Figure 76-1 Schematic representation of the HIV-1 life cycle. Five classes of antiretroviral drugs are available at

present. CCR5 antagonists and fusion inhibitors inhibit the entry of virions into a new target cell. The step of

reverse transcription can be targeted, using nucleoside nucleotide analogs or non-nucleoside reverse-transcriptase

inhibitors (NRTIs, NtRTI, and NNRTIs, respectively). The class of integrase inhibitors prevents integration of viral

DNA into host cell DNA. The class of protease inhibitors interferes with the last state of the life cycle, the

proteolytic processing of the viral proteins, which results in the production of noninfectious particles. (Adapted from

education materials provided by the National Institutes of Health available on AIDSinfo.nih.gov.)

Without intervention, the natural progression of HIV infection results in depletion

of 50 to 100 T cells/μL/year.

26 The severity of immune dysfunction, as evidenced by

T-cell loss, is highly predictive of the potential for the development of specific types

of opportunistic infections. For example, Pneumocystis jirovecii pneumonia rarely

occurs when T-cell counts are greater than 200 cells/μL, whereas retinitis from

cytomegalovirus infection rarely occurs in patients with CD4 counts greater than 75

cells/μL. The diagnosis of AIDS is made when a significant amount of immune

deterioration has occurred, either by depletion of CD4

+ cells to less than 200

cells/μL or because of the development of new opportunistic infections (Tables 76-1

and 76-2). It is important to recognize that not every patient with HIV has a diagnosis

of AIDS. On average, without appropriate drug therapy, death occurs within 10 to 15

years after infection.

26

The interplay between viral load and CD4 T-cell counts is often compared with

that of a train heading toward a particular destination. If the destination is immune

system destruction (and eventually death), then the T-cell count is the distance of the

train from this destination, and the viral load (concentration of HIV RNA in plasma)

is the speed of the train. As both higher speeds and shorter distances reach

destinations faster, so does a high viral load and low T-cell count result in quicker

onset of immune destruction (and death). Potent antiretroviral regimens decrease

viral replication and dramatically alter the natural course of infection by prolonging

the time to opportunistic infection and death.

41

PHARMACOTHERAPY

Pharmacotherapy of HIV has been directed at inhibiting key areas of the HIV life

cycle (Fig. 76-1 and animations found at

http://biosingularity.wordpress.com/2007/03/04/3d-animation-of-hiv-replication/;

Table 76-3). Nucleoside RT inhibitors (NRTIs) include zidovudine, didanosine,

lamivudine, abacavir, emtricitabine, and stavudine, while nucleotide RT inhibitors

currently only include tenofovir. These agents inhibit this enzyme by incorporating

false nucleic acids into the newly forming proviral DNA.

42 This results in an HIV

DNA strand that cannot continue to elongate. Non-nucleoside reverse transcriptase

inhibitors (NNRTIs; nevirapine, efavirenz, rilpivirine, and etravirine) inhibit reverse

transcriptase by directly binding to the enzyme itself and prevent DNA transcription

from RNA.

43 Protease inhibitors (PIs: saquinavir, fosamprenavir, nelfinavir,

indinavir, lopinavir, atazanavir, ritonavir, tipranavir, and darunavir) directly bind to

the catalytic site of HIV protease, inactivating the enzyme and preventing maturation

of the HIV virion.

44

,

45 Unlike reverse transcription, which occurs early in the course

of the HIV life cycle, protease enzyme activity occurs late in virion development. As

a result, inactivation of the protease enzyme inhibits viral replication in any infected

cell regardless of the current stage of HIV replication within that cell. In contrast,

reverse transcriptase inhibitors can protect newly infected cells from becoming

latently infected cells before the formation and insertion of proviral DNA into the

host cell’s genetic material. However, these agents provide no benefit for those

infected cells that are actively producing new strains of virus.

p. 1574

p. 1575

Figure 76-2 Sample disease course for an untreated HIV-infected individualshowing the relationships among

immunologic, virologic, and clinical outcomes over time. Constitutionalsymptoms include fever, night sweats, and

weight loss. Viral load values; CD4 T lymphocytes. (Source: Fauci AS et al. Immunopathogenic mechanisms of

HIV infection. Ann Intern Med. 1996;124:654; Perelson AS et al. HIV-1 dynamics in vivo: virion clearance rate,

infected cell life-span, and viral generation time. Science. 1996;271:1582.)

