Antiretroviral Treatment of Adult HIV Infection: 2008 Recommendations of the International AIDS Society–USA Panel

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DOI: 10.1001/jama.300.5.555 · Source: PubMed
Abstract
The availability of new antiretroviral drugs and formulations, including drugs in new classes, and recent data on treatment choices for antiretroviral-naive and -experienced patients warrant an update of the International AIDS Society-USA guidelines for the use of antiretroviral therapy in adult human immunodeficiency virus (HIV) infection. To summarize new data in the field and to provide current recommendations for the antiretroviral management and laboratory monitoring of HIV infection. This report provides guidelines in key areas of antiretroviral management: when to initiate therapy, choice of initial regimens, patient monitoring, when to change therapy, and how best to approach treatment options, including optimal use of recently approved drugs (maraviroc, raltegravir, and etravirine) in treatment-experienced patients. A 14-member panel with expertise in HIV research and clinical care was appointed. Data published or presented at selected scientific conferences since the last panel report (August 2006) through June 2008 were identified. Data that changed the previous guidelines were reviewed by the panel (according to section). Guidelines were drafted by section writing committees and were then reviewed and edited by the entire panel. Recommendations were made by panel consensus. New data and considerations support initiating therapy before CD4 cell count declines to less than 350/microL. In patients with 350 CD4 cells/microL or more, the decision to begin therapy should be individualized based on the presence of comorbidities, risk factors for progression to AIDS and non-AIDS diseases, and patient readiness for treatment. In addition to the prior recommendation that a high plasma viral load (eg, >100,000 copies/mL) and rapidly declining CD4 cell count (>100/microL per year) should prompt treatment initiation, active hepatitis B or C virus coinfection, cardiovascular disease risk, and HIV-associated nephropathy increasingly prompt earlier therapy. The initial regimen must be individualized, particularly in the presence of comorbid conditions, but usually will include efavirenz or a ritonavir-boosted protease inhibitor plus 2 nucleoside reverse transcriptase inhibitors (tenofovir/emtricitabine or abacavir/lamivudine). Treatment failure should be identified and managed promptly, with the goal of therapy, even in heavily pretreated patients, being an HIV-1 RNA level below assay detection limits.
CLINICIAN’S CORNER
SPECIAL COMMUNICATION
Antiretroviral T reatment of Adult HIV Infection
2008 Recommendations of the International
AIDS SocietyUSA Panel
Scott M. Hammer, MD
Joseph J. Eron Jr, MD
Peter Reiss, MD, PhD
Robert T. Schooley, MD
Melanie A. Thompson, MD
Sharon Walmsley, MD
Pedro Cahn, MD
Margaret A. Fischl, MD
Jose M. Gatell, MD, PhD
Martin S. Hirsch, MD
Donna M. Jacobsen, BS
Julio S. G. Montaner, MD
Douglas D. Richman, MD
Patrick G. Yeni, MD
Paul A. Volberding, MD
T
HE FIELD OF ANTIRETROVIRAL
therapy continues to evolve
rapidly, and, to maintain the
highest possible standard of
care, treatment guidelines must con-
tinually be refined to assist the com-
plex decision-making process. For a dis-
ease that has been transformed from
almost uniformly fatal to manageable
over decades, the impact of treatment
decisions is substantial. Treatment can
provide durable virologic, immuno-
logic, and clinical benefits while mini-
mizing toxicities and drug resistance,
and potentially allow for a normal life
span.
The rationale for the current up-
date of the 2006 International AIDS So-
CME available online at
www.jamaarchivescme.com
and questions on p 596.
Context The availability of new antiretroviral drugs and formulations, including drugs
in new classes, and recent data on treatment choices for antiretroviral-naive and -ex-
perienced patients warrant an update of the International AIDS Society–USA guide-
lines for the use of antiretroviral therapy in adult human immunodeficiency virus (HIV)
infection.
Objectives To summarize new data in the field and to provide current recommen-
dations for the antiretroviral management and laboratory monitoring of HIV infec-
tion. This report provides guidelines in key areas of antiretroviral management: when
to initiate therapy, choice of initial regimens, patient monitoring, when to change therapy,
and how best to approach treatment options, including optimal use of recently ap-
proved drugs (maraviroc, raltegravir, and etravirine) in treatment-experienced pa-
tients.
Data Sources and Study Selection A 14-member panel with expertise in HIV
research and clinical care was appointed. Data published or presented at selected sci-
entific conferences since the last panel report (August 2006) through June 2008 were
identified.
Data Extraction and Synthesis Data that changed the previous guidelines were
reviewed by the panel (according to section). Guidelines were drafted by section writ-
ing committees and were then reviewed and edited by the entire panel. Recommen-
dations were made by panel consensus.
Conclusions New data and considerations support initiating therapy before CD4 cell
count declines to less than 350/µL. In patients with 350 CD4 cells/µL or more, the
decision to begin therapy should be individualized based on the presence of comor-
bidities, risk factors for progression to AIDS and non-AIDS diseases, and patient readi-
ness for treatment. In addition to the prior recommendation that a high plasma viral
load (eg, 100 000 copies/mL) and rapidly declining CD4 cell count (100/µL per
year) should prompt treatment initiation, active hepatitis B or C virus coinfection, car-
diovascular disease risk, and HIV-associated nephropathy increasingly prompt earlier
therapy. The initial regimen must be individualized, particularly in the presence of co-
morbid conditions, but usually will include efavirenz or a ritonavir-boosted protease
inhibitor plus 2 nucleoside reverse transcriptase inhibitors (tenofovir/emtricitabine or
abacavir/lamivudine). Treatment failure should be identified and managed promptly,
with the goal of therapy, even in heavily pretreated patients, being an HIV-1 RNA
level below assay detection limits.
JAMA. 2008;300(5):555-570 www.jama.com
Author Affiliations are listed at the end of this ar-
ticle.
Corresponding Author: Scott M. Hammer, MD, Di-
vision of Infectious Diseases, Columbia University Col-
lege of Physicians and Surgeons, 630 W 168th St, New
York, NY 10032 (smh48@columbia.edu).
