.[Murphy 2008]

Over the last several years, results of the KLEAN, ARTEMIS, CASTLE, andGEMINI trials have demonstrated the noninferiority offosamprenavir/ritonavir,

darunavir/ritonavir, atazanavir/ritonavir, and saquinavir/ritonavircompared withlopinavir/ritonavirat 48 weeks.

[Eron 2006; Molina 2008; Ortiz 2008; Walmsley 2008]However,

based on recent

data from the ARTEMIS and CASTLE trials that demonstrated noninferior 96-week efficacy ofdarunavir/ritonavirand atazanavir/ritonavir, respectively, overlopinavir/ritonavirwhen each was

combined with emtricitabine/tenofovirand better tolerability,[Mills 2009; Molina 2010]

these 2 boostedPI regimens are now the preferred PI-based regimens for first-line therapy, and

lopinavir/ritonaviris among the components of alternative regimens in the 2009 version of the

US Department of Health and Human Services (DHHS) guideline.[DHHS 2011]

and an alternativeboosted PI in the 2010 version of the International AIDS Society-USA guidelines.

[Thompson 2010]

Lopinavir/ritonavirremains a recommended boosted PI for first-line therapy in the European

AIDS Clinical Society guidelines.[EACS 2009]

Lamivudine/zidovudine plus lopinavir/ritonavirremains the preferred regimen for pregnant women in the DHHS guidelines.

[DHHS 2011]

For additional information from CCO inPractice on the experience with lopinavir/ritonavirin

first-line therapy, click here.

The adverse effects oflopinavir/ritonavirinclude diarrhea, nausea, and hyperlipidemia. TheD:A:D cohort found an association with cumulative PI use and myocardial infarction.

[DAD Study

Group 2007]

When evaluating the effects of specific PIs, even after controlling for lipidabnormalities, lopinavir/ritonavirand indinavir(boosted or unboosted) were associated with

increased rates of myocardial infarction, while nelfinavirand saquinavirwere not.[Worm 2010]

Aretrospective French case-control study found myocardial infarction was associated with

cumulative PI use and, when individual agents were evaluated, specifically with fosamprenavirritonavirand lopinavir/ritonavir.

[Lang 2010]Neither study had sufficient exposure-years for the

newer PIs (atazanavir, tipranavir, and darunavir) to evaluate their effects specifically.

For additional information from CCO inPractice on the association of specific antiretroviral

agents with cardiovascular disease, click here.

V32I, I47V/A, L76V, and V82A/F/T/S are primary lopinavir-related resistance mutations.[Johnson

2009] Secondary or accessory mutations may evolve at protease positions 10, 20, 24, 33, 46, 50,

53, 54, 63, 71, 73, 84, and 90. In PI-experienced patients, the accumulation of 6 or more of thesemutations is associated with reduced virologic response to lopinavir/ritonavir.

[Masquelier 2002; Kempf

2001] Clinical trials oflopinavir/ritonavirfirst established the principals that ritonavir-boosted PIshave a high genetic barrier to resistance and that resistance-conferring mutations usually do not

emerge in previously untreated patients upon initial failure of a boosted-PI regimen.[Walmsley 2002]

However, some research suggests that specific mutationsV32I, I47A, and possibly I47V

confer high-level resistance to lopinavir/ritonavir.[Mo 2005; Friend 2004; Kagan 2005]

The addition of L76Vto 3 PI resistance mutations greatly increases resistance to lopinavir/ritonavir.

[Young 2010]In a trial

that enrolled antiretroviral-experienced but lopinavir-naive patients, mutations arose more

readily upon failure oflopinavir/ritonavirthan darunavir/ritonavir.[De Meyer 2009]

Atazanavir

Atazanaviris indicated in combination with other antiretroviral agents for the treatment of HIV

infection.[Atazanavir PI]

It was approved by the US Food and Drug Administration in 2003 as a resultof the AI424-008 trial in which atazanavirwas found to be noninferior to nelfinavirwhen each

was combined with stavudine and lamivudine.[Murphy 2003]

Atazanaviris taken orally at a once-daily dose of 400 mg when unboosted or 300 mg when coadministered with ritonavir100 mg; it

can be administered in the unboosted form to antiretroviral-naive patients or in the ritonavir-boosted form to both antiretroviral-naive or treatment-experienced patients. Boosting of


22/31

atazanavirwith ritonavir100 mg is required when atazanaviris coadministered with tenofovirorefavirenz, as both of these drugs loweratazanavirconcentrations; when used with efavirenz, the

dose should be atazanavir/ritonavir400/100 mg. Atazanavirshould not be prescribed withnevirapine.