Table 76-1

CDC MMWR Revised Surveillance Case Definition for HIV Infection—United

States, 2014

HIV-infection stage

a based on age-specific CD4

+ T-lymphocyte count or CD4

+ T-lymphocyte percentage of

total lymphocytes

Age on date of CD4+ T-lymphocyte test

<1 year 1–5 years ≤6 years

1.

2.

Stage Cells/μL % Cells/μL % Cells/μL %

0

b Staging independent of CD4 count/% and age

1 ≥1,500 ≥34 ≥1,000 ≥30 ≥500 ≥26

2 750–1,499 26–33 500–999 22–29 200–499 14–25

3 <750 <26 <500 <22 <200 <14

aStage is based first on the CD4

+ T-lymphocyte count then on percentage if the count is unavailable. Three

situations can dictate that staging is not based on count or percentage: (1) Stage 0 criteria are met meaning that

the stage is 0 regardless of CD4

+ T-lymphocyte test results and the diagnosis of opportunistic infection; (2) if the

criteria for stage 0 are not met and a stage-3 defining opportunistic illness has been diagnosed (see Table 76-2),

meaning that the stage is 3 regardless of CD4

+ T-lymphocyte test results; or (3) if the criteria for stage 0 are not

met and information on the above criteria for other stages is missing, then the stage is classified as unknown.

bStage 0 can be established either:

Based on testing history (previous negative/indeterminate test results): a negative or indeterminate HIV test

(antibody, combination antigen/antibody, or NAT) result within 180 days before the first confirmed positive

HIV test result of any type. The first positive test result could be any time before the positive supplemental test

result that confirms it or

Based on a testing algorithm: a sequence of tests performed as part of a laboratory testing algorithm that

demonstrate the presence of HIV-specific viral markers such as p24 antigen or nucleic acid (RNA or DNA) 0

to 180 days before or after an antibody test that had a negative or indeterminate result.

Adapted from http://www.cdc.gov/mmwr/preview/mmwrhtml/rr6303a1.htm.

Adapted from http://www.cdc.gov/mmwr/preview/mmwrhtml/rr6303a1.htm.

p. 1575

p. 1576

Table 76-2

CDC MMWR Revised Surveillance Case Definition for HIV Infection—United

States, 2014. Appendix Stage-3 Defining Opportunistic Illnesses in HIV

Infection

Bacterial infections, multiple or recurrent

a

Candidiasis of bronchi, trachea, or lungs

Candidiasis of esophagus

Cervical cancer, invasive

b

Coccidioidomycosis, disseminated or extrapulmonary

Cryptococcosis, extrapulmonary

Cryptosporidiosis, chronic intestinal (>1 month’s duration)

Cytomegalovirus disease (other than liver, spleen, or nodes), onset at age >1 month

Cytomegalovirus retinitis (with loss of vision)

Encephalopathy attributed to HIV

c

Herpes simplex: chronic ulcers (>1 month’s duration) or bronchitis, pneumonitis, or esophagitis (onset at age >1

month)

Histoplasmosis, disseminated or extrapulmonary

Isosporiasis, chronic intestinal (>1 month’s duration)

Kaposisarcoma

Lymphoma, Burkitt (or equivalent term)

Lymphoma, immunoblastic (or equivalent term)

Lymphoma, primary, of brain

Mycobacterium avium complex or Mycobacterium kansasii, disseminated or extrapulmonary

Mycobacterium tuberculosis of any site, pulmonary

b

, disseminated or extrapulmonary

Mycobacterium, other species or unidentified species, disseminated or extrapulmonary

Pneumocystis jirovecii (previously known as Pneumocystis carinii) pneumonia

Pneumonia, recurrent

b

Progressive multifocal leukoencephalopathy

Salmonella septicemia, recurrent

Toxoplasmosis of brain, onset at age >1 month

Wasting syndrome attributed to HIV

c

aOnly among children aged <6 years.

bOnly among adults, adolescents, and children aged ≥6 years.

cSuggested diagnostic criteria for these illnesses, which might be particularly important for HIV encephalopathy

and HIV wasting syndrome, are described in the following references: CDC. 1994 Revised classification system

for human immunodeficiency virus infection in children less than 13 years of age. MMWR. 1994;43(RR-12):1–10;

CDC. 1993 Revised classification system for HIV infection and expanded surveillance case definition for AIDS

among adolescents and adults. MMWR Recomm Rep. 1992;41(RR-17)1–19.

Adapted from http://www.cdc.gov/mmwr/preview/mmwrhtml/rr6303a1.htm.

Fusion inhibitors, such as enfuvirtide, prevent HIV and CD4

+ T cells from being

pulled closer together after HIV binds to CD4 and CCR5 or CXCR-4 co-receptors.