©2008 American Medical Association. All rights reserved. (Reprinted) JAMA, August 6, 2008—Vol 300, No. 5 555
by guest on August 10, 2008 www.jama.comDownloaded from
ciety–USA (IAS-USA) antiretroviral
treatment recommendations
1
is based
on (1) the recent approval of 3 novel
agents: maraviroc, a CC chemokine re-
ceptor 5 (CCR5) antagonist; raltegra-
vir, an integrase strand transfer inhibi-
tor; and etravirine, a second-generation
nonnucleoside reverse transcriptase in-
hibitor (NNRTI); (2) new data that bet-
ter inform the choice of drugs for ini-
tial therapy and the management of
treatment failure; and (3) new patho-
genetic insights into the role of hu-
man immunodeficiency virus (HIV) in
disease processes previously consid-
ered non–AIDS-related conditions.
These guidelines are built on the
precept of pathogenesis- and evidence-
based individualization of therapy in
highly resourced settings. Conse-
quently, they are most applicable to
developed and selected mid-level
economies. However, the core prin-
ciple underlying these guidelines,
namely pathogenesis-directed therapy
with regimens designed to achieve full
virologic suppression with minimal
toxicity and maximal simplicity, is
applicable to the developing world.
Progress with antiretroviral rollout
in the developing world is encourag-
ing,
2
but recent advances in the highly
resourced world need to be adapted
and translated to the developing
world to realize these benefits. Thus,
these guidelines can be viewed in 2
contexts—providing direct, practical
advice to caregivers in the developed
world and serving as an advocacy tool
to help close HIV treatment gaps
between high and low socioeconomic
settings.
METHODS
The volunteer panel was first convened
by the IAS-USA in 1995
3
to develop evi-
dence-based recommendations for an-
tiretroviral therapy in adult HIV infec-
tion in developed world settings.
After a planned partial rotation, the
panel reconvened in February 2008.
The panel met in person and electroni-
cally to consider data produced since
its 2006 report. A MEDLINE search was
conducted (P.A.V.) to identify rel-
evant studies. All manufacturers of ap-
proved or expanded-access antiretro-
viral drugs were contacted for published
or publicly presented data pertaining to
their product(s). Data on file, unpub-
lished observations, personal commu-
nications, and other such information
was not considered except for public re-
leases of data and safety monitoring
board reports. Where recommenda-
tions have not changed, reference to
supporting evidence is available in the
previous report.
1
Each panel member
was assigned to 1 or more writing
teams, and section leaders (J.J.E., P.R.,
R.T.S., M.A.T., and S.W.) prepared
drafts as previously described.
1
The quality and strength of the evi-
dence were rated according to a scale
(B
OX).
1
Clinical recommendations were
made by panel consensus.
WHEN TO START
ANTIRETROVIRAL THERAPY
Established HIV-1 Infection
The primary goal of antiretroviral
therapy is to increase disease-free sur-
vival through maximal suppression of
viral replication and preservation of im-
munologic function. The optimal tim-
ing of initiation of antiretroviral therapy
depends on consideration of these ben-
efits in balance with the risks of drug
toxicity, potential emergence of viral re-
sistance, and the understanding that
HIV infection is a chronic disease re-
quiring continuous therapy, usually
over the course of decades.
Although the benefits of beginning
antiretroviral therapy at CD4 cell counts
above 200/µL are well documented, pre-
vious recommendations were influ-
enced by the perceived need to mini-
mize drug toxicity and preserve
therapeutic options for subsequent regi-
mens.
1
Although these remain crucial
concerns, as treatment options have in-
creased and the risks of untreated vi-
remia are better appreciated, the risk-
benefit ratio is shifting toward earlier
treatment.
The substantial toxicity and inconve-
nience of early regimens dampened en-
thusiasm for starting therapy at higher
CD4 cell counts. However, newer regi-
mens are potent, durable, and less
toxic.
4-10
Fixed-dose combinations with
long half-lives and ritonavir-boosted pro-
tease inhibitors (PIs) have simplified regi-
mens, improved pharmacokinetics and
treatment response,
11
enhanced adher-
ence to therapy,
12
and slowed the emer-
gence of resistance.
11,13,14
New data demonstrate the increased
relative burden of non-AIDS diseases in
HIV-infected persons and require their
inclusion in the definition of HIV dis-
ease progression.
15-21
Clinical trial and ob-
servational cohort data indicate that even
at high CD4 cell counts, uncontrolled
HIV replication and immune activation
are strongly associated with the devel-
opment of diseases not traditionally as-
sociated with HIV infection, such as non-
Box. Strength of
Recommendation and
Quality of Evidence
Rating Scale
Strength of Recommendation
A: Strong evidence to support the
recommendation
B: Moderate evidence to support
the recommendation
C: Insufficient evidence to sup-
port the recommendation
Quality of Evidence
Ia: Evidence from 1 or more ran-
domized, controlled clinical trials
published in the peer-reviewed lit-
erature
Ib: Evidence from 1 or more ran-
domized, controlled clinical trials
presented in abstract form at peer-
reviewed scientific meetings
IIa: Evidence from nonrandom-
ized clinical trials or cohort or
case-control studies published in
the peer-reviewed literature
IIb: Evidence from nonrandom-
ized clinical trials or cohort or
case-control studies presented in
abstract form at peer-reviewed sci-
entific meetings
III: Recommendation based on the
panel’s analysis of the accumu-
lated available evidence
ANTIRETROVIRAL TREATMENT OF ADULT HIV INFECTION
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AIDS cancers (including lung, anal, and
head and neck cancers and Hodgkin lym-
phoma)
22-24
and end-organ damage, in-
cluding cardiovascular,
25
hepatic,
26
and
renal
27,28
dysfunction. A large multico-
hort survival analysis among antiretro-
viral-naive persons with CD4 cell counts
of more than 350/µL demonstrated in-
creased mortality even at high CD4 cell
counts compared with the general popu-
lation.
