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Prior to the start of the program, please check your syllabus
to ensure you have the following printed program materials:
• Baseline Survey
– Located at the front of your syllabus
• CME Evaluation with Post-activity Survey
– Located at the back of your syllabus
Disclosures
• The relevant financial relationships reported by faculty that they or
their spouse/partner have with commercial interests are located on
page 5 of your syllabus
• The relevant financial relationships reported by the steering
committee that they or their spouse/partner have with commercial
interests are provided on page 5 of your syllabus
• The relevant financial relationships reported by the non-faculty
content contributors and/or reviewers that they or their
spouse/partner have with commercial interests are located on page
5 of your syllabus
Off-label Discussion Disclosure
This educational activity may contain discussion of published and/or
investigational uses of agents that are not indicated by the Food and
Drug Administration. PCME does not recommend the use of any agent
outside of the labeled indications. Please refer to the official
prescribing information for each product for discussion of approved
indications, contraindications and warnings. The opinions expressed
are those of the presenters and are not to be construed as those of the
publisher or grantors.
Learning Objectives
• Integrate recent clinical trial data into updated HIV
management guidelines to provide the most individualized
treatment for HIV-1-infected patients
• Develop a patient-centered approach to individualizing
treatment for HIV by minimizing short- and long-term
treatment-related complications
• Incorporate considerations about a patient’s risks for
adverse events, non-adherence, and comorbid conditions
when individualizing HIV treatments
Polling Question
Baseline Survey
• Please take out the Baseline Survey from your packet
• Fill out the demographic information at the top of the form;
then, throughout the program, as Baseline Survey
questions are asked, please take a moment to select your
answer to the corresponding question on this form
• Your answers are important and will help us shape and
improve future CME activities:
– Degree:
___ MD/DO ___ Nursing Professional ___ PharmD
___ Other:_____________________________
– Specialty: ___ Internist
___ Infectious Disease Specialist ___ PCP
___ Other: _____________________________
Polling Question
Baseline Survey
Please rate your confidence in your ability to individualize
antiretroviral therapy for patients newly diagnosed with HIV-1
1. Not at all confident
2. Slightly confident
3. Confident
4. Very confident
5. Expert
Polling Question
Baseline Survey
How often do you consider a patient’s cardiovascular
comorbidities when selecting an initial antiretroviral therapy
for HIV-1?
1. Never
2. Rarely
3. Sometimes
4. Most of the time
5. Always
Polling Question
Baseline Survey
In a recent trial by HPTN 052, early initiation of ART was associated
with which of the following outcomes compared to deferred initiation of
therapy?
A. Decrease in mortality
B. Decreases in risk for transmission of HIV and development of
AIDS-related conditions
C. Decrease in transmission of HIV, but no difference in AIDSrelated conditions or mortality
D. Decreases in mortality, risk for transmission of HIV, and
development of AIDS-related conditions
Case
• 58-year-old man with a new HIV diagnosis.
• Tested as part of an evaluation for prolonged viral syndrome,
now recovered; previous negative test 8 months earlier.
• PMHx:
– Hypertension
– Diabetes
– Non-alcoholic steatohepatitis
– Stage III kidney disease (eGFR 30-59)
– Esophageal reflux
Case
• Medications: amlodipine, lisinopril, glipizide, metformin,
simvastatin, pantoprazole.
• Social history: Works as a medical interpreter at a local
hospital; MSM, in a long-term relationship (partner also
newly diagnosed HIV+); 2-3 drinks/week; no cigarettes or
other drugs.
• PE: BMI = 31; liver edge 2 cm below costal margin;
1+ bilateral edema.
Case
Labs
• Glucose = 185; HgbA1c = 7.9
• Creatinine = 1.6 (eGFR = 50, calculated creatinine clearance 61)
• ALT = 85, AST = 90; HBSAb positive, HCV antibody and RNA negative
• Total cholesterol 230 (non-fasting)
• U/A 1+ protein
• HLA-B*5701: Negative
• CD4 cell count = 780 (34%)
• HIV RNA = 45,000
• Genotype: No resistance
Polling Question
Baseline Survey
Would you treat?
