Slide #1
Antiretroviral Treatment of Adult HIV Infection:
2012 Recommendations of the
International Antiviral SocietyUSA Panel
Melanie A. Thompson, MD; Judith A. Aberg, MD; Jennifer F. Hoy,
MBBS, FRACP; Amalio Telenti, MD, PhD; Constance Benson, MD;
Pedro Cahn, MD, PhD; Joseph J. Eron Jr, MD; Huldrych F. Günthard,
MD; Scott M. Hammer, MD; Peter Reiss, MD, PhD; Douglas D.
Richman, MD; Giuliano Rizzardini, MD; David L. Thomas, MD;
Donna M. Jacobsen, BS; Paul A. Volberding, MD
Thompson et al, JAMA, 2012.
The International Antiviral Society–USA
Slide #2
Available Antiretroviral Agents
Nucleoside RTIs
• Zidovudine (ZDV)
• Didanosine (ddI)
• Zalcitabine (ddC)
• Stavudine (d4T)
• Lamivudine (3TC)
• Abacavir (ABC)
• Emtricitabine (FTC)
Nonnucleos(t)ide RTIs
Protease Inhibitors
• Nevirapine (NVP)
• Delavirdine (DLV)
• Efavirenz (EFV)
• Etravirine (ETR)
• Tenofovir DF (TDF)
• Saquinavir (SQV)
• Ritonavir (RTV)
• Indinavir (IDV)
• Nelfinavir (NFV)
• Amprenavir (APV)
• Lopinavir/r (LPV/r)
• Atazanavir (ATV)
• Fosamprenavir (Fos-APV)
• Tipranavir (TPV)
• Darunavir (DRV)
Integrase Inhibitors
Boosters
• Ritonavir (RTV)
• Raltegravir (RAL)
• Dolutegravir*
• Elvitegravir*
• Cobicistat* (cobi)
* In expanded access or submitted for regulatory approval
Fusion Inhibitor
• Enfuvirtide (T-20)
CCR5 Antagonist
• Maraviroc (MVC)
July 20, 2012
Slide #3
Fixed-Dose Combination Antiretrovirals
• Abacavir/lamivudine
• Elvitegravir/cobicistat/emtricitabine/tenofovir*
• Lopinavir/ritonavir
• Tenofovir/emtricitabine
• Tenofovir/emtricitabine/efavirenz
• Tenofovir/emtricitabine/rilpivirine
* In expanded access or submitted for regulatory approval
July 20, 2012
Slide #4
Antiretroviral Drugs Available in Generic Forms
• Abacavir
• Didanosine
• Lamivudine
• Nevirapine
• Stavudine
• Zidovudine
July 20, 2012
Slide #5
IASUSA
Antiretroviral Guidelines
1996 – 2012
Slide #6
2012 IASUSA Antiretroviral Guidelines Authors
Melanie A. Thompson, MD
Judith A. Aberg, MD
Jennifer F. Hoy, MBBS, FRACP
Amalio Telenti, MD, PhD
Constance Benson, MD
Pedro Cahn, MD, PhD
Joseph J. Eron Jr, MD
Huldrych F. Günthard, MD
Scott M. Hammer, MD
Peter Reiss, MD, PhD
Douglas D. Richman, MD
Giuliano Rizzardini, MD
David L. Thomas, MD
Donna M. Jacobsen, BS
Paul A. Volberding, MD
Slide #7
IASUSA Antiretroviral Guidelines
• Authored by 15-member, international (6 countries) panel
– Members receive no compensation and do not participate in
industry promotional activities while on the panel
• Based upon pathogenesis- and evidence-based
individualization of therapy
• Primarily for clinicians in highly resourced settings; however,
principles are universally applicable
• Reviewed data published or presented 7/10 – 5/12
• 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
Thompson et al, JAMA, 2012.
Slide #8
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
Thompson et al, JAMA, 2012.
