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
No comments:
Post a Comment
اكتب تعليق حول الموضوع