29
The risk of developing non–
AIDS-defining cancers is higher when the
CD4 cell count is less than 500/µL for 1
year or more.
30
Markers of inflamma-
tion (eg, interleukin 6) and coagulation
(eg, D dimer) are strong predictors of
mortality, even at higher CD4 cell counts,
and are tightly correlated with plasma
HIV-1 RNA levels.
31-33
In addition, main-
taining CD4 cell counts of more than
500/µL may result in a normal life ex-
pectancy through the prevention of ir-
reversible immune damage associated
with prolonged immune activation.
34
Although not designed to address the
issue of when to initiate therapy, re-
cent evidence from the Strategic Man-
agement of Antiretroviral Therapy
(SMART) trial supports the hypoth-
esis that uncontrolled viral replication
carries an increased risk of morbidity
and mortality at all CD4 strata.
35
In this
trial, opportunistic diseases and death
occurred at higher rates when therapy
was interrupted than when therapy was
continuous, even with CD4 cell counts
of more than 350/µL. At high CD4 cell
counts, these outcomes were associ-
ated with HIV-1 RNA levels above 400
copies/mL. The risks of cardiovascu-
lar, hepatic, and renal complications
also were higher in the drug interrup-
tion group than in the continuous vi-
ral suppression group.
36
When therapy
was reinstituted, risk decreased but did
not return to baseline.
37
In a subset of
patients who were antiretroviral-
naive or not currently receiving therapy,
those in the deferred therapy group had
an increased rate of serious non-AIDS
events compared with those in the im-
mediate group who began treatment
with CD4 cell counts of more than 350/
µL.
38
These results demonstrate a strong
relationship between uncontrolled HIV
replication and multiple non–AIDS-
defining diseases that substantially
affect both quality and length of life,
even at CD4 cell counts of more than
350/µL. Treatment for all infected per-
sons with HIV-related symptoms and
for all asymptomatic HIV-infected per-
sons with CD4 cell counts at or less than
200/µL has been a consistent recom-
mendation.
1
Additionally, longitudi-
nal cohort studies and randomized
clinical trials have shown that those
who begin therapy with CD4 cell counts
between 200/µL and 350/µL have lower
rates of AIDS-defining diseases and
death and are more likely to achieve
maximal suppression of virus replica-
tion and higher CD4 cell counts than
those who begin therapy at lower CD4
cell levels.
19,34,39-52
Although not all per-
sons with higher CD4 cell counts are
appropriate candidates for treatment,
these data support the benefit of
therapy, especially when other comor-
bidities or risk factors for HIV disease
progression exist. In particular, high vi-
ral load (ie, 100 000 copies/mL), rapid
CD4 cell count decline (100/µL per
year), hepatitis B or C virus (HBV or
HCV) coinfection, HIV-associated ne-
phropathy (HIVAN), and risk factors
for non-AIDS diseases, particularly car-
diovascular diseases, merit consider-
ation of initiation of therapy indepen-
dent of CD4 cell counts.
Other benefits of antiretroviral
therapy include decrease of mother-to-
child HIV transmission
53
and poten-
tial reduction of HIV transmission
among adults.
54
Because antiretroviral
therapy can decrease HIV transmis-
sion in the setting of couples with dis-
cordant HIV status,
55,56
consideration
should be given to initiation of therapy
in the HIV-seropositive partner but
should not supplant traditional pre-
vention methods. Risk reduction coun-
seling should be a routine part of care
and reinforced at each clinician-
patient interaction.
Primary HIV-1 Infection
Although knowledge continues to
evolve regarding the pathogenesis of
primary HIV infection, no definitive evi-
dence has emerged that supports rou-
tine initiation of antiretroviral therapy
in primary HIV infection.
Recommendations
The patient’s readiness for treatment
should always be assessed when con-
sidering initiation of therapy. Therapy
is recommended (T
ABLE 1) for all pa-
tients with symptomatic established
HIV disease (rating A1a in the Box) af-
ter appropriate counseling. For asymp-
tomatic individuals, therapy should be
initiated before the CD4 cell count de-
creases to less than 350/µL (AIIa, AIIb).
At present, there are no definitive ran-
domized clinical trial data to define a
specific CD4 cell count threshold of
350/µL or more for beginning therapy.
Therefore, in this group, decisions
should be based on comorbidities, risk
of disease progression (including risk
of non-AIDS diseases), and patient will-
ingness and estimated ability to ad-
here to long-term treatment. Rapid de-
cline in CD4 cell count (ie, 100/µL
per year), a plasma HIV-1 RNA level
greater than 100 000 copies/mL, and
risk factors for cardiovascular and other
non-AIDS diseases are indicators that
favor earlier therapy (AIIa, AIIb). Risk
Table 1. Recommendations for Initiating
Antiretroviral Therapy in Treatment-Naive
Adults With Established HIV-1 Infection
a
Measure
Recommendation
(Rating)
Symptomatic HIV
disease
Antiretroviral therapy
recommended
(AIa)
Asymptomatic HIV
disease
CD4 cell count
350/µL
Antiretroviral therapy
recommended
(AIIa, AIIb)
CD4 cell count
350/µL
Antiretroviral therapy
should be
individualized (see
“When to Start”
section of text)
(AIIa, AIIb)
b
Abbreviation: HIV, human immunodeficiency virus.
a
In nonpregnant adults only. For all individuals, regardless
of whether they are receiving treatment, intensive coun-
seling to prevent secondary transmission is recom-
mended.
b
Considerations include high viral load (100 000 HIV RNA
copies/mL), rapid decline in CD4 cell count (100/µL per
year), high risk of cardiovascular disease, active hepatitis
B or C virus coinfections, or presence of HIV-associated
nephropathy.