Slide #9
Methods
• Systematic Literature Review of PubMed and EMBASE
 Search terms: HIV and antiretroviral and treatment (or
prevention or toxicity or monitoring).
 Filters: English, dates (July 2012-May 2012), humans,
adults, clinical trial OR meta-analysis OR guidelines OR
editorials OR review OR full text OR free text OR abstracts
• Hand searches for newly published reports and
scientific abstracts, safety reports
• ARV manufacturers provided product efficacy or safety
data
• Data not published or presented in a peer-reviewed
setting were not considered
Thompson et al, JAMA, 2012.
Slide #10
Methods
• Drugs, formulations, combinations considered:
Approved by regulatory agencies (eg, FDA)
Available in expanded access program
Submitted for regulatory approval (ie, in late
development stages)
Thompson et al, JAMA, 2012.
Slide #11
When to Start
Slide #12
Risks and Benefits of Earlier Initiation of ART
Benefits
Prevention of progressive immune
dysfunction (reduced immune activation)
Delayed progression to AIDS and
prolonged survival
Decreased risk of non-AIDS/HIVrelated morbidity (HIVAN, malignancies,
neurocognitive dysfunction, cardiovascular
disease, etc)
Decreased drug resistance
Decreased risk for some ARV
toxicities
Decreased HIV transmission
Risks
Reduced quality of life
Development of drug resistance if
adherence is suboptimal
Limitation in future choices of ART
if drug resistance occurs
Uncertain long-term toxicities and
duration of effectiveness for some
drugs/regimens
Possible transmitted drug
resistance
Slide #13
Rationale for Recommending ART for
All HIV-Infected Adults
• Uncontrolled HIV replication, immune activation and
inflammation associated with ‘non-AIDS’ illnesses
– Cardiovascular, hepatic, renal, malignancies
– ART and high CD4 associated with decreased disease
incidence
• Patients starting ART when CD4 counts are < 350/μL
have greater morbidity and mortality than those
starting when CD4 counts are < 500/μL
• Increasing evidence of detrimental effects of
uncontrolled viremia at CD4 cell counts > 500/µL
Thompson et al, JAMA, 2012.
Slide #14
Rationale for Recommending ART for
All HIV-Infected Adults
• Strength and quality of evidence are highest with
– CD4 count < 500 cells/µL
– Pregnancy
– HBV or HCV coinfection
– HIV-associated nephropathy
– Active or high risk for cardiovascular disease
– Opportunistic infections, including tuberculosis and
meningitis
– Age older than 60 years
– Primary HIV infection
– High risk for HIV transmission
Thompson et al, JAMA, 2012.
When to Start ART: IAS–USA
Recommendations 2012
Slide #15
• Patient readiness should be considered when deciding to initiate
antiretroviral therapy (ART)
• ART should be offered regardless of CD4 cell count (increasing strength
of the recommendation as CD4 decreases)
–
–
–
–
–
–
–
–
CD4 < 500 cells/µL (AIa)
CD4 > 500 cells/µL (BIII)
Pregnancy (AIa)
Chronic HBV (AIIa)
HCV (may delay until after HCV treatment if CD4 > 500) (CIII)
Age older than 60 (BIIa)
HIV-associated nephropathy (AIIa)
Acute phase of primary HIV infection, regardless of symptoms (BIII)
Slide #16
Initial Regimens in the
Treatment-Naive Patient
Slide #17
Initial Regimen Considerations
• Patient readiness to begin lifelong therapy
• Baseline assessment
–Evaluate for HBV or HCV coinfection, diabetes
mellitus, hyperlipidemia, cardiovascular disease,
smoking, renal disease, other comorbid conditions
–Consider drug interactions
–Perform resistance testing
–Assess for pregnancy or risk thereof
Thompson et al, JAMA, 2012.