A. Yes, as soon as possible
B. Yes, as soon as he is ready
C. Would focus on correcting metabolic issues first
D. Only if he has partners outside of relationship
E. Other
Polling Question
Baseline Survey
According to DHHS guidelines, all of the following
antiretroviral regimens recommended for initial therapy might
be appropriate for patient, EXCEPT:
A. Dolutegravir/ABC/3TC
B. Efavirenz/TDF/FTC
C. Elvitegravir/cobicistat/TDF/FTC
D. Raltegravir + TDF/FTC
When to Start HIV Therapy
Guidelines Compared
CD4 Count (cells/mm3)
AIDS or
HIV-related
Symptoms
<200
200-350
350-500
>500
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
British HIV Association (2013)
Yes
Yes
Yes
Consider
Defer
European AIDS Society (2013)
Yes
Yes
Yes
Consider
Consider
WHO (2013)
Yes
Yes
Yes
Yes
Defer
United States
DHHS (2014)
IAS-USA (2014)
DHHS. Available at: www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision May 1, 2014.
IAS-USA. Gunthard HF et al. JAMA. 2014;312:410-425.
EACS. Available at: www.europeanaidsclinicalsociety.org. Version 7.0 October 2013.
BHIVA. Available at: www.bhiva.org.
WHO. Available at: www.who.int/publications/guidelines/hiv_aids/en/index.html.
Earlier ART Associated with Decreased
Mortality and Disease Progression
Observational Studies
Study
NA-ACCORD
n
8,362
Endpoint
Death
NA-ACCORD
9,155
Death
When to Start
Consortium
HIV-CAUSAL
24,444
CASCADE
9,455
AIDS or
Death
AIDS or
Death
Death
COHERE
75,336
20,971
AIDS or
Death
Relative Hazard or Hazard Ratio
1.69
CD4 <350 vs 350-500
1.94
CD4 <500 vs >500
1.28 (HR)
CD4 251-350 vs 351-400
1.38 (HR)
CD4 <350 vs <500
0.51 (HR)
CD4 350-499 vs deferred
0.74 (HR)
CD4 350-<500 on ART
0.96 (HR)
CD4 ≥500 on ART
P or 95% CI
<0.001
<0.001
1.04-1.57
1.23-1.56
0.33-0.80
0.58-0.80
0.92-0.99
Kitahata MM et al. N Engl J Med. 2009;360):1815-1826. When To Start Consortium; Sterne JA et al. Lancet. 2009;373:1352-1363.
HIV-CAUSAL Collaboration. Ann Intern Med. 2011;154:509-515. Writing Committee for the CASCADE Collaboration. Arch Intern Med.
2011;171:1560-1569. Opportunistic Infections Project Team of the Collaboration of Observational HIV Epidemiological Research in
Europe (COHERE) in EuroCoord. PLoS Med. 2012;9:e1001194.
Prevention of HIV-1 Infection with Early
Antiretroviral Therapy
Linked HIV Transmission
• Randomized study of early vs
delayed ART in 1763 serodiscordant
couples
0.2
• Linked HIV transmission to
HIV-negative partner
– Early therapy (n=1)
– 0.1 per 100 person-years
– Delayed therapy (n=27)
– 7 per 100 person-years
• Early ART led to a 96% reduction of
sexual transmission of HIV in
serodiscordant couples
Cohen MS et al. N Engl J Med. 2011;365:493-505.
Cumulative Probability
• Study stopped early by DSMB
HR: 0.04
(95% CI 0.01-0.27)
(P<0.001)
0.15
Delayed
ART
0.1
0.05
Early
ART
0
0
1
2
3
Years
4
5
HPTN 052
Early Treatment Delays AIDS Events
Time to First AIDS-Defining Disease
Number of Subjects Experiencing ≥1 Event
Delayed
Immediate
P=0.03
875
825
445
166
31
29
886
838
464
172
36
36
Grinsztejn B et al. Lancet Infect Dis. 2014;14:281-290.