Atazanavirshould be taken with a light meal and has improved bioavailability in the presence of

stomach acid. Because of the results of the CASTLE study,[Molina 2008; Molina 2010]

atazanavir/ritonavirplus emtricitabine/tenofoviris one of the 2 preferred PI-based regimens for

first-line therapy in the US Department of Health and Human Services guidelines[DHHS 2011]

;

atazanavir/ritonavircombined with abacavir/lamivudine orlamivudine/zidovudine are listed asalternative regimens. Atazanavir/ritonaviris also a recommended PI in the International AIDSSociety-USA guidelines[Thompson 2010] and the European AIDS Clinical Society guidelines.[EACS

2009]Unboosted atazanavirplus eitherabacavir/lamivudine orlamivudine/zidovudine have been

classified as acceptable first-line therapy regimens in the US Department of Health and Human

Services guidelines.[DHHS 2011]

The 96-week primary endpoint results of ACTG 5202 that compared atazanavir/ritonavirvsefavirenz, each on a backbone of eitherabacavir/lamivudine oremtricitabine/tenofovir, showed a

similar time to virologic failure with atazanavir/ritonavirvs efavirenz when combined with eitherabacavir/lamivudine oremtricitabine/tenofovirin the overall population analysis (Capsule

Summary).[Daar 2010]

This is the first time that a boosted PI has been shown to be noninferior toefavirenz in a randomized clinical trial.

For additional information from CCO inPractice on the choice of boosted PI in first-line therapy,click here.

Atazanaviris well tolerated with little effect on cholesterol and triglyceride levels, although lipid

increases are slightly greater with boosted vs unboosted atazanavir.[Malan 2008]

Unconjugatedhyperbilirubinemia is a common and reversible adverse effect, which occurs in most patients but

generally does not require treatment discontinuation. It may be accompanied by jaundice andsclera icterus in a small percentage of patients (4% to 9% of patients in clinical trial). Although

not harmful, these conditions may be a cause for discontinuation if patients are concerned abouttheir appearance. In general, atazanaviris contraindicated with proton pump inhibitors, and its

dosing should be separated from histamine 2 blockers and antacids (Table 11).[Atazanavir PI]

Although there is some evidence that treatment-naive patients can be successfully treated with

ritonavir-boosted atazanavirwhile receiving a proton pump inhibitor, other options are generallypreferable for patients on proton pump inhibitors.

[Guiard-Schmid 2006]

Table 11. Atazanavir Dosing With Gastric Acid-Reducing Agents

Agent Dosing Recommendations

Treatment-Naive PatientsTreatment-Experienced

Patients

Antacids

Atazanaviroratazanavir/ritonavirshould be

administered 2 hrs before or 1 hrafter these medications.

Atazanaviroratazanavir/ritonavirshould be

administered 2 hrs before or 1 hrafter these medications.

H2-receptor

antagonists

Unboosted: Atazanavir400 mgshould be administered at least 2

hrs before and at least 10 hrsafter a dose of the H2-receptor

antagonist. No single dose of theH2-receptor antagonist should

exceed a dose comparable to

Atazanavir/ritonavir300/100 mgshould be administered

simultaneously with, and or atleast 10 hrs after, a dose of the

H2-receptor antagonist. The H2-receptor antagonist dose should

not exceed a dose comparable to


23/31

Agent Dosing Recommendations

Treatment-Naive PatientsTreatment-Experienced

Patientsfamotidine 20 mg, and the total

daily dose should not exceed adose comparable to famotidine

40 mg.

Boosted: Atazanavir/ritonavir

300/100 mg should beadministered simultaneously

with, and or at least 10 hrs after,

a dose of the H2-receptorantagonist. An H2-receptor

antagonist dose comparable tofamotidine 20 mg once daily up

to a dose comparable tofamotidine 40 mg twice daily

can be used withatazanavir/ritonavir300/100 mg

famotidine 20 mg twice daily. If

given with tenofovir, theatazanavir/ritonavirdose should

be 400/100 mg. Unboostedatazanavirshould not be used.