Enfuvirtide prevents fusion of the virus with the T-cell by binding to a double coil–

coil complex at the gp41–gp120–CD4 receptor area.

46 The newest classes of

antiretroviral agents are co-receptor blockers and integrase inhibitors. Maraviroc is

a CCR5 co-receptor blocker which prevents HIV from fully binding to cells and

causing infection.

47

Integrase strand transfer inhibitors (INSTIs: raltegravir,

dolutegravir, and elvitegravir) prevent the integrase enzyme from integrating HIV

DNA into the immune cell’s genome.

48 The final class of agents used for HIV

treatment, pharmacokinetic enhancers, are drugs that strongly inhibit CYP3A4, a liver

enzyme responsible for metabolizing several PIs, NNRTIs, and INSTIs.

49 These

agents are used with certain PIs and elvitegravir to impede metabolism and increase

serum drug concentrations in order to decrease dosing requirements. Ritonavir, a PI

itself, is now used primarily for its boosting effect rather than its anti-HIV activity.

The newest pharmacokinetic enhancer, cobicistat, does not directly affect HIV

replication.

With the development of newer, more potent antiretroviral regimens, researchers

have speculated about the possibility of complete eradication of HIV from an

infected patient. This outcome may require complete inhibition of viral replication in

all cells and body stores where HIV resides.

13 However, a barrier to eradication is

the varying half-lives of cell populations (e.g., 1–2 days for peripheral T cells vs. 14

days for macrophages).

50

,

51

In addition, extremely long-lived infected T cells with

half-lives lasting more than 6 to 44 months have been identified.

52

,

53 Thus, it may

require complete suppression of HIV replication for 60 years or more to eradicate

HIV infection completely from the body.

52–54 Another complicating factor is the

potential for HIV to reside in sites that achieve low antiretroviral concentrations,

thereby serving as sanctuaries for HIV replication (e.g., central nervous system

[CNS], testes). Once therapy is discontinued, these sites could theoretically release

unaffected virions and repopulate the host. As a result, research has shifted toward

immune-based therapies that can identify and destroy HIV-infected cells, in addition

to preventing HIV acquisition.

p. 1576

p. 1577

Table 76-3

Characteristics of Antiretroviral Agents for the Treatment of Adult Human

Immunodeficiency Virus Infection

3,5

Drug Dose Pharmacokinetic Parameters

Administration

Considerations

p. 1577

p. 1578

Nucleoside Reverse Transcriptase Inhibitors

Abacavir (ABC)

Ziagen

Preparations

Tablets: 300 mg

Oralsolution: 20 mg/mL

Epzicom: ABC 600 mg +

3TC 300 mg

Trizivir: ABC 300 mg +

ZDV 300 mg + 3TC 150

mg

Triumeq: ABC 600 mg +

3TC 300 mg + DTG 50

mg

300 mg every 12 hours, or

600 mg daily

Epzicom: one tablet daily

Trizivir: one tablet BID

Triumeq: one tablet daily

Oral bioavailability: 83%

Serum t1/2

: 1.5 hours

Intracellular t1/2

: 12–26 hours

Elimination: alcohol

dehydrogenase and

glucuronyltransferase; 82%

renal elimination of metabolites

Can be administered

without regard to

meals

Alcohol raises

abacavir exposure

by 41%

HLA testing

required before

administration

Lamivudine (3TC)

Epivir

Preparations

Tablets: 150, 300 mg

Solution: 10 mg/mL

Combivir: 3TC 150 mg +

ZDV 300 mg

150 mg PO BID or 300

mg PO daily

Combivir: one tablet BID

Epzicom: one tablet BID

Trizivir: one tablet BID

Triumeq: one tablet daily

Oral bioavailability: 86%

Serum t1/2

: 5–7 hours

Intracellular t1/2

: 18–22 hours

Elimination: 70% unchanged in

urine

Can be administered

without regard to

meals

Epzicom: 3TC 300 mg +

ABC 600 mg

Trizivir: 3TC 150 mg +

ZDV 300 mg + ABC 300

mg

Triumeq: ABC 600 mg +

3TC 300 mg + DTG 50

mg

Emtricitabine (FTC)

Emtriva

Preparations

Capsules: 200 mg

Oralsolution: 10 mg/mL

Truvada: FTC 200 mg +

TDF 300 mg

Atripla: FTC 200 mg +

TDF 300 mg + EFV 600

mg

Complera: FTC 200 mg +

RPV 25 mg + TDF 300

mg

Stribild: FTC 200 mg +

EVG/c 150/150 mg + TDF

300 mg

Descovy: FTC 200 mg +

TAF 300 mg

Odefsey: FTC 200 mg +

RPV 25 mg + TAF 25 mg

Genvoya: FTC 200 mg +

EVG/c 150/150 mg + TAF

10 mg

200 mg daily for patients

with calculated CrCl >50

mL/minute

Dose needs to be adjusted

for renal dysfunction: CrCl

30–49 mL/minute: 200 mg

every 48 hours

CrCl 15–29 mL/minute:

200 mg every 72 hours

CrCl <15 mL/minute: 200

mg every 96 hours

Truvada: one tablet daily.