ANTIRETROVIRAL TREATMENT OF ADULT HIV INFECTION
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factors for cardiovascular disease, such
as hypertension, hyperlipidemia, dia-
betes, and tobacco use, should be ag-
gressively managed in all patients. Al-
though controlled clinical trials have
not directly addressed whether earlier
initiation of antiretroviral therapy might
reduce cardiovascular or other non–
AIDS-related disease risks, it is clear that
the risk is higher when viral replica-
tion is uncontrolled. Patient readi-
ness, drug interactions, adherence chal-
lenges, toxicities, and costs should be
considered when determining whether
to initiate therapy at higher CD4 cell
counts, recognizing that treatment must
be sustained. There is no upper CD4
cell limit for starting therapy when 1
or more of these considerations are
present. An individual risk-benefit as-
sessment is appropriate in such cir-
cumstances. Clinicians should follow
routine screening recommendations for
malignancies, implementing earlier
screening when risk factors warrant it.
Because infected individuals continue
to be identified at an advanced stage of
disease, implementing routine volun-
tary HIV testing and counseling using
rapid testing technology is important
for the earlier identification and treat-
ment of HIV infection.
WHAT TO START
Recent Data: Choice of Initial
Regimen
The initial selection of an antiretroviral
regimen depends on the drug suscepti-
bility of the individual patient’s HIV.
Transmission of resistant variants in de-
veloped countries ranges from 5% to
20%.
57,58
The selection is additionally in-
fluenced by factors like pill burden, fre-
quency of dosing, anticipated tolerabil-
ity, comorbid conditions, and short- and
long-term adverse event profiles. Poten-
tial for emergence of resistance during
therapy and subsequent treatment op-
tions may also affect the design of an ini-
tial regimen.
PI vs NNRTI Comparisons. AIDS
Clinical Trials Group (ACTG) study
A5142 compared 3 initial regimens in
757 patients: efavirenz plus 2 nRTIs, rito-
navir-boosted lopinavir (lopinavir/r) plus
2 nRTIs, and efavirenz plus lopinavir/r
without nRTIs. Efavirenz plus 2 nRTIs
led to a longer time to virologic failure
and a lower rate of virologic failure than
lopinavir/r plus 2 nRTIs (24% vs 37%,
respectively).
59
Eighty-nine percent of pa-
tients initiating efavirenz plus 2 nRTIs
had HIV RNA levels of less than 50 cop-
ies/mL at 96 weeks compared with 77%
of those initiating lopinavir/r plus 2
nRTIs. The CD4 cell count increases at
96 weeks were greater in patients tak-
ing lopinavir/r plus 2 nRTIs than in those
taking efavirenz plus 2 nRTIs (287/µL vs
230/µL, respectively). Grade 3 or 4 di-
arrhea and triglyceride changes oc-
curred more often in the group taking
lopinavir/r plus 2 nRTIs, whereas lipase
elevations of this severity were more
common with efavirenz plus 2 nRTIs. In-
creases in median total cholesterol, non–
high-density lipoprotein cholesterol, and
high-density lipoprotein cholesterol lev-
els were similar in the 2 nRTI-contain-
ing groups, whereas increases in triglyc-
eride levels were lower with efavirenz
plus 2 nRTIs.
60
Fat loss was most pro-
nounced when efavirenz was combined
with stavudine or zidovudine. There is
no evidence that efavirenz combined
with nonthymidine nRTIs is associated
with lipoatrophy.
61
NNRTI-Based Regimens. The viro-
logic response of regimens containing
efavirenz plus 2 nRTIs is durable
59,62,63
and consistent across viral load and CD4
cell count strata.
64
In a retrospective study
examining the activity of efavirenz plus
2 nRTIs across broad CD4 and HIV RNA
strata, time to virologic failure did not dif-
fer for patients with pretreatment viral
loads above 300 000 RNA copies/mL and
CD4 cell counts of less than 50/µL com-
pared with all other patients.
65
Al-
though sample sizes were limited, pa-
tients with baseline HIV RNA levels of
more than 750 000 copies/mL had simi-
lar treatment responses.
PI-Based Regimens (T
ABLE 2). In an
open-label, randomized study, fosam-
prenavir/r twice daily was noninferior to
lopinavir/r twice daily.
13
Treatment
responses were similar for those with viral
loads of at least vs less than 100 000 cop-
ies/mL and across CD4 cell count strata.
Virologic failures were uncommon
(6%-7%) and no major PI resistance–
associated mutations were observed.
Atazanavir/r was also noninferior to
lopinavir/r at 48 weeks in an open-
label study. Fewer patients in either
group achieved an HIV RNA level of less
than 50 copies/mL if their baseline HIV
RNA level was at least 100 000 copies/
mL. Patients with lower CD4 cell counts
appeared to respond less well to lopi-
navir/r. The percentage changes in total
cholesterol and triglyceride (but not
low- or high-density lipoprotein cho-
lesterol) levels were greater in the lopi-
navir/r group.
66
Darunavir/r was compared with lopi-
navir/r at 48 weeks in a randomized,
open-label study.
68
Lopinavir/r could be
administered once (25% of patients)
or twice daily; only 2% initiated treat-
ment with the tablet formulation of lopi-
navir/r. The darunavir/r dose was 800 mg/
100 mg once daily, not the currently
approved dose of 600 mg/100 mg twice
daily for treatment-experienced pa-
tients. The difference between groups in
response to less than 50 HIV-1 RNA cop-
ies/mL at 48 weeks favoring the daruna-
vir regimen met criteria for noninferior-
ity but not for superiority. In the HIV
RNA stratum of 100 000 copies/mL or
greater, the response in the darunavir/r
group was superior to that in the lopi-
navir/r group. Differences between the
groups appeared to be driven by the re-
sponse in patients who received lopina-
vir/r once daily. No patients acquired ma-
jor PI resistance mutations. Saquinavir/r
was also noninferior to lopinavir/r in a
randomized, open-label study.
67
Use of the soft-gel formulation of
lopinavir/r, which will soon no longer
be available, complicates the interpre-
tation of the aforementioned studies. A
randomized, open-label study com-
pared once-daily vs twice-daily lopina-
vir/r combined with tenofovir and em-
tricitabine.
