Antiretroviral Treatment of Adult HIV Infection:
2014 Recommendations of the
International Antiviral SocietyUSA Panel
Huldrych F. Günthard, MD; Judith A. Aberg, MD; Joseph J.
Eron, MD; Jennifer F. Hoy, MBBS, FRACP; Amalio Telenti,
MD, PhD; Constance A. Benson, MD; David M. Burger,
PharmD, PhD; Pedro Cahn, MD, PhD; Joel E. Gallant, MD,
MPH; Marshall J. Glesby, MD, PhD; Peter Reiss, MD, PhD;
Michael S. Saag, MD; David L. Thomas, MD, MPH; Donna
M. Jacobsen, BS; Paul A. Volberding, MD
Günthard et al, JAMA, 2014.
IASUSA
Antiretroviral Guidelines
1996 – 2014
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2014 IASUSA Antiretroviral Guidelines Authors
Huldrych F. Günthard, MD
Judith A. Aberg, MD
Joseph J. Eron, MD
Jennifer F. Hoy, MBBS, FRACP
Amalio Telenti, MD, PhD
Constance A. Benson, MD
David M. Burger, PharmD, PhD
Pedro Cahn, MD, PhD
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Günthard et al, JAMA, 2014.
Joel E. Gallant, MD, MPH
Marshall J. Glesby, MD, PhD
Peter Reiss, MD, PhD
Michael S. Saag, MD
David L. Thomas, MD, MPH
Donna M. Jacobsen, BS
Paul A. Volberding, MD
IASUSA Antiretroviral Guidelines
• Authored by 14-member, international (5 countries) panel
o
Members receive no compensation and do not participate in industry
promotional activities while on the panel
• Based upon pathogenesis- and evidence-based individualization
•
•
•
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of therapy
Primarily for clinicians in highly resourced settings; however,
principles are universally applicable
Reviewed data published or presented 7/12 – 6/14
Rated on strength of recommendations and quality of evidence
Focused on when to start therapy; pre-exposure prophylaxis;
what to start; patient monitoring; treatment-experienced patients
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Rationale for Issuing Revised Guidelines
• Evaluate new data showing all patients may benefit
from ART
• Evaluate new data that ART reduces likelihood of HIV
transmission
• Consider issues of relevance to persons with hepatic,
renal, or cardiovascular comorbidities; opportunistic
infections; or at high risk for HIV transmission
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Methods
• Systematic Literature Review of PubMed and EMBASE
• Hand searches for newly published reports and scientific
abstracts, safety reports
• ARV manufacturers submitted lists of recent publications or
abstracts meeting established criteria
• Data not published or presented in a peer-reviewed setting
were not considered
• Drugs, formulations, combinations considered:
o
o
o
Approved by regulatory agencies (eg, FDA)
Available in expanded access program
Submitted for regulatory approval (ie, in late development
stages)
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When to Start
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Günthard et al, JAMA, 2014.
When to Start ART:
IAS-USA Recommendations 2014
ART is recommended for treatment of HIV infection and
prevention of transmission of HIV regardless of CD4 cell
count (AIa-BIII)
 Lack of demonstrated harm with early initiation, cost
effective, clinically beneficial
 ART is cost-effective in resource-rich and –poor countries
 In next 4 years, more than 20 drugs are expected to
become available as generics
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When to Start ART:
IAS-USA Recommendations 2014
Offer ART to all patients with acute or early infection; start
as soon as possible to maximize benefit
 Reduced proviral DNA and plasma viral load, lower viral
set point, robust immune reconstitution, and CD4 cell
counts greater than 900/µL
 Planned discontinuation after specific duration is not
recommended except in research settings
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Günthard et al, JAMA, 2014.