Not for patients with CrCl

<30 mL/minute

Atripla: one tablet daily.

Not for patients with CrCl

<50 mL/minute

Complera: one tablet daily

Stribild: one tablet daily.

Not for patients with CrCl

<70 mL/minute

Stribild: one tablet daily.

Not for patients with CrCl

<70 mL/minute

Oral bioavailability: 93%

Serum t1/2

: 10 hours

Intracellular t1/2

: >20 hours

Elimination: 86% recovered in

urine

Can be administered

without regard to

meals

Tenofovir Disoproxil

Fumarate (TDF)

Viread

Preparations

Tablets: 150, 200, 250, 300

mg

Oral powder: 40 mg/g

Truvada: TDF 300 mg +

FTC 200 mg

Atripla: TDF 300 mg +

FTC 200 mg + EFV 600

mg

Complera: FTC 200 mg +

RPV 25 mg + TDF 300

mg

Stribild: FTC 200 mg +

EVG/c 150/150 mg + TDF

300 mg

300 mg daily for patients

with CrCl >60 mL/minute

Truvada: one tablet daily.

Not for patients with CrCl

<30 mL/minute

Atripla: one tablet daily.

Not for patients with CrCl

<50 mL/minute

Complera: one tablet daily

Stribild: one tablet daily.

Not for patients with CrCl

<70 mL/minute

Oral bioavailability: 25% fasting;

39% with high-fat meal

Serum t1/2

: 17 hours

Intracellular t1/2

: >60 hours

Elimination: primarily by

glomerular filtration and active

tubular secretion

Can be administered

without regard to

meals

Non-Preferred Nucleoside Reverse Transcriptase Inhibitors

Tenofovir alafenamide

(TAF) Preparations

25 mg for patients with

CrCl >30 mL/min

Oral Bioavailability: 40% Can be administered

without regard to

Descovy: TAF 25 mg +

FTC 200 mg Odefsey:

FTC 200 mg + RPV 25

mg + TAF 25 mg

Genvoya: FTC 200 mg +

EVG/c 150/150 mg + TAF

10 mg

Descovy: one tablet daily

Odefsey: one tablet daily

Genvoya: one tablet daily

Serum t1/2

: 0.51 hours

Intracellular t1/2

: 150-180 hours

Elimination: primarily by

glomerular filtration and active

tubular secretion

meals

Zidovudine (ZDV)

Retrovir (R)

Preparations

Oral Solution: 10 mg/mL

Capsule: 100 mg

Tablet: 300 mg

IV Solution: 10 mg/mL

Combivir: ZDV 300 mg +

3TC 150 mg

Trizivir: ZDV 300 mg +

3TC 150 mg + ABC 300

mg

300 mg BID or 200 mg

TID

Combivir (R) or Trizivir

(R): one tablet BID

Oral bioavailability: 60%

Serum t1/2

: 1.1 hours

Intracellular t1/2

: 3 hours

Elimination: hepatic

glucuronidation; renal excretion

of glucuronide metabolite

Can be administered

without regard to

meals (manufacturer

recommends

administration 30

minutes before or 1

hour after a meal)

Didanosine (ddI)

Videx

Preparations

Videx EC (R): 125, 200,

250, 400 mg capsule

Pediatric powder for oral

solution (when

reconstituted as solution

containing antacid): 10

mg/mL

Generic ddI enteric-coated

capsule also available

>60 kg: 400 mg daily (with

TDF, use 250 mg daily)

<60 kg: 250 mg daily (with

TDF, use 200 mg daily)

Oral bioavailability: 30%–40%

Serum t1/2

: 1.6 hours

Intracellular t1/2

: 25–40 hours

Elimination: renal excretion

∼50%

Food decreases

absorption (↓ 55%);

administer ddI on

empty stomach (1

hour before or 2

hours after meal)

Separate ATV and

TPV/r administration

by at least 2 hours

Stavudine (d4T)