69
An 8-week comparative
trial of soft-gel capsules with tablets was
embedded in the overall trial, al-
though all patients received the tablet
formulation after 8 weeks. The once-
daily group was noninferior to the
twice-daily group, in contrast with the
ANTIRETROVIRAL TREATMENT OF ADULT HIV INFECTION
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comparative study of lopinavir/r and da-
runavir/r, and no substantial differ-
ences in treatment responses were seen
between HIV RNA strata (100 000
and 100 000 copies/mL). There were
no differences in tolerability or ad-
verse events.
In a smaller randomized study, there
were fewer virologic failures and less re-
sistance emergence with atazanavir/r
(300 mg/100 mg once daily) than with
unboosted atazanavir (400 mg once
daily), both combined with 2 nRTIs.
Differences in the median changes in
lipids were small.
70
Since the previous guidelines, once-
daily fosamprenavir, 1400 mg, with rito-
navir, 100 mg, was approved for use in
treatment-naive patients, although com-
parative data are limited. A small ran-
domized trial comparing fosamprena-
vir/r with atazanavir/r once daily, both
with fixed-dose combination tenofovir/
emtricitabine, found no substantial dif-
ferences between the groups.
71
Dual nRTI Components. Dual nRTIs
remain the backbone of most initial
Table 2. Selected Comparative Studies of Ritonavir-Boosted Protease Inhibitors
a
Source
No. of
Patients
No. of Patients With
50 HIV RNA
Copies/mL at 48 wk, % Comments
Eron et al,
13
2006 (KLEAN)
b
878 Similar results in viral load ( or 100 000 copies/mL) and
CD4 strata
Similar adverse events
Fosamprenavir, 700 mg twice daily
ritonavir, 100 mg twice daily
66
Lopinavir, 400 mg twice daily ritonavir,
100 mg twice daily
c
65
Molina et al,
66
2008 (CASTLE)
d
883 Percentage with 50 HIV RNA copies/mL was 8%-9% less in
each treatment group in stratum with 100 000
copies/mL; no substantial differences between groups in
either viral load stratum
Decreased response to lopinavir in lower CD4 strata
Hyperbilirubinemia more common with atazanavir
Nausea, diarrhea, elevated total cholesterol and triglyceride
levels more common with lopinavir
Atazanavir, 300 mg once daily
ritonavir, 100 mg once daily
78
Lopinavir, 400 mg once daily ritonavir,
100 mg once daily
c
76
Walmsley et al,
67
2007 (GEMINI)
d
337 Results by viral load strata not reported
More diarrhea and greater increases in triglycerides with
ritonavir-boosted lopinavir
Saquinavir, 1000 mg twice daily
ritonavir, 100 mg twice daily
65
Lopinavir, 400 mg twice daily ritonavir,
100 mg twice daily
c
64
Clumeck et al,
68
2007 (ARTEMIS)
d
689 Most received capsule formulation of lopinavir; 25% used
lopinavir once daily
Treatment response was lower in both groups in stratum with
100 000 HIV RNA copies/mL; in this stratum, darunavir
was superior (P .05)
Diarrhea less frequent and mean triglyceride levels lower with
darunavir
Darunavir, 800 mg once daily
ritonavir, 100 mg once daily
84
Lopinavir, 400 mg twice daily ritonavir,
100 mg twice daily or lopinavir, 800
mg once daily ritonavir, 200 mg
once daily
78
Gathe et al,
69
2008 (M05-730) 664 No significant difference between groups by viral load strata
( or 100 000 HIV RNA copies/mL) or CD4 strata
No substantial differences in tolerability or laboratory adverse
events
Lopinavir, 800 mg once daily ritonavir,
200 mg once daily
77
Lopinavir, 400 mg twice daily ritonavir,
100 mg twice daily
76
Abbreviation: HIV, human immunodeficiency virus.
a
In each study, noninferiority of the comparator group (listed first) was established.
b
All patients received fixed-dose combination abacavir/lamivudine, 600 mg/300 mg once daily.
c
Capsule formulation of lopinavir/ritonavir.
d
All patients received fixed-dose combination tenofovir/emtricitabine, 300 mg/200 mg once daily.
ANTIRETROVIRAL TREATMENT OF ADULT HIV INFECTION
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regimens. Extensive data support in-
clusion of lamivudine or emtricita-
bine as 1 of the 2 nRTIs. Tenofovir/
emtricitabine and abacavir/lamivudine
are taken once daily. Long-term data for
tenofovir/emtricitabine support its use
in initial therapy,
61-63
although indi-
viduals with underlying renal dysfunc-
tion or requiring other nephrotoxic
agents may be at increased risk of re-
nal toxicity. Modest decreases in bone
density have been observed,
63
and hy-
pophosphatemia can occur.
72
The long-
term impact of tenofovir on bone me-
tabolism, phosphate metabolism,
73
and
renal function needs further evalua-
tion. Tenofovir, emtricitabine, and efa-
virenz are coformulated in a single pill
taken once daily.
Abacavir/lamivudine is currently being
compared with tenofovir/emtricitabine
in a randomized, blinded, 96-week clini-
cal trial of 688 treatment-naive pa-
tients.
10
Both dual-nRTI combinations are
paired with once-daily lopinavir/r. At the
48-week primary end-point analysis, 68%
of patients receiving abacavir/lamivu-
dine and 67% of those receiving tenofo-
vir/emtricitabine had HIV RNA levels of
less than 50 copies/mL. In the stratum
with screening viral loads of 100 000 cop-
ies/mL or greater, 63% and 65% of pa-
tients had HIV RNA levels below 50 cop-
ies/mL in the abacavir and tenofovir
groups, respectively; confirmed viro-
logic failure occurred in 12% and 11%,
respectively, of the patients over 48
weeks. Median changes in triglyceride
and low-density lipoprotein cholesterol
levels were greater in the abacavir group.