When to Start ART:
IAS-USA Recommendations 2014
 ART is recommended regardless of CD4 cell count
 The patient must be willing and ready to initiate
therapy; patients not ready to start ART should
remain in clinical care, with regular monitoring and
ongoing discussion about need for ART
 The strength of recommendations and evidence
increase as CD4 cell counts decrease and in the
presence of certain conditions
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When to Start ART:
IAS-USA Recommendations 2014
Strength of recommendation and quality of evidence
varies
 According to CD4 cell count:


CD4 cell counts <500 µL(AIa)
CD4 cell counts of >500 µL (BIII)
 According to clinical condition with CD4 cell counts of
>500 µL:



Pregnancy (AIa)
Chronic HBV co-infection (AIIa)
HIV-associated nephropathy (AIIa)
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When to Start ART:
IAS-USA Recommendations 2014
 According to clinical condition (cont’d):
 Acute
phase of primary HIV infection, regardless of
symptoms (BIII)
 Preferably within first 2 weeks of diagnosis of
opportunistic infections (AIa)
 Early in treatment for cryptococcal meningitis, when
expert management of both HIV and cryptococcal
infection is available (BIII)
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What Treatment to Start
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Günthard et al, JAMA, 2014.
What Treatment to Start:
IAS-USA Recommendations 2014
 ART is considered lifelong; sustained viral suppression
is foundation for immune recovery, optimal health, and
prevention of resistance and transmission.
 Maximize adherence and minimize toxicity: Goal is to
treat with effective, well-tolerated therapy, with limited
drug interactions and effects on comorbid conditions.
 Base selection on baseline resistance testing and
patient characteristics and preferences
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Recommended Initial ART Regimens:
INSTI plus 2 nRTIs
INSTI plus 2 nRTI
Combinations
DTG plus TDF/FTC
Rating
Comments
AIa
DTG plus ABC/3TC
AIa
EVG/cobi/TDF/FTC
AIa
RAL plus TDF/FTC
AIa
DTG is dosed once daily. Associated with modest
increases in creatinine level due to inhibition of
creatinine secretion
No evidence that ABC/3TC performs less well at
HIV-1 RNA levels >100 000 copies/mL when given
with DTG. A fixed-dose combination is in late-stage
development.
Once-daily fixed-dose combination. Cobi is
associated with modest increases in creatinine
level; has drug interactions similar to RTV.
RAL is taken twice daily.
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Günthard et al, JAMA, 2014.
Recommended Initial ART Regimens:
NNRTI plus 2 nRTIs
NNRTI plus 2 nRTI
Combinations
Rating Comments
EFV/TDF/FTC
AIa
EFV central nervous symptoms may persist beyond
2-4 weeks, but is no longer contraindicated for use
in pregnant women
EFV plus ABC/3TC
AIa
EFV central nervous symptoms may persist beyond
2-4 weeks, but is no longer contraindicated for use
in pregnant women
RPV/TDF/FTC
AIa
Once-daily fixed-dose combination. RPV-based
therapy is not recommended in patients with
baseline HIV-1 RNA levels > 100 000 copies/mL
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Günthard et al, JAMA, 2014.
Recommended Initial ART Regimens:
RTV-boosted PI plus 2 nRTIs
RTV-boosted PI plus 2
NRTI Combinations
Rating
Comments
ATV plus TDF/FTC
AIa
ATV is associated with nephrolithiasis,
cholelithiasis, and chronic kidney injury.
ATV plus ABC/3TC
AIa
ATV is associated with nephrolithiasis,
cholelithiasis, and chronic kidney injury.
DRV plus TDF/FTC
AIa
During initial therapy, 800 mg of DRV is given
once daily with 100 mg of RTV given once
daily
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Alternatives to Recommended Initial Regimens
Type of Regimen
Rating
Comments
ISTI plus 2 nRTIs
Alternative ARV Drug
Combinations
RAL plus ABC/3TC
BI1
No evidence that ABC/3TC
performs less well at HIV-1 RNA
levels >100 000 copies/mL when
taken with RAL.