Slide #18
Recommendations for When to Initiate ART
• Patient readiness for treatment should be considered
when deciding to initiate ART. Clinicians should engage
supportive services as needed to assist with ART
education and to address barriers to adherence (AIII)
• ART is recommended and should be offered regardless
of CD4 cell count (AIa-CIII). The strength of the
recommendation increases as CD4 cell count
decreases and in the presence of certain conditions,
with the following grades:
– For CD4 cell count of 500/µL and below: AIa
– For CD4 cell count above 500/µL: BIII
Thompson et al, JAMA, 2012.
Slide #19
Recommendations for When to Initiate
ART (cont’d)
– Ratings for specific conditions are as follows:
 Pregnancy: AIa
 Chronic HBV coinfection when HBV treatment is indicated:
(AIIa)
 HCV coinfection: CIII (however, coinfection with CD4 cell count
>500/µL may delay ART until after completion of HCV
treatment)
 Age older than 60 years: BIIa
 HlV-associated nephropathy: AIIa
• ART is recommended and should be offered to persons
during the acute phase of primary HIV infection, regardless
of symptoms (BIII)
Thompson et al, JAMA, 2012.
Slide #20
Recommendations for When to Initiate
ART (cont’d)
• ART should be started as soon as possible,
preferably within the first 2 weeks of diagnosis, in
patients with opportunistic infections (AIa)
• The optimal timing for patients with cryptococcal
meningitis is less certain, but initiating ART early
during cryptococcal treatment may be associated with
higher mortality; therefore, ART initiation in these
patients should be managed in consultation with
experts (BIII)
Thompson et al, JAMA, 2012.
Slide #21
Recommendations for When to Initiate
ART (cont’d)
• ART is recommended in all HlV-infected persons
with tuberculosis (TB) and should be started within
2 weeks of TB treatment when the CD4 cell count
is below 50/µL and by 8 to 12 weeks for those with
higher CD4 cell counts (Ala).
• The optimal timing for patients with TB meningitis is
less certain, but ART should be started within the
first 2 to 8 weeks of diagnosis and managed in
consultation with experts (BIII).
Thompson et al, JAMA, 2012.
Slide #22
Choice of Initial Regimen
Tenofovir/emtricitabine (TDF/FTC) OR
Abacavir/lamivudine (ABC/3TC)
WITH
Third agent (NNRTI, boosted PI, or InSTI):
• Efavirenz OR
• Atazanavir/r OR
• Darunavir/r OR
• Raltegravir
Thompson et al, JAMA, 2012.
Slide #23
Recommended Initial Antiretroviral Regimens*
Component
Recommended Regimens
NNRTI plus nRTIs
• Efavirenz/tenofovir/emtricitabine (AIa)
• Efavirenz plus abacavir/lamivudine (AIa) in
HLA-B*5701-negative patients with baseline
plasma HIV-1 RNA <100,000 copies/mL
PI/r plus nRTIs
• Darunavir/r plus tenofovir/emtricitabine (AIa)
• Atazanavir/r plus tenofovir/emtricitabine (AIa)
• Atazanavir/r plus abacavir/lamivudine (AIa) in
patients with plasma HIV-1 RNA <100,000
copies/mL
InSTI plus nRTIs
• Raltegravir plus tenofovir/emtricitabine (AIa)
* See comments
Thompson et al, JAMA, 2012.
Slide #24
Alternative Initial Antiretroviral Regimens*
Component
Alternative Regimens
NNRTI plus nRTIs
• Nevirapine plus tenofovir/emtricitabine or
abacavir/lamivudine (BIa)
• Rilpivirine/tenofovir/emtricitabine (or rilpivirine
plus abacavir/lamivudine) with baseline plasma
HIV-1 RNA < 100,000 copies/mL (BIa)
PI/r plus nRTIs
• Darunavir/r plus abacavir/lamivudine (BIII)
• Lopinavir/r plus tenofovir (BIa) (or
abacavir/lamivudine) (BIa)
InSTI plus nRTIs
• Raltegravir plus abacavir/lamivudine (BIIa)
• Elvitegravir/cobicistat/tenofovir/emtricitabine**
(BIb)
* See comment
**Submitted for regulatory approval
Thompson et al, JAMA, 2012.