In contrast with these results, the on-
going ACTG A5202 study of approxi-
mately 1800 treatment-naive patients
comparing the same 2 dual-nRTI com-
binations, in conjunction with a com-
parison of efavirenz with atazanavir/r, was
modified when a data and safety moni-
toring board interim review noted a
higher rate of virologic failure in pa-
tients with screening viral loads of
100 000 copies/mL or higher in the aba-
cavir/lamivudine group than in the te-
nofovir/emtricitabine group. The esti-
mated hazard ratio for cumulative
virologic failure in this stratum was 2.33
(95% confidence interval [CI], 1.46-
3.72; P =.0003) (http://www.aactg.org
/news_results.asp).
A large, collaborative cohort study in-
vestigated the association of nRTI use
with subsequent myocardial infarc-
tion.
74,75
After controlling for numer-
ous factors, an increased risk of myo-
cardial infarction associated with recent
abacavir or didanosine use (relative
rates, 1.90 [95% CI, 1.47-2.45] and 1.49
[95% CI, 1.14-1.95], respectively) was
demonstrated. Cumulative exposure
was not predictive, and those who had
not taken abacavir or didanosine for 6
months or more did not have an in-
creased risk. The overall absolute risk
was small but was greatest in those at
highest risk of myocardial infarction,
based on traditional cardiovascular risk
factors. Although an association has
been demonstrated in this study, cau-
sation is not established.
Other Initial Combinations. The
ACTG A5142 study included an nRTI-
sparing group of efavirenz, 600 mg once
daily, with lopinavir, 533 mg/
ritonavir, 133 mg, twice daily
59
that had
a time to virologic failure similar to efa-
virenz plus 2 nRTIs in the overall analy-
sis, although in the stratum of 100 000
HIV RNA copies/mL or greater, the time
to virologic failure was shorter. Limb-
fat increase was greatest in the efavirenz/
lopinavir/r group, laboratory toxicity
was more common (predominantly be-
cause of rises in triglyceride levels), and
emergence of resistance was more fre-
quent than in the 2 nRTI groups.
Initial PI monotherapy has also been
evaluated in a small, randomized, open-
label study comparing lopinavir/r alone
with lopinavir/r plus zidovudine and la-
mivudine in patients with baseline vi-
ral loads below 100 000 copies/mL.
76
Fewer patients receiving PI mono-
therapy achieved HIV RNA levels be-
low the limit of detection, and a greater
number receiving PI monotherapy had
emergence of PI resistance mutations,
suggesting that this approach should
currently be considered suboptimal.
In another randomized, open-label
study of 114 patients, 4 nRTIs (zido-
vudine, lamivudine, abacavir, and te-
nofovir) had similar antiretroviral ac-
tivity as efavirenz plus zidovudine and
lamivudine; 68% and 67% had HIV
RNA levels of less than 50 copies/mL
at 48 weeks, respectively.
77
New Drug Classes in Initial
Therapy. Raltegravir, an integrase
strand transfer inhibitor,
78
was ap-
proved in 2007 for use in highly treat-
ment-experienced patients.
79,80
It was
compared with efavirenz in treatment-
naive patients in a randomized, par-
tially blinded trial in which patients re-
ceived 1 of 4 doses of raltegravir (100,
200, 400, or 600 mg twice daily) or efa-
virenz, each combined with tenofovir
and lamivudine. At 48 weeks, the pro-
portions of individuals who had an HIV
RNA level of less than 50 copies/mL
were similar among the 5 groups, rang-
ing from 83% to 88%.
81
Phase 3 stud-
ies comparing raltegravir, 400 mg twice
daily, with efavirenz once daily, each
paired with 2 nRTIs, are under way.
Maraviroc, a CCR5 antagonist ap-
proved in 2007 for use in treatment-
experienced patients, has antiretrovi-
ral activity only in patients with HIV-1
variants that exclusively use the CCR5
coreceptor (termed R5 viruses). Mara-
viroc was compared with efavirenz, each
combined with zidovudine/lamivu-
dine, in a randomized, double-blind,
phase 3 study in treatment-naive pa-
tients with R5 virus.
82
At 48 weeks,
69.3% and 65.3% of patients achieved
a viral load of less than 50 copies/mL
in the efavirenz and the maraviroc
groups, respectively; the prespecified
criterion for noninferiority was not met.
Recommendations
Two nRTIs plus either efavirenz (AIa)
or a PI/r (AIa, AIb) are recommended
for initial therapy (T
ABLE 3). Simplic-
ity of therapy, pill number, tolerabil-
ity, desire for pregnancy, drug interac-
tions, primary drug resistance, and
comorbid conditions are likely to in-
fluence the choice between these 2 rec-
ommended options. Efavirenz is not
recommended for women in the first tri-
mester of pregnancy or who are con-
templating pregnancy (AIIa). Treat-
ment for patients with transmitted drug
ANTIRETROVIRAL TREATMENT OF ADULT HIV INFECTION
560 JAMA, August 6, 2008—Vol 300, No. 5 (Reprinted) ©2008 American Medical Association. All rights reserved.
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resistance should be guided by resis-
tance test results (BIIa, BIIb). Nevira-
pine is an alternative to efavirenz when
an NNRTI-based regimen is desired and
the CD4 cell count is less than 250/µL
and 400/µL in women and men, respec-
tively (AIa).
Of the ritonavir-boosted PIs, recom-
mended components include lopina-
vir/r (AIa), atazanavir/r (AIb), fosam-
prenavir/r (AIa), darunavir/r (AIb), or
saquinavir/r (AIb). Choice of PI/r is in-
fluenced by factors such as frequency
of dosing, pill number, coformula-
tion, need for refrigeration, adverse
effect profile, concomitant medica-
tions, comorbid illnesses, presence of
primary drug resistance, and cost.
Lopinavir/r has been the most ex-
tensively studied ritonavir-boosted PI
and served as the comparator for most
clinical trials of other ritonavir-
boosted PIs. It is the only coformu-
lated boosted PI option, and the com-
bination tablet does not require
refrigeration. It may be given once (BIa,
AIb) or twice (AIa, AIb) daily in treat-
ment-naive patients, may be the most
likely to cause diarrhea, and may have
the greatest negative effect on triglyc-
eride levels.