NNRTI plus 2 nRTIs
NVP plus 2 nRTIs
BIa
RPV plus ABC/3TC
AIa
Severe hepatotoxicity may occur in
initial therapy when CD4 cell count
is >250 µ/L in women and >400 µ/L
in men. Severe rash is more
common than with other NNRTIs.
RPV-based therapy is not
recommended in patients with
baseline HIV-1 RNA levels
>100 000 copies m/L.
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Alternatives to Recommended Initial Regimens, cont’d
Type of Regimen
PI plus 2 nRTIs
Alternative ARV Drug
Combinations
ATV/cobi with 2 nRTIs
Rating
Comments
BIa
ATV plus cobi as a fixed-dose
combination achieves ATV levels
similar to those with RTV
boosting.
As separate agents, they were
noninferior to RTV-boosted ATV,
both in combination with TDF
/FTC.
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Alternatives to Recommended Initial Regimens, cont’d
Protease inhibitor plus 2 nucleoside reverse transcriptase inhibitors, cont’d.
DRV/cobi with 2 nRTIs
BIII
DRV plus cobi as a fixed-dose
combination achieves DRV levels
similar to those with RTV boosting.
DRV plus ABC/3TC
BIb
Comparative clinical data from a
subset of patients from a single
randomized study.
LPV fixed-dose
BIa
Main advantage is fixed-dose
combination with 2 nRTIs
combination. May have increased
cardiovascular risk and be less
tolerable than recommended
options.
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Alternatives to Recommended Initial Regimens, cont’d
Type of Regimen
nRTIs
Alternative ARV Drug
Combinations
DRV plus RAL
Rating Comments
LPV plus 3TC
BIa
LPV plus RAL
BIa
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BIb
RAL taken twice daily, RTV-boosted
DRV taken once daily. Less
effective at CD4 cell counts of <200
µ/L and possibly HIV-1 RNA levels
>100 000 copies/mL.
Single study; comparator nRTIs
included ZDV (53.9%), TDF
(36.6%), and ABC (9.4%), each with
3TC.
Both medications taken twice daily;
single study with relatively small
sample size and low baseline
plasma HIV-1 RNA level.
Recommendations for Initial Treatment in
the Settings of Specific Conditions
 Pregnancy: ART should be initiated in all HIV-infected
women who become pregnant; ZDV/3TC plus either
RTV-boosted LPV or RTV-boosted ATV are preferred.
 Comorbid diseases: Choice of regimen is influenced by
chronic and acute comorbidities; assess for
exacerbation of comorbid conditions, negative clinical
outcomes, increased ARV toxicity, drug interactions with
ARV agents.
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Recommendations for Initial Treatment in
the Settings of Specific Conditions, cont’d.
 In patients with or at high risk of cardiovascular disease,
avoiding use of ABC, RTV-boosted LPV, or RTVboosted Fos-APV might be considered.
 In patients with reduced renal function, TDF should be
avoided, especially in combination with a boosted PI.
 Given the increased risk of fragility fractures, it may be
prudent to avoid TDF as part of initial therapy in
postmenopausal women.
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Recommendations for Initial Treatment in
the Settings of Specific Conditions, cont’d.
 The recommended initial ART regimen in the setting of
rifampinbased TB treatment is 600 mg EFV plus 2 NRTIs; if EFV
cannot be used, rifabutin-based therapy with a boosted PI plus 2
NRTIs is an alternative.
 A 3-month, once-weekly regimen of isoniazid with rifapentine for
treatment of latent TB infection is as effective as 9 months of
isoniazid alone and is equally effective in HIV-infected individuals.
 No data yet on use of bedaquiline for treatment of multidrugresistant TB in HIV-infected patients receiving ART; expert
consultation is recommended.
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Recommendations for Initial Treatment in
the Settings of Specific Conditions, cont’d.
 The ART regimen for HIV- and HBVcoinfected persons should
include TDF and FTC or 3TC as the NRTI background.