Slide #25
Initial Antiretroviral Regimens: Comments
Component
Comments
NNRTI plus nRTIs
• Severe hepatotoxicity and rash with nevirapine
are more common in initial therapy when CD4
cell count is >250/µL in women and >400/µL in
men.
PI/r plus nRTI
• Other alternative PIs include fosamprenavir/r
and saquinavir/r but indications to use these
options for initial treatment are rare.
InSTI plus nRTIs
• Raltegravir is given twice daily; experience with
elvitegravir/cobicistat/tenofovir/emtricitabine is
limited to 48-week data.
Thompson et al, JAMA, 2012.
Slide #26
CCR5 AntagonistBased and nRTI-Sparing Initial
Regimens in Special Circumstances Only
Component
Regimens
CCR5 antagonist plus nRTIs,
(NNRTI-, PI-, and InSTIsparing)
• Maraviroc plus tenofovir/emtricitabine or
abacavir/lamivudine (CIII)
PI/r plus InSTI (nRTI-sparing)
• Darunavir/r plus raltegravir (BIIa)
• Lopinavir/r plus raltegravir (BIa)
* See comments
Thompson et al, JAMA, 2012.
Slide #27
CCR5 AntagonistBased and nRTI-Sparing Initial
Regimens in Special Circumstances Only
Component
Comments
CCR5 antagonist plus nRTIs
(NNRTI-, PI-, and InSTIsparing)
• Tropism assay to confirm R5 virus should
be done before prescribing maraviroc.
Maraviroc is not effective in persons who
have X4 or dual/mixed X4/R5 virus
infection. Few data are available for
maraviroc with tenofovir/emtricitabine or
abacavir/lamivudine
PI/r plus InSTI (nRTI-sparing)
• Data emerging for these regimens.
Clinical trial evidence needed before
formal recommendation can be made.
Thompson et al, JAMA, 2012.
Slide #28
Recommendations for Initial Treatment in the
Settings of Specific Conditions
• In patients with or at high risk of cardiovascular disease,
avoiding use of abacavir, lopinavir/r, or fosamprenavir/r
might be considered (BIIa)
• In patients with reduced renal function, tenofovir should
be avoided, or if treatment for HBV coinfection is
needed, dosing should be adjusted according to the
prescribing information (AIIa)
• Given the increased risk of fragility fractures, it may be
prudent to avoid tenofovir as part of initial therapy in
postmenopausal women (BIIa)
Thompson et al, JAMA, 2012.
Slide #29
Recommendations for Initial Treatment in the
Settings of Specific Conditions (cont’d)
• The recommended initial ART regimen in the setting of
rifampinbased tuberculosis treatment is efavirenz plus 2
nRTls (AIa)
• The recent recommendation for use of a 3-month, onceweekly regimen of isoniazid with rifapentine for treatment
of latent TB infection is not recommended for HlV-infected
patients receiving ART (BIII).
• The ART regimen for HIV- and HBVcoinfected persons
should include tenofovir and emtricitabine or lamivudine
as the nRTI background (AIIa)
Thompson et al, JAMA, 2012.
Slide #30
Patient Monitoring
Slide #31
Recommendations for Monitoring
• Plasma HIV-1 RNA levels should be monitored at least every
3 months after treatment is initiated or changed for virologic
failure to confirm suppression of viremia below 50 copies/mL
(AIa).
• CD4 cell count should be monitored at least every 3 months
after initiation of therapy, especially among patients with less
than 200/µL, to determine the need for primary opportunistic
infection prophylaxis (BIII).
• Once viral load is suppressed for 1 year and CD4 cell count
is stable at 350/µL or greater, HIV-1 RNA and CD4 cell count
can be monitored at intervals of up to 6 months in patients
with dependable adherence (CIII).
Thompson et al, JAMA, 2012.