Tuberculosis
Serious bacterial infection
WHO Stage 4 event
Esophageal candidiasis
Cervical carcinoma
Cryptococcosis
HIV-related encephalopathy
Herpes simplex, chronic
Kaposi’s sarcoma
CNS Lymphoma
Pneumocystis pneumonia
Septicemia
HIV Wasting
Bacterial pneumonia
34 (4%)
13 (1%)
19 (2%)
2
2
0
1
8
1
1
1
0
2
1
17 (2%)
20 (2%)
8 (1%)
2
0
1
0
2
1
0
0
1
0
2
HIV Viremia Is Hazardous to Your Health
• Cumulative uncontrolled viral replication associated with all-cause mortality
– 2027 patients contributing 6579 person-years of follow-up in a longitudinal cohort
of patients initiating ART from 2000-2008
– Hazard ratio for mortality was 1.44 (1.07-1.94) per log10 copy y/mL
– Stronger predictor of mortality than CD4 cell count
1.00
Proportion surviving
.95
.90
Viremia copy-years (log 10)
.85
<5
5-7
>7
.80
.75
0
6
12
18
24
30
36
42
48
Months from antiretroviral therapy initiation
Mugavero MJ et al. Clin Infect Dis. 2011;53:927-935.
54
60
Treatment May be Deferred for Some
• Patients starting ART should be willing and able to commit
to treatment and should understand the benefits and risks
of therapy and the importance of adherence
• Patients may choose to postpone ART
• Providers may elect to defer ART, based on an individual
patient’s clinical or psychosocial factors
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected
adults and adolescents. Department of Health and Human Services. Available at:
http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. Revised August, 2014.
Special Cases – HIV Treatment
Generally Indicated
• Pregnancy
• Acute infection
• Cardiovascular disease
• Malignancies
• HIV-associated nephropathy (HIVAN)
• HBV/HCV co-infection
• Neurologic complications
• Serodiscordant relationships
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected
adults and adolescents. Department of Health and Human Services. Available at:
http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. Revised August, 2014.
Historical Trends in CD4 Thresholds for
When to Start Antiretroviral Therapy
ACTG 019 and other NRTI
monotherapy studies in
asymptomatic individuals
(2 NRTIs)
BW 002: ZDV reduces
deaths in patients with AIDS
MK 035 and ACTG 320
demonstrate virologic
suppression and
improved clinical
outcomes: "Hit Hard and
Early" Era and “HAART”
Low potency
and high toxicity
Adapted from Vittoria M.
Integrase inhibitors & 2ndgeneration PIs/NNRTIs;
single-tablet regimens
SMART study
1st generation
PIs & NNRTIs
Disappointing
results form
Concorde, VA, &
Delta Trials
HPTN 052
Lypodystrophy & other ARVassociated metabolic side
effects described
Higher potency,
higher toxicity
Treatment reduces
immune activation,
non-AIDS events, &
HIV transmission
Still greater potency,
decreased toxicity.
DHHS 2014 Guidelines: What to Start
Recommended Regimens
for all VL strata
NNRTI
 EFV/TDF/FTC
Boosted
PI
 ATV/RTV + TDF/FTC
 DRV/RTV + TDF/FTC
INSTI




RAL + TDF/FTC
EVG/COBI/TDF/FTC‡
DTG + TDF/FTC
DTG + ABC/3TC*
Recommended Regimens for
VL < 100,000 c/mL
Alternative Regimens
 EFV + ABC/3TC*
 RPV/TDF/FTC
 ATV/RTV + ABC/3TC*
 DRV/RTV + ABC/3TC*
 LPV/RTV + (TDF/FTC or
ABC/3TC*)
 RAL + ABC/3TC*
*In HLA-B*5701–negative patients
RPV is not recommended in patients with baseline HIV-1 RNA >100,000 copies/mL or CD4 <200
‡EVG/COBI/TDF/FTC should not be started in patients with an estimated CrCl <70 mL/min.
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected
adults and adolescents. Department of Health and Human Services. Available at:
http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. Revised August, 2014.
IAS-USA 2014 Guidelines: What to Start
Recommended Regimens
Alternative Regimens
NNRTI
• EFV/TDF/FTC or
• EFV + ABC/3TC*€
• RPV/TDF/FTC
• NVP + (TDF/FTC or ABC/3TC*)
• RPV + ABC/3TC*
Boosted PI
• ATV/RTV + (TDF/FTC or
ABC/3TC*€)
• DRV/RTV + TDF/FTC
•
•
•
•
INSTI
•
•
•
•
DTG + TDF/FTC
DTG + ABC/3TC*
ELV/COB/TDF/FTC
RAL + TDF/FTC
NRTI-sparing
ATV/COB + (TDF/FTC or ABC/3TC*)
DRV/COB + (TDF/FTC or ABC/3TC*)
DRV/RTV + ABC/3TC*
LPV/RTV + (TDF/FTC or ABC/3TC*)
• RAL + ABC/3TC*
• DRV/RTV + RAL (only cd4>200, ? VL< 100K)
• LPV/RTV + 3TC
• LPV/RTV + RAL
* ABC has been associated with increased CV risk, although data are conflicting; use with caution in patients with high CV risk.