 DTG- or RAL-based regimens are recommended for patients
receiving anticancer or immunosuppressive drugs.
 In the setting of HCV and HIV co-infection, consult guidance from
the AASLD, IDSA, or IAS-USA.
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Monitoring
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Günthard et al, JAMA, 2014.
Recommendations for Monitoring Upon
Initiation of or Change in ART
HIV-1 RNA levels:
 Monitor at approximately 4 weeks after treatment initiation
or change;
 Monitor every 3 months to confirm suppression of viremia to
below the limitation of quantification of sensitive commercial
assays (AIa).
CD4 cell count:
 Monitor every 3 months after initiation of ART, especially for
patients with cell counts of <200 µL;
 results will determine need to initiate or discontinue primary
opportunistic infection prophylaxis (BIII)
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Recommendations for Ongoing Monitoring
 Monitor at intervals of ≤6 months if viral load is suppressed for 1
year, CD4 cell count is stable at ≥350 µL, and patient’s adherence
is dependable (CIII).
 Monitoring is optional if viral load is suppressed consistently for
more than 2 years, CD4 cell counts are persistently >500/µL,
except in setting of virologic failure or immunosuppressive
treatments or conditions (CIII).
 If HIV-1 RNA level is detectable (>50 copies/mL) during therapy,
confirm within 4 weeks before making changes (BIII).
 If HIV-1 RNA level is greater than 200 copies/mL during therapy,
evaluate factors leading to failure and consider switch in ART
(AIIa).
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Recommendations for Ongoing Monitoring, cont’d.
 Perform baseline genotypic testing for resistance in all
treatment-naive patients (AIIa) and in cases of confirmed
virologic failure (AIa).
 Routine therapeutic drug monitoring is not recommended,
though selected patients may benefit (BIII).
 Laboratory monitoring for ART toxicity is recommended,
guided by presence or absence of comorbidities and by
components of the regimen.
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Changing ART Regimens
I A S - U S A R E C O M M E N D AT I O N S 2 0 1 4
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Recommendations for Changing the ART
Regimen in Treatment-Experienced Patients
 Design of a new regimen should consider previous ART
exposure, previous resistance profile, and history of
intolerance or toxic effects (AIIa).
 Depending on the resistance profile, viral tropism, and
options available for patients with multidrug resistance,
inclusion of a boosted PI and agents from newer drug
classes (eg, an INSTI or maraviroc) should be considered
(AIa).
 Monotherapy with a boosted PI is not recommended when
other options are available (AIa).
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Recommendations for Changing the ART Regimen
in Treatment-Experienced Patients, cont’d.
 Maintenance of virologic suppression is paramount when
switching the regimen to improve tolerability, reduce toxicity,
and improve convenience (AIa).
 Switching or regimen simplification in virologically
suppressed individuals is generally safe if prior treatment
and resistance profile are considered. Full activity of the
NRTIs is important when switching from a RTV-boosted to a
drug with a lower barrier to resistance (AIa).
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Summary of Selected New
Recommendations
AND THOSE FOR WHICH THE STRENGTH OR QUALITY
O F E V I D E N C E H A S C H A N G E D S U B S TA N T I A L LY
I A S - U S A R E C O M M E N D AT I O N S 2 0 1 4
Günthard et al, JAMA, 2014.
Summary of Selected New Recommendations
and Those for Which the Strength or Quality
of Evidence Has Changed Substantially
Changes in Recommendations for When to Start ART:
 ART is recommended for the treatment of HIV infection and
prevention of transmission regardless of CD4 cell count (AIaBIII).
 ART should be started as soon as possible, preferably within the
first 2 weeks of diagnosis, in patients with opportunistic infections
(AIa) and other opportunistic diseases and AIDS-defining
illnesses (AIa-BIII).
 Optimal timing of ART initiation in patients with cryptococcal
meningitis is less certain, but early start should be considered
where expert management for both cryptococcal and HIV-1
infection is available (BIII).