Zerit

Preparations

Solution: 1 mg/mL

Capsules: 15, 20, 30, 40

mg

>60 kg: 40 mg BID

<60 kg: 30 mg BID

Sustained release: >60 kg

use 100 mg daily; <60 kg

use 75 mg daily

Oral bioavailability: 86%

Serum t1/2

: 1.0 hour

Intracellular t1/2

: 3.5 hours

Elimination: renal excretion

∼50%

Can be administered

without regard to

meals

Non-Nucleoside Reverse Transcriptase Inhibitors

a

Rilpivirine (RPV)

Edurant

Preparations

Tablets: 25 mg

Complera: RPV 25 mg +

TDF 300 mg + FTC 200

mg

Odefsey: RPV 25 mg +

TAF 25 mg + FTC 200 mg

25 mg daily

Complera: one tablet daily

Oral bioavailability: not

established

Serum t1/2

: ∼50 hours

Intracellular t1/2

: unknown

Elimination: hepatic metabolism

primarily by CYP3A4 with 85%

fecal excretion.

Take with moderateto-high-calorie meal

(increases

absorption 40%)

Efavirenz (EFV)

Sustiva

Preparations

Capsules: 50, 100, 200 mg

Tablets: 600 mg

600 mg at bedtime

Atripla one tablet at

bedtime. Not for patients

with CrCl <50 mL/minute

Oral bioavailability: ∼60%–70%

Serum t1/2

: 40–55 hours

Intracellular t1/2

: unknown

Elimination: hepatically

metabolized by CYP2B6 and

Avoid taking with

high-fat meals,

concentrations ↑

50% (increased risk

for CNS toxicity)

Atripla: EFV 600 mg +

TDF 300 mg + FTC 200

mg

CYP3A4 (also CYP3A4 mixed

inhibitor/inducer)

Etravirine (ETV)

Intelence

Preparations

Tablets: 100, 200 mg

200 mg BID Oral bioavailability: unknown

Serum t1/2

: 40 ± 20 hours

Intracellular t1/2

: unknown

Elimination: hepatically

metabolized by CYP3A4,

CYP2C9, CYP2C19 (also 3A4

inducer, 2C9 and 2C19

inhibitors)

Take after a meal

p. 1578

p. 1579

Non-Preferred Non-Nucleoside Reverse Transcriptase Inhibitors

a

Nevirapine (NVP)

Viramune

Preparations

Suspension: 50 mg/5 mL

Tablets: 200 mg

200 mg PO daily × 14

days, then 200 mg PO

BID

Oral bioavailability: >90%

Serum t1/2

: 25–30 hours

Intracellular t1/2

: unknown

Elimination: metabolized by

CYP2B6 and CYP3A4 (also a

CYP3A4 inducer) with 80%

excreted in urine as the

glucuronide metabolite

Can be administered

without regard to

meals

Protease Inhibitors

Darunavir (DRV)

Prezista

Preparations

Tablet: 75, 150, 600, 800

mg

Suspension: 100 mg/ml

Prezcobix: DRV 800 mg +

COBI 150 mg

DRV 800 mg + RTV 100

mg daily

In patients with ≥1 DRV

resistance mutations: DRV

600 mg + RTV 100 mg

BID

Prezcobix: one tablet daily

Oral bioavailability: 37% alone,

82% with RTV

Serum t1/2

: 15 hours

Intracellular t1/2

: unknown

Elimination: hepatic metabolism

via CYP3A4 (inhibitor)

Food ↑ Cmax

and

AUC by 30%:

administer with food

Atazanavir (ATV)

Reyataz

Preparations

Capsules: 100, 150, 200,

300 mg

Evotaz: ATV 300 mg +

COBI 150 mg

400 mg daily

Atazanavir/RTV: 300/100

daily

Evotaz: one tablet daily

Oral bioavailability: 60%–70%

Serum t1/2

: 6–7 hours

Intracellular t1/2

: unknown

Elimination: hepatic metabolism

via CYP3A4 (modest inhibitor)

Take with food, and

avoid acid

suppressing agents

(which prevent ATV

solubility and

absorption)

Lopinavir

(LPV)/ritonavir (RTV)

Kaletra

Preparations

Tablet: LPV 200 mg +

RTV 50 mg

Solution: LPV 80 mg+

RTV 20 mg per mL

Two tablets or 5 mL BID

or

Four tablets or 10 mL daily

(recommended for

treatment-naïve patients

only)

Oral bioavailability: not

determined

Serum t1/2

: 5–6 hours

Intracellular t1/2

: unknown

Elimination: hepatic metabolism

via CYP3A4 (inhibitor)