Should only be used in HLA-B*5701-negative patients.
† Rilpivirine-based therapy is not recommended in patients with baseline HIV-1.
€ The combination of abacavir and lamivudine was less efficacious with baseline HIV-1 RNA level above 100,000 copies/mL than the
combination of tenofovir and emtricitabine when combined with efavirenz or ritonavir-boosted atazanavir.
Gunthard HF et al JAMA. 2014;312:410-425.
NNRTI-based Regimens
Long the Default First Choice, But Time for Reconsideration?
Strengths
• One pill, once per day
– (TDF/FTC/EFV) Atripla and TDF/FTC/RPV
(Complera)
• TDF/FTC/EFV
– Effective across CD4/VL strata2
• High risk of resistance at virologic failure3
• Transmitted NNRTI resistance more common
than other drug classes
• TDF/FTC/EFV
– Until recently, had never lost a head-to-head with
another regimen6
- CNS/rash/hepatic effects1
– Longest clinical experience
- Dyslipidemia (LDL, Triglycerides)5
– Least expensive of recommended regimens
- Drug-drug interactions (including methadone)1
• TDF/FTC/RPV
– Smallest pill size among single tablet regimens
– Favorable metabolic profile
1.
2.
3.
4.
Weaknesses
TDF/FTC/EFV [package insert]
Ribaudo HJ et al. J Infect Dis. 2008;197:1006-1010.
Gallant JE et al. N Engl J Med. 2006;354:251-260.
Recommendations for Use of Antiretroviral Drugs in Pregnant
HIV-1-Infected Women for Maternal Health and Interventions to
Reduce Perinatal HIV Transmission in the United States.
www.aidsinfo.nih.gov/guidelines/html/3/perinatalguidelines/143/introduction. Updated March 2014.
- Concern for teratogenesis in first trimester4
• TDF/FTC/RPV
- More virologic failure with HIV RNA >100K or
CD4 <2007
- Must be taken with meal
- PPIs contra-inidicated
5 Daar E et al. Ann Intern Med. 2011;154:445-456.
6. Walmsley S et al. N Engl J Med. 2013;369:1807-1818.
7. Molina JM et al. Lancet. 2011:378:238-246.
0.05
Increased Risk of Suicidality
Associated with EFV
Efavirenz
Efavirenz-free
0.03
HR (95% CI)
2.28 (1.27 to 4.10), P=0.006
0.02
47 events/5817 PY*
(8.08/ 1000 PY)
0.01
Probability
0.04
5%
0
15 events/4099 PY*
(3.66/1000 PY)
As-treated HR
2.16 (1.16-4.00)
0
24
48
72
96
120
144
Weeks to Suicidality
*Person Years = sum of at-risk follow-up
Mollan KR et al. Ann Intern Med. 2014;161:1-10.
168
192
If you couldn’t (or didn’t want to) use an NNRTIbased regimen, which would you choose?
Differentiating Between
Non-NNRTI Regimens
Polling Question
Baseline Survey
In ACTG study A5257, which compared raltegravir to
darunavir/ritonavir and atazanavir/ritonavir, each with
tenofovir/emtricitabine in treatment-naïve subjects, which of the
following outcomes was reported?