Protonpump

inhibitors

The proton pump inhibitor doseshould not exceed a dose

comparable to omeprazole20 mg and must be taken

approximately 12 hrs prior toatazanavir/ritonavir.

Proton pump inhibitors should

not be used in treatment-experienced patients receiving

atazanavir/ritonavir.

H2, histamine 2.

In January 2011, new information about the dosing ofatazanavirin pregnancy and thepostpartum period was added to the prescribing information.

[Atazanavir PI]These instructions

included:

y Atazanavir should not be administered without ritonavir in pregnancyy No dose adjustment is required for atazanavir in pregnant patients with the following

exceptions:

o For treatment-experienced pregnant women during the second or third trimester, whenatazanavir is coadministered with eitheran H2-receptor antagonist or tenofovir,

atazanavir 400 mg plus ritonavir 100 mg once daily is recommended

o There are insufficient data to recommend a atazanavir dose for use with both an H2-receptor antagonist and tenofovir in treatment-experienced pregnant women

y No dose adjustment is required for postpartum patients. However, patients should be closelymonitored for adverse events because atazanavir exposures might be higher during the first 2

months after delivery

The primary atazanavirresistance mutations are I50L, I84V, and N88S.[Johnson 2009]

Secondary or

accessory mutations may arise at protease positions 10, 16, 20, 24, 32, 33, 34, 36, 46, 48, 53, 54,60, 62, 64, 71, 73, 82, 85, 90, and 93. Boosting atazanavirwith ritonavirraises the barrier to

resistance. M46I plus L76V may make HIV more susceptible to atazanavir.[Young 2010]

Fosamprenavir

Fosamprenaviris indicated in combination with other antiretroviral agents for the treatment of

HIV-1 infection.[Fosamprenavir PI]

It was approved by the US Food and Drug Administration in 2003


24/31

as a result of the NEAT trial in which fosamprenavirwas shown to be noninferior to nelfinavirwhen each was combined with abacavirand lamivudine.

[Rodriguez-French 2004]Fosamprenaviris a

prodrug of amprenavir, but requires a lower pill burden and has therefore completely replaced[amprenavir]. For PI-naive patients, it can be given orally at a dose offosamprenavir1400 mg

twice daily, 700 mg with ritonavir100 mg twice daily, and 1400 mg once daily with ritonavir100 mg or 200 mg. PI-experienced patients should receive a twice-daily regimen of 700 mg of

fosamprenavircoadministered with ritonavir100 mg.

Fosamprenavir/ritonaviris a component of alternative regimens for first-line therapy in the US

Department of Health and Human Services guidelines.[DHHS 2011] and is an alternativeboosted PIin the International AIDS Society-USA guidelines

[Thompson 2010]and the European AIDS Clinical

Society guidelines.[EACS 2009] Unboosted fosamprenavirplus abacavir/lamivudine,

lamivudine/zidovudine, oremtricitabine/tenofovirhas been classified as a regimen to be usedwith caution (defined as regimens that have demonstrated virologic efficacy in some studies but

also have safety, resistance, or efficacy concerns) in the US Department of Health and HumanServices guidelines.

[DHHS 2011]

Fosamprenaviris well tolerated by most patients. When administered as a boosted PI,

fosamprenavir/ritonaviris associated with lipid effects that are similar to those oflopinavir/ritonavir.

[Eron 2006]A retrospective French case-control study found myocardial

infarction was associated with cumulative PI use and, when individual agents were evaluated,significantly only with fosamprenavir ritonavirand lopinavir/ritonavir.

[Lang 2010]Fosamprenavir

(like darunavirand tipranavir) contains a sulfonamide moiety, and patients with a sulfa allergyshould be alerted when taking fosamprenavir. There is a potential for rash when using this agent.

For additional information from CCO inPractice on the association of specific antiretroviralagents with cardiovascular disease, click here.