Take with food

(increases AUC by

48%). Tablet stable

at room temperature

Non-Preferred Protease Inhibitors

Indinavir (IDV)

Crixivan

Preparations

Capsule: 200, 333, 400 mg

800 mg every 8 hours

(BID dosing ineffective

when sole protease

inhibitor)

IDV/RTV: IDV 800 mg +

100 mg or 200 mg RTV

BID

Oral bioavailability: 65%

Serum t1/2

: 1.5–2 hours

Intracellular t1/2

: unknown

Elimination: hepatically

metabolized via CYP3A4 (also

inhibitor of CYP3A4)

Must be taken on

empty stomach (1

hour before or 2

hours after a meal);

may be taken with

skim milk or low-fat

meal

Adequate hydration

necessary (at least

1.5 L/24 hours of

liquid) to minimize

risk of nephrolithiasis

Nelfinavir (NFV)

Viracept

Preparations

Powder for oral

suspension: 50 mg per one

levelscoop (200 mg per

one level teaspoon)

Tablets: 250 and 625 mg

750 mg TID or 1,250 mg

BID

Oral bioavailability: 20%–80%

Serum t1/2

: 3.5–5 hours

Intracellular t1/2

: unknown

Elimination: hepatic metabolism

via CYP3A4

Administer with

meal or light snack

(exposure increased

twofold to threefold)

Saquinavir (SQV)

Invirase (hard gel

capsules)

Preparations

Hard gel capsule: 200 mg

Tablets: 500 mg

Unboosted saquinavir not

recommended

Saquinavir/ritonavir:

1,000/100 BID; 1,600/100

daily under investigation

Oral bioavailability: 4% (as the

sole PI)

Serum t1/2

: 1–2 hours

Intracellular t1/2

: unknown

Elimination: hepatic metabolism

via CYP3A4 (inhibitor)

Take within 2 hours

of a meal and take

with RTV

Fosamprenavir (FPV)

Lexiva

Tablet: 700 mg

In ARV-naïve patients:

FPV 1,400 mg BID or

FPV 1,400 mg + RTV 200

mg daily or FPV 700 mg +

RTV 100 mg BID

In PI-experienced patients:

FPV 700 mg + RTV 100

mg BID

Oral bioavailability: not

determined

Serum t1/2

: 7.1–10.6 hours

(APV)

Intracellular t1/2

: unknown

Elimination: hepatic metabolism

via CYP3A4 (inhibitor)

Can be taken

without regard to

meals but should not

be taken with highfat meals

p. 1579

p. 1580

Tipranavir (TPV)

Aptivus

Capsules: 250 mg

TPV 500 mg + RTV 200

mg BID

DO NOT USE

WITHOUT RTV

Oral bioavailability: not

determined

Serum t1/2

: 6 hours

Intracellular t1/2

: unknown

Elimination: hepatic metabolism

via CYP3A4 (inhibitor and

inducer)

Administer with food

to increase

bioavailability

Entry Inhibitors

Enfuvirtide (T-20)

Fuzeon

90 mg SC BID in upper

arm, thigh, or abdomen

Oral bioavailability: 84.3%

compared with IV

Serum t1/2

: 3.8 hours

Intracellular t1/2

: not applicable

Elimination: non-renal, nonReconstitute with

1.1 mL sterile water

for injection; gently

tap vial for 10

seconds and then roll

hepatic gently between

hands to avoid

foaming and ensure

all drug is off vial

walls

After reconstitution,

use immediately or

refrigerate for 24

hours. Refrigerated

T-20 should be

brought to room

temperature before

injection

Chemokine Receptor Antagonists (CCR5)

Maraviroc (MVC)

Selzentry

Preparations

Tablet: 150, 300 mg

300 mg BID (with all

NRTIs, NVP, TPV, ENF),

150 mg BID with CYP3A

inhibitors (with or without

a CYP3A inducer)

including protease

inhibitors (except

tipranavir/ritonavir),

delavirdine, ketoconazole,

itraconazole,

clarithromycin, and other

strong CYP3A inhibitors

(e.g., nefazodone,

telithromycin)

600 mg BID with CYP3A

inducers (without a strong

CYP3A inhibitor) including

Efavirenz, etravirine

(TMC125), rifampin,

carbamazepine,

phenobarbital, and

phenytoin

Oral bioavailability: ∼33%

Serum t1/2

: 14–18 hours

Elimination: hepatic metabolism

by CYP3A; 20% recovered in

urine, 76% recovered in feces

Can be administered

without regard to

meals (high-fat meal

decreases Cmax

and

AUC by ∼30%)