A. Similar incidence of tolerability failure between all 3 groups
B. Greater virologic efficacy with atazanavir/ritonavir compared to
raltegravir
C. Similar cumulative incidence of virologic or tolerability failure
between all 3 groups
D. A higher rate of discontinuations due to toxicity with
atazanavir/ritonavir compared to raltegravir
Polling Question
Baseline Survey
In addition to virologic outcomes, which of the following effects on
cardiovascular risk was identified in the A5257 study:
A. Greater decreases in HDL-C with raltegravir compared to the
protease inhibitors
B. No differences between groups in incidence of metabolic
syndrome or lipid profile
C. Greater increases in triglycerides and LDL-C with the protease
inhibitors compared to raltegravir
D. Greater incidence of new-onset metabolic syndrome with
raltegravir compared to the protease inhibitors
ACTG A5257 Study Design*
HIV-infected patients, ≥18 yr, with no previous ART,
VL ≥ 1000 c/mL at US Sites, n=1809
Randomized 1:1:1 to Open Label Therapy
Stratified by screening HIV-1 RNA level (≥ vs < 100,000 c/mL) cardiovascular risk
ATV 300 mg QD + RTV 100 mg QD
+ FTC/TDF 200/300 mg QD
n=605
RAL 400 mg BID +
FTC/TDF 200/300 mg QD
n=603
DRV 800 mg QD + RTV 100 mg QD
+ FTC/TDF 200/300 mg QD
n=601
Study Conclusion 96 weeks after final participant enrolled
Follow-up continued for 96 weeks after randomization of last subject (range 2-4 years)
regardless of status on randomized ART
*With the exception of RTV, all ART drugs were provided by the study
Landovitz RJ et al. Efficacy and tolerability of atazanavir, raltegravir, or darunavir with FTC/tenofovir: ACTG 5257. Program and
abstracts of the 2014 Conference on Retroviruses and Opportunistic Infections; March 3-6, 2014; Boston, MA. Abstract 85.
Cumulative Incidence of Virologic Failure
1.00
Cumulative incidence
ATV/r
RAL
DRV/r
Difference in 96 wk cumulative incidence (97.5% CI)
ATV/r vs RAL
3.4% (-0.7%, 7.4%)
0.75
DRV/r vs RAL
5.6% (1.3%, 9.9%)
ATV/r vs DRV/r
0.50
-20
-10
0
10
-2.2% (-6.7%, 2.3%)
20
0.25
0.00
0
24
48
64
80
96
112
128
144
Weeks since study entry
Landovitz RJ et al. Efficacy and tolerability of atazanavir, raltegravir, or darunavir with FTC/tenofovir: ACTG 5257. Program and
abstracts of the 2014 Conference on Retroviruses and Opportunistic Infections; March 3-6, 2014; Boston, MA. Abstract 85.
Cumulative Incidence of Tolerability Failure
1.00
Cumulative incidence
ATV/r
RAL
DRV/r
Difference in 96 wk cumulative incidence (97.5% CI)
Favors RAL
ATV/r vs RAL
13% (9.4%, 16%)
0.75
DRV/r vs RAL
3.6% (1.4%, 5.8%)
Favors DRV/r
0.50
-20
-10
0
10
ATV/r vs DRV/r
9.2% (5.5%, 13%)
20
0.25
0.00
0
24
48
64
80
96
112
128
144
Weeks since study entry
Landovitz RJ et al. Efficacy and tolerability of atazanavir, raltegravir, or darunavir with FTC/tenofovir: ACTG 5257. Program and
abstracts of the 2014 Conference on Retroviruses and Opportunistic Infections; March 3-6, 2014; Boston, MA. Abstract 85.
Cumulative Incidence of Virologic or
Tolerability Failure
1.00
Cumulative incidence
ATV/r
RAL
DRV/r
Difference in 96 wk cumulative incidence (97.5% CI)
Favors RAL
ATV/r vs RAL
15% (10%, 20%)
0.75
Favors RAL
DRV/r vs RAL
7.5% (3.2%, 12%)
Favors DRV/r
0.50
-20
-10
0
10
ATV/r vs DRV/r
7.5% (2.3%, 13%)
20
0.25
0.00
0
24
48
64
80
96
Weeks since study entry
112
128
144
*Consistent results seen with TLOVR at a 200 copies/ml threshold
Landovitz RJ et al. Efficacy and tolerability of atazanavir, raltegravir, or darunavir with FTC/tenofovir: ACTG 5257. Program and
abstracts of the 2014 Conference on Retroviruses and Opportunistic Infections; March 3-6, 2014; Boston, MA. Abstract 85.