Slide #32
Recommendations for Monitoring (cont’d)
• Detectable HIV-1 RNA (>50 copies/mL) during therapy
should be confirmed in a subsequent sample between 2
and 4 weeks afterward and prior to making management
decisions (BIII)
• Sustained elevation of HIV-1 RNA between 50 and 200
copies/mL should prompt evaluation of factors leading to
failure and consideration of switching of ART (BIII)
• Baseline genotypic testing for resistance should be
performed in all treatment-naive patients (AIIa) and in
cases of confirmed virologic failure (AIa)
Thompson et al, JAMA, 2012.
Slide #33
Recommendations for Monitoring (cont’d)
• Therapeutic drug monitoring is not recommended in
routine care; however, selected patients (eg, pregnant
women, children, and patients with renal or liver
impairment) might benefit from this intervention (BIII)
• Health care practitioners and health systems should
initiate strategies to monitor and improve entry into and
retention in care and ART adherence and to incorporate
and analyze quality-of-care indicators (CIII)
Thompson et al, JAMA, 2012.
Slide #34
Changing Therapy:
When and What
Slide #35
When and What to Change: Principles
• Assess possible causes for virologic failure
–Nonadherence to drug regimen
–Drug interactions
–Intercurrent infections
–Recent vaccinations
• Repeat to exclude measurement error or selfresolving transient viremia
Thompson et al, JAMA, 2012.
Slide #36
When and What to Change: Principles
• Regimen intolerance, inconvenience, or toxicity
–Single agent substitutions acceptable if virus is
suppressed
–Monotherapy with boosted PI not recommended
• Treatment failure
–Treatment goal is virologic suppression to < 50
copies/mL in both initial and multiple failures
–Ideally 3, but at least 2, fully active agents
Thompson et al, JAMA, 2012.
Slide #37
Recommendations for Management of TreatmentExperienced Patients
• In the setting of confirmed virologic failure, changing to
a new regimen should occur promptly, with
consideration of potential contributory factors to
prevent further evolution of drug resistance (AIIa).
• A new regimen should be constructed using resistance
testing (both past and present), treatment history and
consideration of tolerability and adherence issues
(AIa).
Thompson et al, JAMA, 2012.
Slide #38
Recommendations for Management of TreatmentExperienced Patients (cont’d)
• Initial failed regimen should be changed to regimens
including a minimum of 2 and ideally 3 fully active
drugs (AIa).
• Management of multidrug resistance is complex and
expert advice should be sought (BIII).
• In virologically suppressed patients, switching single
agents for toxicity or prevention of anticipated adverse
reactions or drug interactions is generally safe and
effective (AIa).
Thompson et al, JAMA, 2012.
Slide #39
Recommendations for Management of TreatmentExperienced Patients (cont’d)
• Intensification of or switching therapy has not been
successful in improving suboptimal CD4 cell count
responses in the setting of durable virologic
suppression and is not recommended (AIa).
• Treatment interruptions (outside of clinical trial) should
be avoided because of increased risk of death, AIDS,
and serious non-AIDS morbidity associated with
untreated HIV infection (AIa).
Thompson et al, JAMA, 2012.
Slide #40
Recommendations for Management of TreatmentExperienced Patients (cont’d)
• PI/r monotherapy is associated with an increased risk
of virologic failure and is not recommended when
other options are available (AIa).
Thompson et al, JAMA, 2012.
Slide #41
Conclusions
Slide #42
Conclusions I
• Recommendation to begin therapy earlier in
asymptomatic persons is informed by
–Increased evidence of the harmful effects of
uncontrolled viremia and its associated immune
activation and inflammation, even at higher CD4 cell
counts
–Evidence that all HIV-infected adults may benefit
from ART
–Data showing ART reduces likelihood of
transmission
Thompson et al, JAMA, 2012.
Slide #43
Summary of Selected New Recommendations
and Those for Which Strength or Quality of
Evidence Has Changed Substantially in 2012
• ART is recommended and should be offered
regardless of CD4 cell count (A1a-CIII depending on
CD4 cell count and existing conditions).