Once-daily ritonavir-boosted atazana-
vir (AIb) has similar activity to lopina-
vir/r, with fewer gastrointestinal ad-
verse effects, a more favorable lipid
profile, and a lower pill burden.
66
Coad-
ministration with acid-reducing agents
must be done cautiously.
86,87
Fosampre-
navir/r may be given twice daily (AIa)
13
Table 3. Recommended Components of Initial Antiretroviral Therapy and Considerations for Choosing a Regimen
Component Considerations for Choice Major Toxic Effects and Cautions
Nucleoside reverse transcriptase inhibitors
a
Tenofovir/emtricitabine
b,c
Well tolerated
Efficacy superior to zidovudine/lamivudine
4,62
and similar to stavudine/lamivudine
63
Available as a once-daily fixed dose
Baseline renal function should be evaluated
before initiating tenofovir
Reduce dose or avoid in patients with renal
dysfunction
Abacavir/lamivudine
d
Noninferior to tenofovir/emtricitabine in 1 trial
10
May have less activity in patients with viral load
100 000 HIV RNA copies/mL
83
Available as a once-daily fixed dose
Hypersensitivity syndrome in 5% to 8% of
persons (risk associated with HLA-B*5701
genotype)
Risk reduced with HLA-B*5701 screening
84,85
May be associated with increased risk of
myocardial infarction
74,75
Nonnucleoside reverse transcriptase inhibitors
e
Efavirenz Standard-of-care comparator in many trials
Available as a once-daily fixed dose with
tenofovir/emtricitabine
Central nervous system toxicity may be limiting
Potentially teratogenic in first trimester of
pregnancy
Associated with lipoatrophy when given with
thymidine reverse transcriptase inhibitors
60
Ritonavir-boosted protease inhibitors
f
Lopinavir Substantial clinical trial data and phase 4
experience supporting efficacy
Heat-stable tablet
1 or 2 doses per day for treatment-naive
patients
Gastrointestinal adverse effects
Hyperlipidemia, especially hypertriglyceridemia
Atazanavir Noninferior to ritonavir-boosted lopinavir
Less hyperlipidemia and diarrhea
66
Once-daily dosing
Hyperbilirubinemia (UGT1A1-28 alleles and
T3435C polymorphism in MDR1 gene)
Occasionally associated with nephrolithiasis
Acid-reducing agents decrease atazanavir
concentrations; proton pump inhibitors
should be used cautiously
Fosamprenavir Noninferior to ritonavir-boosted lopinavir
13
Once-daily or twice-daily dosing possible; more
robust data with twice-daily dose
Similar adverse effect profile to ritonavir-boosted
lopinavir
Rash
Darunavir Noninferior to ritonavir-boosted lopinavir and
superior in those with viral load 100 000
HIV RNA copies/mL
Less nausea, lower triglyceride levels
68
800 mg 100 mg ritonavir once daily
Rash
Saquinavir Noninferior to ritonavir-boosted lopinavir, with
lower triglyceride levels.
67
Twice-daily dosing
High pill burden
Abbreviation: HIV, human immunodeficiency virus.
a
Zidovudine/lamivudine is considered an alternative (see “When to Start” section of text).
b
A baseline urinalysis and estimation of creatinine clearance or glomerular filtration rate for assessment of renal function are recommended.
27
All patients receiving tenofovir should
be observed for development of renal dysfunction.
c
Or lamivudine.
d
Or emtricitabine.
e
Nevirapine (in women with 250 CD4 cells/µL and men with 400 CD4 cells/µL) is considered an alternative (see “What to Start” section of text).
f
Substantial clinical trial data exist for ritonavir-boosted lopinavir as initial antiretroviral therapy, including data on long-term outcomes. Each of the other ritonavir-boosted protease
inhibitors has been compared with ritonavir-boosted lopinavir but not with one another. Choice of ritonavir-boosted protease inhibitor should be individualized (see “What to Start”
section of text).
ANTIRETROVIRAL TREATMENT OF ADULT HIV INFECTION
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or once daily with either 200 or 100 mg
of ritonavir (BIa). With twice-daily dos-
ing, the adverse effect profile and lipid
effects are similar to lopinavir/r.
13
Twice-
daily saquinavir/r (AIb) was also nonin-
ferior to twice-daily lopinavir/r,
67
with
less diarrhea and more favorable triglyc-
eride changes.
Once-daily darunavir/r (AIb) is also
well tolerated, with similar activity to
lopinavir/r.
68
At present, the formula-
tion of darunavir studied in the phase
3 trial is not available. Using daruna-
vir/r in initial therapy must be bal-
anced against its proven efficacy in pa-
tients with multidrug-resistant virus.
Debate exists whether darunavir should
be used in patients with drug-
susceptible virus or should be re-
served for patients with primary or ac-
quired drug resistance.
88-91
Unboosted PIs are not recom-
mended. However, consideration of
their use arises in highly selected cir-
cumstances; eg, in individuals who are
not candidates for NNRTI-based
therapy or who have intolerance or con-
traindications to ritonavir. Atazana-
vir, fosamprenavir, and, in some cases,
nelfinavir are candidates to consider,
but a non-PI–, non-NNRTI–based regi-
men such as raltegravir plus 2 nRTIs is
another alternative, pending results of
phase 3 studies.
Recommended nRTIs in the initial
regimen are the fixed-dose combina-
tions tenofovir/emtricitabine (AIa) or
abacavir/lamivudine (AIa). Data pub-
lished or presented since the 2006 pub-
lication of these guidelines continue to
support the efficacy and safety of teno-
fovir/emtricitabine. The recently re-
ported association of abacavir with an
increased risk of myocardial infarc-
tion should be considered in patients
with known or high risk of cardiovas-
cular disease. The diminished viro-
logic efficacy of abacavir/lamivudine
compared with tenofovir/emtricita-
bine (each in combination with efavi-
renz or atazanavir/ritonavir) in pa-
tients with viral loads of more than
100 000 copies/mL reported in 1 ran-
domized study should also be consid-
ered. The data are as yet insufficient,
however, to remove abacavir as a rec-
ommended nRTI component of initial
therapy.