Proportion VL ≤50 copies/mL
ATV/r
1.0
RAL
DRV/r
0.8
1.6
0.4
0.2
0.0
ATV/r
RAL
DRV/r
Number of
subjects
contributing data
605
603
601
563
566
564
553
555
542
0
24
48
515
526
518
64
80
96
394
410
387
120
ITT, off-ART=failure (SNAPSHOT)
Prop of subjects w/HIV-1 RNA <=50 copies/mL
Prop of subjects w/HIV-1 RNA <=50 copies/mL
ITT, regardless of ART change
ATV/r
1.0
RAL
DRV/r
1.6
0.4
0.2
0.0
ATV/r
RAL
DRV/r
144
Number of
subjects
contributing data
605
603
601
605
603
601
605
603
601
0
24
48
605
603
601
64
80
96
471
483
468
120
144
Study Week
Study Week
24
48
96
144
ATV/r
70%
73%
63%
62%
94%
RAL
84%
83%
80%
76%
90%
DRV/r
77%
77%
73%
71%
24
48
96
144
ATV/r
83%
90%
88%
90%
RAL
90%
92%
94%
DRV/r
83%
88%
89%
*Consistent results seen with TLOVR at a 200 copies/ml threshold
Landovitz RJ et al. Efficacy and tolerability of atazanavir, raltegravir, or darunavir with FTC/tenofovir: ACTG 5257. Program and
abstracts of the 2014 Conference on Retroviruses and Opportunistic Infections; March 3-6, 2014; Boston, MA. Abstract 85.
Change in CD4 Count from Baseline
ATV/RTV
Median (Q1-Q3)
Mean (95% CI)
ATV/r
CD4 count change from baseline (cells/mm3)
CD4 count change from baseline (cells/mm3)
1000
750
500
250
0
-250
400
300
200
100
24 48 96 114
24 48 96 114
24 48 96 114
RAL
DRV/r
400
300
200
ATV/r: 284 (269,300)
RAL: 288 (272, 304)
DRV/r: 256 (240, 271)
100
Number of
subjects
contributing data
0
ATV/r
RAL
DRV/r
605
603
601
564
565
559
523
541
525
395
418
394
175
179
173
0
48
66
144
192
Study Week
Landovitz RJ et al. Efficacy and tolerability of atazanavir, raltegravir, or darunavir with FTC/tenofovir: ACTG 5257. Program and
abstracts of the 2014 Conference on Retroviruses and Opportunistic Infections; March 3-6, 2014; Boston, MA. Abstract 85.
Analysis of CIMT Progression
Carotid Bifurcation CIMT
CCA CIMT
ATV
100
75
ATV
DRV
RAL
ATV/r vs DRV/r
P=0.013
ATV/r vs RAL
P=0.15
DRV/r vs RAL
P=0.31
100
75
50
50
25
25
0
0
-25
-25
0
48
Study week
96
CIMT: Carotid intima media thickness
Stein JW et al. Presented at: ACC 2014, Abstract 147.
144
0
DRV
RAL
ATV/r vs DRV/r
P=0.007
ATV/r vs RAL
P=0.30
DRV/r vs RAL
P=0.11
48
Study week
96
144
Take Home Messages from A5257/A5260s
• Virologic suppression: RAL = DRV/r = ATV/r
• Tolerability: RAL=DRV/r > ATV/r
– ATV/r discontinuations most commonly caused by cosmetic
jaundice/hyperbilirubinemia
• Combined endpoints: RAL > DRV/r > ATV/r
– Slightly better virologic outcomes and absence of GI side effects
• Lipids and bone mineral density loss favored RAL over both PIs
– Increased fasting TC, non-HDL-C and LDL-C with ATV/r and DRV/r, while they
decreased or remained unchanged with RAL.
• CIMT progression most favorable with ATV/r
– Mechanism unclear
Ofotokum I et al. Presented at: ACTG 5257 Conference on Retroviruses and Opportunistic Infections. March 3-6, 2014; Boston, MA.
Brown T et al. Presented at: 2014 Conference on Retroviruses and Opportunistic Infections. March 3-6, 2014; Boston, MA. Abstract 779LB.
SINGLE: ABC/3TC + DTG vs TDF/FTC/EFV
for Treatment-naïve Patients
HIV-infected treatment
naïve men and women
VL >1000 c/mL
n=844
Primary
Proportion <50 c/mL at 48 weeks
Secondary
Time to virologic suppression
Change in CD4
Safety
Resistance at virologic failure
Walmsley S et al. N Engl J Med. 2013;369:1807-1818.