• ART is recommended and should be offered to
persons during the acute phase of primary HIV
infection, regardless of symptoms (BIII).
Thompson et al, JAMA, 2012.
Slide #44
Summary of Selected New Recommendations
and Those for Which Strength or Quality of Evidence Has
Changed Substantially in 2012 (cont’d)
• ART should be started as soon as possible, preferably within
the first 2 weeks of diagnosis, in patients with opportunistic
infections (other than cryptococcal and tuberculous
meningitis),with attention to drug interactions and the
potential for immune reconstitution inflammatory syndrome
(IRIS) (AIa).
• The optimal timing of ART initiation in patients with
cryptococcal meningitis is less certain, but initiating ART
early during cryptococcal treatment may be associated with
higher mortality; therefore, ART initiation in patients with
cryptococcal meningitis should be managed in consultation
with experts (BIII).
Thompson et al, JAMA, 2012.
Slide #45
Summary of Selected New Recommendations
and Those for Which Strength or Quality of Evidence Has
Changed Substantially in 2012 (cont’d)
• ART is recommended in all HlV-infected persons with TB
and should be started within weeks of TB treatment when
CD4 cell count is below 50/µL and by 8 to 12 weeks for
those with higher CD4 cell counts (AIa).The optimal timing
for patients with TB meningitis is less certain, but ART
should be started within the first 2 to 8 weeks of TB
treatment and managed in consultation with experts (BIII).
• Abacavir/lamivudine (in patients with HIV-1 RNA levels <
100,000 copies/mL) is now a recommended rather than
alternative dual nRTI component of initial ART (AIa).
Thompson et al, JAMA, 2012.
Slide #46
Summary of Selected New Recommendations
and Those for Which Strength or Quality of Evidence Has
Changed Substantially in 2012 (cont’d)
• Rilpivirine has been added as an alternative NNRTI
component of the initial regimen (BIa).
• Coformulated elvitegravir/cobicistat/tenofovir/emtricitabine
has been added as an initial regimen component, pending
regulatory approval (BIb). Elvitegravir is an investigational
InSTI and cobicistat is an investigational pharmocokinetic
booster.
• Given increased risk of fragility fractures in postmenopausal
women, it may be prudent to consider avoiding tenofovir as
part of initial therapy in this group (BIIa).
Thompson et al, JAMA, 2012.
Slide #47
Summary of Selected New Recommendations
and Those for Which Strength or Quality of Evidence Has
Changed Substantially in 2012 (cont’d)
• The recommended initial ART regimen in the setting of
rifampin-based TB therapy is efavirenz plus 2 nRTIs
(AIa).
• The recent recommendation for use of a 3-month, onceweekly regimen of isoniazid with rifapentine for treatment
of latent TB infection is not recommended for HlV-infected
patients receiving ART (BIII).
• Sustained elevation of plasma HIV-1 RNA between 50
and 200 copies/mL should prompt evaluation of factors
leading to failure and consideration for switching of ART
(BIII).
Thompson et al, JAMA, 2012.
Slide #48
Summary of Selected New Recommendations
and Those for Which Strength or Quality of Evidence Has
Changed Substantially in 2012 (cont’d)
• Health care practitioners and health systems should
initiate strategies to monitor and improve entry into
and retention in care and ART adherence and to
incorporate and analyze quality-of-care indicators
(CIII).
• Management of multidrug resistance is complex and
expert advice should be sought (BII).
Thompson et al, JAMA, 2012.