I50V and I84V are primary resistance mutations forfosamprenavir.[Johnson 2009]

Secondary or

accessory mutations may arise at protease residues 10, 32, 46, 47, 54, 73, 76, 82, and 90. Certainsimilarities between the resistance associated mutations between fosamprenavirand darunavir

result in a degree of cross-resistance between these agents. In an analysis of 113 PI-experiencedpatients starting fosamprenavir/ritonavir700/100 mg twice daily in 2 trials, the mutations I15V,

M46I/L, I54L/M/V, D60E, L63P/T, and I84V correlated most strongly with virologicresponse.

[Marcelin 2008]The 9 patients with none of these mutations had the greatest Week-12

responses.

Tipranavir

Tipranavirboosted with ritonaviris indicated for combination antiretroviral treatment of HIV-infected patients who are treatment-experienced and infected with HIV-1 strains resistant to

more than 1 PI.[Tipranavir PI]

Tipranavirwas approved by the US Food and Drug Administration in

2005 based on the 24-week results of the RESIST trials in which tipranavir/ritonavirplus anoptimized background regimen was found to be superior to an optimized background regimenalone in highly treatment experienced patients.

[Cahn 2006; Gathe 2006]Tipranaviris active against

many PI-resistant HIV variants. It must be coadministered with ritonavirat a dose oftipranavir500 mg with ritonavir200 mg twice daily.

For additional information from CCO inPractice on the management of treatment-experienced

HIV-infected patients, click here.

Tipranavir/ritonavirhas many significant drug interactions which must be taken into account; of

particular note, it should not be coadministered with etravirine or other PIs.[Tipranavir PI]

The most


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common adverse effects associated with tipranavirare nausea, vomiting, diarrhea, fatigue, rash(8% to 10% of patients in clinical trials), lipid abnormalities, and headache. The tipranavir

prescribing information carries a black box warning of the risk of clinical hepatitis and hepaticdecompensation, including some fatalities, and it should be used with caution in patients with

hepatitis B virus or hepatitis C virus coinfection, which increases the risk of hepatotoxicity.Tipranaviris contraindicated in patients with moderate to severe hepatic dysfunction. There is

also a black box warning regarding association oftipranavirwith reports of both fatal andnonfatal intracranial hemorrhage. These safety issues, drug interactions, pill burden, and the

availability of other potent PIs have limited the use oftipranavir. Tipranavir(like darunavirand

fosamprenavir) contains a sulfonamide moiety, and patients with a sulfa allergy should be alertedwhen taking tipranavir. There is a potential for rash when using this agent.

Tipranavirhas 3 primary resistance mutations not shared by other PIs as primary mutationsL33F, Q58E, and T74P.

[Johnson 2009]Primary mutations that tipranavirshares with one or more

other PIs are I47V, V82L/T, and I84V. Substitutions at codons 10, 13, 20, 35, 36, 43, 46, 54, 69,83, and 90 may evolve as secondary or accessory tipranavirmutations. Presence of 2 or more

mutations from the following listL24I, I50L/V, I54L, and L76Vare associated withdecreased resistance to tipranavirin vitro and a better short-term virologic response if 2 or more

are present.[Johnson 2009]

A scoring system has been developed to evaluate the likelihood oftipranaviractivity in a patientwith PI-resistant virus. Resistance to tipranavirin clinical isolates is mediated by 21 tipranavir

resistanceassociated mutations (major: 82L/T; minor: 10V, 13V, 20M/R, 33F, 35G, 36I, 43T,46T, 47V, 54A/M/V, 58E, 69K, 74P, 83D, 84V, 90M).The presence of 5 of these mutations is

associated with reduced clinical response, and the presence of 8 of these mutations isassociated with lack of efficacy oftipranavir.

[Baxter 2008]

Darunavir

Darunaviris indicated for the treatment of HIV infection; it must be coadministered with

ritonavirand other antiretroviral agents.[Darunavir PI] Darunavirwas initially approved by the US

Food and Drug Administration (FDA) in 2006 as a result of the POWER trials in whichdarunavir/ritonavirplus an optimized background regimen was found to be superior to anoptimized background regimen alone in highly treatmentexperienced patients.