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Günthard et al, JAMA, 2014.
Summary of Selected New Recommendations
and Those for Which the Strength or Quality
of Evidence Has Changed Substantially, cont’d.
Changes in Recommendations for What Treatment to Start:
 DTG-based regimens and co-formulated EVG/cobi/TDF/FTC
have been added to the list of recommended initial regimens
(AIa).
 Co-formulated RPV/TDF/FTC has been added as an initial
recommended regimen in patients with HIV-1 RNA levels
<100,000 copies/mL (AIa).
 RAL plus ABC/3TC has been added as an alternative initial
regimen (BIa).
 ATV/cobi plus 2 NRTIs was added as an alternative initial
regimen (BIa).
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Günthard et al, JAMA, 2014.
Summary of Selected New Recommendations
and Those for Which the Strength or Quality
of Evidence Has Changed Substantially, cont’d.
Changes in Recommendations for What Treatment to Start,
cont’d:
 DRV/cobi plus 2 NRTIs was added as an alternative initial
regimen (BIII).
 RTV-boosted DRV plus ABC/3TC was added as an alternative
initial regimen (BIb).
 RTV-boosted DRV plus RAL has been added as NRTI-sparing
alternative regimen only to be used in certain circumstances (BIb)
 RTV-boosted LPV plus 3TC has been added as an NRTI-limiting
alternative regimen only to be used in certain circumstances
(BIb).
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Günthard et al, JAMA, 2014.
Summary of Selected New Recommendations and
Those for Which the Strength or Quality of Evidence
Has Changed Substantially, cont’d.
Changes in Recommendations for Monitoring:
 HIV-1 RNA level should be monitored approximately 4 weeks
after treatment is initiated or changed, and then every 3
months to confirm suppression of viremia below the limit of
quantification of sensitive commercial assays (AIa).
 Once viral load has been suppressed consistently for >2 years
and CD4 cell counts are consistently >500/µL, monitoring CD4
cell counts is optional unless virologic failure occurs or there
are intercurrent immunosuppressive treatments or conditions
(CIII).
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Günthard et al, JAMA, 2014.
Summary of Selected New Recommendations and
Those for Which the Strength or Quality of Evidence
Has Changed Substantially, cont’d.
 HIV-1 RNA level >200 copies/mL should prompt evaluation of
factors leading to failure and consideration of switching ART
(AIIa).
 Laboratory monitoring for ART toxicity is recommended. In the
absence of new abnormalities after week 16 of treatment, the
frequency of monitoring—generally between 3–6 months—should
be guided by the presence or absence of comorbidities and by
the components of the regimen (CIII).
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Günthard et al, JAMA, 2014.
Summary of Selected New Recommendations
and Those for Which the Strength or Quality
of Evidence Has Changed Substantially, cont’d.
Changes in Recommendations for Treatment-Experienced Patients
 Depending on resistance, viral tropism, and available options, inclusion
of a boosted PI and agents from newer drug classes should be
considered in patients with multidrug resistance (AIa).
 Maintenance of virologic suppression is paramount when switching a
regimen to improve tolerability, reduce toxicity, and improve
convenience (AIa).
 Switching or regimen simplification in virologically suppressed
individuals is generally safe if prior treatment and resistance profile are
considered. Full activity of the NRTIs is important when switching from
a RTV-boosted to a drug with a lower barrier to resistance (AIa).
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Conclusions
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Conclusions
 Early, intensified, widespread, and uninterrupted treatment is
best option for controlling the epidemic.
 To exploit full potential of ART, greater efforts are needed to
diagnose and treat infection as early as possible, and
particularly acute and recent infection, which is a major
driver of the epidemic.
 New, less toxic drugs with convenient dosing facilitates
widespread acceptance of early ART.
 New strategies are needed to reduce stigmatization and
discrimination that delay care.
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