Trofile assay must

be performed before

administration

Integrase Inhibitors

Dolutegravir (DTG)

Tivicay

Preparations

Tablet: 50 mg

Triumeq: DTG 50 mg +

ABC 600 mg + 3TC 300

mg

50 mg once daily

50 mg BID when

coadministered with EFV,

FPV/r, TPV/r, or Rifampin

50 mg BID when INSTI

mutations present

Triumeq: one tablet daily

Oral bioavailability: unknown

Serum t1/2

: ˜14 hours

Intracellular t1/2

: unknown

Elimination: hepatic metabolism

by UGT1A1 (major) CYP3A4

(minor); 31% recovered in

urine, 53% recovered in feces

Increased serum

creatinine because

of inhibition of

tubular secretion not

decreased renal

glomerular filtration.

Mean (range)

increase from

baseline = 0.15 (–

0.32 to 0.65) mg/dL

Elvitegravir (EVG)

Vitekta

Preparations

Tablet: 85, 150 mg

Stribild: EVG 150 mg +

COBI 150 mg + FTC 200

85 mg once daily if

coadministered with

ATV/r or LPV/r

150 mg once daily if

coadministered with

DRV/r 600/100 mg BID,

Oral bioavailability: not

established

Serum t1/2

: 9 hours when

administered with RTV

Intracellular t1/2

: unknown

Vitekta must be

administered with

ritonavir unboosted

EVG is not

recommended

Take with food

mg + TDF 300 mg

Genvoya: EVG 150 mg +

COBI 150 mg + FTC 200

mg + TAF 10 mg

FPV/r 700/100 mg BID, or

TPV/r 500/200 mg BID

50 mg BID when INSTI

mutations present

Stribild: one tablet daily

Elimination: hepatic metabolism

by CYP3A, and UGT1A1/3;

6.7% recovered in urine, 94.8%

recovered in feces

p. 1580

p. 1581

Raltegravir (RAL)

Isentress

Preparations

Tablet: 400 mg, 1,200 mg

HD

Chewable tablet: 25, 100

mg

Single packet for oral

suspension: 100 mg

400 mg BID or 1,200 mg

(HD) daily

Oral bioavailability: not

established

Serum t1/2

: 9 hours

Intracellular t1/2

: unknown

Elimination: hepatic metabolism

by UGT1A1 glucuronidation;

32% recovered in urine, 51%

recovered in feces

Can be administered

without regard to

meals (high-fat meal

decreases Cmax

by

∼34% and increases

AUC by ∼19%)

Pharmacokinetic Enhancers

Ritonavir (RTV)

Norvir

Preparations

Oralsolution: 80 mg/mL

Capsules: 100 mg

Tablets: 100 mg

RTV is a PI currently

used as a pharmacokinetic

enhancer for other PIs and

EVG, using 100–400

mg/day in one to two

divided doses

Oral bioavailability: Not

determined

Serum t1/2

: 3–5 hours

Intracellular t1/2

: unknown

Elimination: extensive hepatic

metabolism via CYP3A4 (also

potent CYP3A4 inhibitor and

mixed inhibitor/inducer of other

isozymes)

Take with food if

possible to improve

tolerability

Dose should be

titrated upward to

minimize

gastrointestinal

adverse events

Refrigerate capsules

but not liquid or

tablets

Solution contains

43% alcohol

Tybost

(COBI)

Cobicistat

Preparations

Tablets: 150 mg

Stribild: EVG 150 mg +

COBI 150 mg + FTC 200

mg + TDF 300 mg

Prezcobix: DRV 800 mg +

COBI 150 mg

Evotaz: ATV 300 mg +

COBI 150 mg

150 mg daily when

coadministered with ATV

300 mg daily

150 mg daily when

coadministered with DRV

800 mg daily

Stribild: one tablet daily.

Not for patients with CrCl

<70 mL/min Prezcobix:

one tablet daily

Evotaz: one tablet daily

Oral bioavailability: Not

determined

Serum t1/2

: 3–5 hours

Intracellular t1/2

: unknown

Elimination: extensive hepatic

metabolism via CYP3A4 (also

potent CYP3A4 inhibitor and

mixed inhibitor/inducer of other

isozymes)

8.2% recovered in urine, 86.2%

recovered in feces

Not interchangeable

with RTV

Increased serum

creatinine because

of inhibition of

tubular secretion not

decreased renal

glomerular filtration.