Slide #49
Earlier ART Associated with Decreased
Mortality and Disease Progression:
Observational Studies
Study
Published
N
Endpoint
Relative Hazard
P or 95% CI
NA-ACCORD
NEJM, 2009
8,362
Death
1.69
CD4 <350 vs 350-500
< 0.001
NA-ACCORD
NEJM, 2009
9,155
Death
1.94
CD4 <500 vs > 500
< 0.001
When to Start
Consortium
Lancet, 2009
24,444
AIDS or
Death
1.28
CD4 251-350 vs 351-400
HIV-CAUSAL
Ann Int Med,
2011
AIDS or
Death
1.38
CD4 <350 vs <500
CASCADE
Arch Int Med,
2011
9,455
Death
0.51 (HR)*
CD4 350-499 vs deferred
0.33-0.80
COHERE
Plos Med,
2012
75,336
AIDS or
Death
0.74 (HR)*
CD4 350-<500 on ART
0.96 (HR)*
CD4 > 500 on ART
0.58-0.80
0.92-0.99
Slide #50
• CASCADE
Seroconvertor Cohort
– Compared with
deferred ART in any
given month, starting
ART was associated
with slowed disease
progression in all CD4
strata except 500-799
cells/µL
$$$Add reference$$$
Slide #51
HPTN 052
• 1,750 heterosexual serodiscordant couples in resourceconstrained countries randomized to receive ART early
(CD4 350-550 cells/µL) or defer until CD4 < 250 cells/µL
(Cohen M, et al. NEJM 2011)
Event Rates
Early ART
Deferred ART
HR
P-value
Transmission Rate
per 100 pt-years
(95% CI)
0.3
(0.1-0.6)
2.2
(1.6-3.1)
0.11
(0.04-0.32)
< 0.001
Clinical Event Rate
per 100 pt-years
(95% CI)
2.4
(1.7-3.3)
4.0
(3.5-5.0)
0.59
(0.40-0.88)
<0.001
Cohen et al, NEJM, 2011
Slide #52
Effect of ART Timing on TB Death (CAMELIA) or
Death/AIDS Progression (STRIDE, SAPIT)
34% ↓
p=0.004
Earlier: 2-4 weeks
after TB treatment
started
19% ↓
p=0.45
11% ↓
p=0.73
Later: 8-12 weeks
after TB treatment
started
Blanc NEJM 2011, Havlir NEJM 2011, Abdool Karim NEJM 2011
Slide #53
Significant Reduction in Death/AIDS Among
Those with TB and CD4 < 50 Cells/µL
42% ↓
p=0.02
34% ↓
p=0.004
68% ↓
p=0.06
Earlier: 2-4
wks after TB
treatment
started
Later: 8-12
wks after TB
treatment
started
Blanc NEJM 2011, Havlir NEJM 2011, Abdool Karim NEJM 2011
Slide #54
Greater Reduction in Mortality at Lower CD4
P = 0.004
P = 0.45
P = 0.73
Blanc NEJM 2011, Havlir NEJM 2011, Abdool Karim NEJM 2011
Cryptococcal Meningitis and
Antiretroviral Therapy
Slide #55
• Randomized clinical trial in Zimbabwe; ART started
within 72 hours vs. 8 weeks after initiation of
fluconazole alone for treatment of CM (Makadzange C, et al.
Clin Infect Dis 2010)
– Trial stopped by the DSMB due to increased HR for death
(HR 2.85) in the early ART arm
• Randomized clinical trial in Uganda, South Africa
(COATS) in patients with CM
– After 7-11 days of treatment with amphotericin B +
fluconazole, patients were randomized to start ART within 48
hours or > 4 weeks
– Trial stopped by the DSMB due to increased mortality in the
early ART arm
When to Start ART During Acute
Opportunistic Infections: IAS–USA
Recommendations 2012
Slide #56
• Start ART as soon as possible, preferably within the
first two weeks (AIa) except for TB and cryptococcal
meningitis as indicated below:
– Patients with cryptococcal meningitis should be managed
in consultation with experts (BIII)
– Patients with TB should start TB treatment first; start ART
as soon as possible but within the first 2 weeks for those
with CD4 < 50 cells/µL
– Within the first 2-8 weeks of TB treatment for those with TB
meningitis
– Within the first 8-12 weeks of TB treatment for others