Zidovudine/lamivudine twice daily is
an alternative dual-nRTI component
(AIa), although the gastrointestinal and
central nervous system adverse effects
and associations with lipoatrophy and
anemia make this choice less desirable.
The quadruple nRTI combination of
abacavir/lamivudine/zidovudine/
tenofovir (BIIa)
77
may be considered in
special circumstances, such as coad-
ministration with tuberculosis therapy
or when comorbid conditions man-
date treatment with other medica-
tions that have substantial drug inter-
actions with NNRTIs and PIs.
Lopinavir/r plus efavirenz (AIa)
59
also
may be considered to avoid nRTI use,
although lipid abnormalities are com-
mon. Currently, initial therapy with
raltegravir should be considered only
in highly selected circumstances (BIa).
Use of maraviroc (CIb) or PI/r mono-
therapy (CIa) for initial therapy is not
currently recommended.
PATIENT MONITORING
Considerations
Recommendations for the initial
workup of newly diagnosed HIV-
infected persons have not changed sub-
stantially except that baseline geno-
typic testing for resistance should be
performed in all treatment-naive pa-
tients regardless of estimated duration
of infection.
92
Baseline and periodic
CD4 cell counts and plasma HIV-1 RNA
measurements guide timing of initial
therapy. Presence of HBV or HCV in-
fection, evidence of HIVAN, or cardio-
vascular risk may also influence therapy
initiation and regimen and, therefore,
should be assessed.
Monitoring Treatment Response
Effective therapy should generally re-
sult in at least a 10-fold (1.0 log
10
) de-
crease in HIV-1 RNA copies/mL in the
first month and suppression to less than
50 copies/mL by 24 weeks, depending
on pretreatment viral load.
1
Once HIV-1
RNA suppression is confirmed, it
should be assessed at regular intervals
(eg, every 3 or 4 months).
1
Isolated epi-
sodes of low-level viremia (“blips”) are
not predictive of subsequent virologic
failure, but consistent elevations to
more than 50 copies/mL meet a strict
definition of virologic failure. Con-
firmed viral load rebound should
prompt a careful evaluation of regi-
men tolerability, drug-drug interac-
tions, and patient adherence. CD4 cell
counts should generally be assessed in
concert with viral load. Once CD4 cell
counts are consistently at least 350/
µL, however, less frequent monitor-
ing of CD4 cell count (ie, every 6
months) is reasonable if the viral load
remains suppressed.
Resistance Testing
Updated IAS-USA guidelines for the use
of antiretroviral drug resistance test-
ing have been published.
92
For treat-
ment failure with HIV-1 RNA levels of
more than 500 to 1000 copies/mL, re-
sistance testing is essential and should
be performed while the patient is tak-
ing the failing regimen.
92
Tropism
Human immunodeficiency virus 1 re-
quires a second receptor, either CCR5
or CX chemokine receptor 4 (CXCR4),
to enter CD4 cells. Virus may exclu-
sively use either CCR5 (R5 virus) or
CXCR4 (X4 virus) or may use both re-
ceptors (dual-tropic). Human immu-
nodeficiency virus 1 variants within an
infected individual may be R5 only, X4
only, or a mixture of R5, X4, and dual-
tropic variants (so-called dual-/mixed-
tropic populations). Most transmitted
variants are R5, and R5 virus predomi-
nates early in the course of infection.
The CCR5 antagonist maraviroc inhib-
its R5 virus and can provide added vi-
rologic activity in patients with R5 vi-
rus
93
; it has little or no activity in
patients with dual-/mixed- or X4-
tropic virus.
94
Thus, assessment of tro-
pism prior to use of maraviroc is es-
sential.
92,95
Monitoring for Treatment Toxicity
When balancing the risks and benefits
associated with a particular treat-
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ment, it is important to realize that car-
diovascular, hepatic, and renal compli-
cations may not only reflect drug
toxicity but may also be associated with
uncontrolled HIV replication.
36-39
Ap-
propriate clinical and laboratory as-
sessment of relevant comorbid condi-
tions should be performed before
initiating treatment and during follow-
up. For example, cardiovascular dis-
ease risks should be assessed by avail-
able algorithms. The Framingham risk
algorithm may be the most appropri-
ate, although it can underestimate car-
diovascular disease risk in the setting
of HIV infection.
96
Guidelines for the
prevention and management of meta-
bolic complications in HIV infection are
available.
97
Assessment of renal function should
be made before initiation and during use
of tenofovir, allowing avoidance, dose
modification, or timely substitution of
the drug when appropriate.
27
HLA-B*5701 Screening
The Prospective Randomized Evalua-
tion of DNA Screening in a Clinical
Trial (PREDICT) study demonstrated
the clinical value of prospective HLA-
B*5701 screening to identify patients
at risk of abacavir-associated hypersen-
sitivity reaction (HSR).
84
Those screen-
ing negative for HLA-B*5701 rarely de-
velop immunologically confirmed
abacavir HSR; approximately 50% of
HLA-B*5701–positive patients de-
velop immunologically confirmed HSR
when given abacavir. Thus, HLA-
B*5701–positive patients should not re-
ceive abacavir. When a patient screens
negative for HLA-B*5701, this should
not replace careful follow-up because
clinically diagnosed forms of abacavir
HSR may still occur in such patients,
albeit infrequently.
Therapeutic Drug Monitoring
The clinical role of therapeutic drug
monitoring remains controversial, and
no definitive data have emerged since
the last edition of the guidelines on
which to base a clear-cut recommen-
dation.
98-100
When available with as-
says performed by a quality-assured
laboratory,
101
therapeutic drug moni-
toring of PIs and NNRTIs may be se-
lectively useful in pregnant wom-
en,
102,103
children,
104,105
and patients with
renal or liver failure
106-108
; to poten-
tially minimize overexposure and ad-
verse effects
108-110
; when managing