Monitor for renal

safety if increased

from baseline >0.4

mg/dL

a

In clinical trials, the NNRTIs were discontinued because of rash in 7% of patients taking nevirapine, 4.3% of

patients taking delavirdine, and 1.7% of patients taking efavirenz. Rare cases of Stevens–Johnson syndrome have

been reported with all three NNRTIs.

ABC, abacavir; ARV, antiretroviral; ATV, atazanavir; AUC, area under the curve; BID, twice daily; CNS,

central nervous system; CrCl, creatinine clearance; COBI, cobicistat; ddI, didanosine; d4T, stavudine; DLV,

delavirdine; DRV, darunavir; DTG, dolutegravir; EFV, efavirenz; ENF, enfuvirtide; ETV, etravirine; EVG,

elvitegravir; FPV, fosamprenavir; FTC, emtricitabine; HLA, human leukocyte antigen; IDV, indinavir; IV,

intravenous; LPV, lopinavir; MVC, maraviroc; NFV, nelfinavir; NNRTI, non-nucleoside reverse transcriptase

inhibitor; NRTIs, nucleoside reverse transcriptase inhibitors; NVP, nevirapine; PI, protein inhibitor; PO, orally;

QID, four times daily; RAL, raltegravir; RPV, rilpivirine; RTV, ritonavir; SC, subcutaneously; SQV, saquinavir;

3TC, lamivudine; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate; TID, three times daily; TPV,

tipranavir; TPV/r, tipranavir/ritonavir; T-20, enfuvirtide; ZDV, zidovudine.

DIAGNOSIS

CASE 76-1

QUESTION 1: E.J. is a 27-year-old man who presents with new complaints of fevers, night sweats, weight

loss, and white patches in his mouth. He states that these symptoms have been present for the past 4 to 6

weeks. E.J. admits to intravenous drug use in the past; however, he states that he has been “clean” for 3 years.

E.J. is diagnosed with thrush caused by Candida albicans. HIV infection is suspected and consent for an HIV

test is obtained. Why is HIV suspected and how is it confirmed?

In otherwise healthy, immunocompetent individuals, opportunistic infections, such

as thrush, are rare because an intact cell-mediated immunity protects against

infection. In immunosuppressed individuals, such as those infected with HIV, the

immune system is significantly compromised and places patients at risk for

opportunistic infections. Infections such as shingles (herpes zoster), tuberculosis,

thrush, and recurrent candidal vaginal infections in an otherwise healthy person

warrant further evaluation for the possibility of HIV infection. More advanced

diseases, such as P. jirovecii pneumonia, Mycobacterium avium bacteremia, and

cytomegalovirus retinitis infections, among others, generally occur in patients with

severely depressed immune systems and strongly suggest HIV infection. This

suggestion is especially true for those patients with risk factors for HIV infection.

Despite E.J.’s discontinuation of intravenous drugs, his prior use places him at

p. 1581

p. 1582

risk for HIV infection. Given his social history and current clinical presentation,

an HIV test is warranted.

Laboratory methods used to diagnose HIV infection rely on detecting antigens

produced by HIV viral replication or antibodies produced by the host’s immune

response to HIV infection. After HIV infection, there is an initial eclipse period

where no antigen or antibody laboratory markers can be consistently detected.

55 The

first laboratory marker that can be reliably detected in the plasma after infection is

HIV RNA by nucleic acid tests (NAT) approximately 10 days after infection, then

p24 (a protein produced during viral replication) approximately 4 to 10 days after

HIV RNA can be detected. The immune response to HIV infection is characterized

first by the production of anti-HIV immunoglobulin (Ig)M proteins (10–13 days after

HIV RNA can be detected) then IgG (18–38 days after HIV RNA can be detected).

The period between infection with HIV and the ability to detect these antibodies is

known as the seroconversion window, and the duration of this window can vary

based on assay sensitivity or antibody type. Established infection is characterized by

a fully developed IgG response.

While early laboratory methods which utilized enzyme-linked immunosorbent

assays (ELISA) and confirmatory Western blot to detect anti-HIV IgG antibodies

were highly sensitive (>99%), the turnaround time for test results could be up to 1 to

2 weeks and the seroconversion window was 1 to 2 months long, making it difficult

to diagnose early infections.

55 Third-generation HIV assays decreased the

seroconversion window by including anti-HIV IgM.

55 Fourth-generation

antigen/antibody combination assays further reduced this timeframe by testing for p24

antigen and anti-HIV-1 and -2 IgM/IgG. Current Center for Disease Control (CDC)

guidelines recommend using of one of two US Food and Drug Administration (FDA)-

approved fourth-generation antigen/antibody combination assays.

56