[Clotet 2007]Like

tipranavir, darunaviris active against many PI-resistant HIV variants. It is given orally at a doseofdarunavir600 mg with ritonavir100 mg twice daily for treatment-experienced patients and

darunavir800 mg with ritonavir100 mg once daily for treatment-naive patients. As a result ofthe results of the ARTEMIS study,[Ortiz 2008; Mills 2009] darunavir/ritonavir800/100 mg once daily

was approved for use in treatment-naive patients, and this boosted PI combined withemtricitabine/tenofoviris one of the 2 preferred PI-based first-line regimens in the US

Department of Health and Human Services guidelines[DHHS 2011]

; in addition, darunavir/ritonaviris a recommended PI for first-line therapy in the International AIDS Society-USA panel

guidelines[Thompson 2010] and the European AIDS Clinical Society guidelines.[EACS 2009] The resultsof the ODIN study suggest that once-daily dosing ofdarunavir/ritonavirmight safely be

extended to treatment-experienced patients without PI-associated resistance (CapsuleSummary)

[Cahn 2010]; however, at present the FDA-approved dosing ofdarunavir/ritonavirin

treatment-experienced patients remains 600/100 mg twice daily.

Darunaviris a potent and well-tolerated agent with limited gastrointestinal or lipid abnormalities

associated with its use. Darunavir(like fosamprenavirand tipranavir) contains a sulfonamidemoiety, and patients with a sulfa allergy should be alerted when taking any of these agents. There

is a potential for rash when using this agent.


26/31

Eleven darunavirresistanceassociated mutations have been identified (major: I47V, I50V,I54M/L, L76V, I84V; minor: V11I, V32I, L33F, T74P, L89V).

[Johnson 2009]The presence of 3

darunavirmutations is associated with a diminished virologic response to this drug.[Winters 2008]

Some darunavir-associated resistance mutations sensitize HIV to tipranavir(eg, I50V, I54L,

L76V)[Johnson 2009]


Keywords: Cardiovascular Disease, Fat Perturbations, Initial Antiretroviral Therapy, Special Populations

NNRTIs

The NNRTIs bind to the HIV reverse transcriptase outside of the active domain, therebyallowing them to noncompetitively inhibit the enzyme. Currently, there are 4 US Food and Drug

Administrationapproved NNRTIs (Table 12) and 1 (rilpivirine [TMC 278]) that has recentlycompleted phase III clinical trials and has been submitted to the US Food and Drug

Administration for approval both as a single entity and as a fixed-dose combination with

emtricitabine and tenofovir.

Rash is a class-wide adverse effect with use of currently approved NNRTIs. These range in

severity from mild to life threatening.

One limitation to the use of first-generation NNRTIs nevirapine, delavirdine, and efavirenz, is

their low genetic barrier to resistance. That is, the presence of a single NNRTI resistanceassociated mutation confers high-level resistance to all 3 of these agents. Resistance to etravirine,

on the other hand, requires the presence of a combination ofetravirine-resistancemutations.

[Vingerhoets 2010]

Table 12. Currently Approved NNRTIs and Their Characteristics


MonitoringNotes

Nevirapine

200 mg

orallyonce

daily for2 weeks

then 200mg twice

daily

Rash, fever,

potential for

hypersensitivityreaction

Hepatictransaminases

Avoid in women with

pretreatment CD4+counts

> 250 cells/mm and inmen with pretreatment

CD4+ counts> 400 cells/mm

Delavirdine

400 mg

orally 3times

daily

Rash None Very rarely used

Efavirenz

600 mgorally

oncedaily

Central nervoussystem effects,

rash, potentiallyteratogenic

Pregnancy

testing

Take on empty

stomach to avoid ordecrease adverse

neuropsychiatriceffects. Should not be

administered in firsttrimester of pregnancy


27/31


MonitoringNotes

Etravirine

200 mgorally

twicedaily

Rash andhypersensitivity

reactions

NoneActive against many

NNRTI-resistant

variants

Nevirapine

Nevirapine is indicated for combination antiretroviral treatment of HIV-1 infection. It wasapproved by the US Food and Drug Administration in 1996 and can be used in both treatment-

naive and experienced patients.[Nevirapine PI] The full dose ofnevirapine is 200 mg twice daily.However, because nevirapine is both an inducer of and substrate for the drug metabolism

enzyme cytochrome P450 3A4, it is initially administered at a dose of 200 mg once daily. If welltolerated after the induction of its own metabolism, the full dose can be administered 2 weeks

following initiation of the once-daily dose. An investigational extended-release formulation thatcan be administered once daily has demonstrated noninferior activity to the current twice-daily

formulation in treatment-naive patients (Capsule Summary)[Gathe 2010]

and in virologicallysuppressed patients switching from the current nevirapine formulation.[Arasth 2010]

Nevirapine is a recommended NNRTI for first-line therapy in the European AIDS ClinicalSociety guidelines (Management Guidelines).

[EACS 2009]Nevirapine plus lamivudine/zidovudine is

an alternative first-line regimen in the US Department of Health and Human Services guidelines

(Management Guidelines).[DHHS 2011] Nevirapine plus eitherabacavir/lamivudine oremtricitabine/tenofovirhave been classified as regimens to be used with caution. Previous data

had raised concerns about the use ofnevirapine plus emtricitabine/tenofovirbased on thefindings of pilot studies suggesting that these combinations had questionable virologic

efficacy.[Lapadula 2008]

However, results of the large ARTEN trial suggested that this combinationwas similar in efficacy to atazanavir/ritonavirplus emtricitabine/tenofovir; however, there was a

higher rate of discontinuation due to toxicity in the nevirapine arm (13.6% vs 3.6%).[Soriano 2009]

Likewise, the OCTANE-2 study suggested that nevirapine plus emtricitabine/tenofovirhad

comparable virologic activity to lopinavir/ritonavirplus emtricitabine/tenofovir; however, therate of discontinuation due to adverse events was 14% in the nevirapine arm vs 0% in the

lopinavir/ritonavirarm (P< .0001).[Lockman 2010]

Nevirapine is the NNRTI of choice for patients planning pregnancy or those who are pregnantprovided their CD4+ cell counts at initiation are < 250 cells/mm3 (Management

Guidelines).[Perinatal Guidelines 2010]

It is widely used in treatment regimens for patients in resource-limited settings, where generic coformulations with NRTIs are available.

For additional information from CCO inPractice on the choice of first-line therapy, click here.

For additional information from CCO inPractice on management of patients in resource-limitedsettings, click here.

The nevirapine prescribing information contains a black box warning about severe, life-

threatening, and in some cases fatal hepatotoxicity that generally occurs during the first 18 weeksof therapy, as well as severe and potentially fatal skin reactions that may be part of a

hypersensitivity reaction, and that occur most frequently during the first 6 weeks of therapy. Incontrolled trials, symptomatic hepatic events occurred in 4% ofnevirapine recipients, and grade3 or 4 rashes occurred in 1.5% of patients. Although hepatotoxicity can occur in any patient,

women and individuals with higher CD4+ cell counts are at greatest risk. Because of this risk,nevirapine should be used only with great caution in women with pretreatment CD4+ cell counts

> 250 cells/mm3

and in men with CD4+ cell count > 400 cells/mm3

. Nevirapine should be


28/31

immediately and permanently discontinued in any patient who develops severe skin rash, skinrash associated with increased transaminases, or hypersensitivity reaction.

The mutations L100I, K101P, K103N, V106A/M, V108I, Y181C/I, Y188C/L/H, and G190A

confer resistance to nevirapine.[Johnson 2009] L100I, K101P, K103N, V106M, V108I, Y181C/I,Y188L, and G190A also render HIV resistant to efavirenz. L100I and Y181C can reduce

susceptibility to etravirine. Majornevirapine-related resistance mutations can emerge in mothersand infants after single-dose nevirapine prophylaxis and may persist in resting CD4+ cells.

[Wind-

Rotolo 2009]

Delavirdine

Delavirdine was approved by the US Food and Drug Administration in 1997 and is indicated forthe treatment of HIV infection in combination with at least 2 other active antiretroviral agents

when therapy is warranted.[Delavirdine PI] Delavirdine is rarely used in current antiretroviral therapydue to the relatively limited clinical evidence regarding its efficacy, a high pill burden, and an

inconvenient dosing schedule. When used, delavirdine is given orally at a dose of 400 mg 3times daily. The most common adverse effect associated with this agent is rash.

The majordelavirdine-related resistance mutations are K103N, V106M, Y181C, Y188L, and

P236L.[Johnson 2003] The first 4 of these mutations also confer high-level resistance to efavirenz andnevirapine. Because delavirdine is so infrequently used in the United States, its resistance profile

is not currently included in the International AIDS Society-USA update on drug resist

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