ABC/3TC FDC PO QD + DTG 50 mg PO QD
TDF/FTC/EFV STR PLACEBO PO QHS
n=422
ABC/3TC FDC PLACEBO PO QD + DTG PLACEBO PO QD
TDF/FTC/EFV STR PO QHS
n=422
SINGLE
DTG + ABC/3TC Superior to EFV/TDF/FTC at Week 48
HIV-1 RNA < 50 c/mL at Wk 48 (%)
100
Difference 7.4%
(95% CI: +2.5 to +12.3; P=0.003)
88
81
80
60
40
20
0
DTG 50 mg +
ABC/3TC QD
(n = 414)
EFV/TDF/FTC QD
(n = 419)
Walmsley S et al. N Engl J Med. 2013;369:1807-1818.
• DTG superior to EFV at week 48
primary efficacy endpoint
• 4% on each arm with protocoldefined VF
• Among pts with VF in EFV
arm, 1 pt with NRTI, and 4
with NNRTI resistance vs 0 pts with
resistance in DTG arm
• Treatment-related study
discontinuation in 10% on EFV vs
2% on DTG
• CNS events and rash more common
with EFV
SPRING-2: 2 NRTIs + DTG vs 2 NRTIs + RAL for
Treatment-naïve Patients
HIV-infected treatment
naïve men and women
VL >1000 c/mL
n=822
Primary
Proportion <50 c/mL at 48 weeks
Secondary
Time to virologic suppression
Change in CD4
Safety
Resistance at virologic failure
Raffi F et al. Lancet. 2013;381:735-743.
Raffi F et al. Lancet Inf Disease. 2013;13:927-935.
2NRTIs + DTG 50 mg PO QD
RAL PLACEBO PO BID
n=411
2NRTIs + RAL 400 mg PO BID
DTG PLACEBO QD
n=411
Stratified by baseline VL > or ≤100,000 c/mL
and NRTI backbone
SPRING-2: Dolutegravir QD Non-inferior to
Raltegravir BID Through Week 96
• DTG non-inferior to RAL
through 96 weeks
DTG 50 mg QD (n = 411)
RAL 400 mg BID (n = 411)
NRTIs: investigator chosen ABC/3TC (40%)
or TDF/FTC 60%)
HIV-1 RNA <50 c/mL (%)
100
88
85
80
81
76
60
40
20
0
Wk 48
Raffi F et al. Lancet. 2013;381:735-743.
Raffi F et al. Lancet Inf Disease. 2013;13:927-935.
Wk 96
• Adverse events and
discontinuation rates similar
• No resistance at VF with DTG
vs 1 subject with integrase
resistance and 4 with NRTI
resistance in RAL group
FLAMINGO: DTG vs DTV/r for Treatment-naïve Patients
HIV-infected treatment
naïve men and women
VL >1000 c/mL
n=488
Primary
Proportion <50 c/mL at 48 weeks
Secondary
Time to virologic suppression
Change in CD4
Safety
Resistance at virologic failure
Patient Reported Outcomes
Clotet B et al. Lancet. 2014;383:2222-2231.
2NRTIs + DTG 50 mg PO QD
n=243
2NRTIs + RTV 100 mg PO QD + DRV 800 mg PO QD
n=245
Stratified by baseline VL > or ≤100,000
c/mL and NRTI backbone
FLAMINGO: DTG + NRTIs Superior to
DRV/RTV + NRTIs at Week 48
HIV-1 RNA <50 c/mL at Wk 48 (%)
Difference 7.1%
(95% CI: +0.9 to +13.2; P = 0.025)
100
90
83
80
• VF: 2 pts (1%) on each arm
• No treatment-emergent resistance in
either arm
60
• Treatment-related study
discontinuation in 1% of DTG pts and
4% of DRV/RTV patients
40
20
0
• DTG superior to DRV/RTV (both with
TDF/FTC or ABC/3TC) at week 48
primary efficacy endpoint
DTG 50 mg
QD +
NRTIs
(n = 242)
DRV/RTV 800/100 mg
QD + NRTIs
(n = 242)
Clotet B et al. Lancet. 2014;383:2222-2231.
• More diarrhea with DRV/RTV; more
headache with DTG
NRTIs: investigator chosen ABC/3TC (33%) or
TDF/FTC 67%)
Several Drugs Inhibit Tubular Secretion of
Creatinine, Raising Serum Creatinine Levels
Proximal Tubule
ATP
ATP
ATP
OCT2
Creatinine
Dolutegravir
Pgp
MRP2
MATE1
Cobicistat
Ritonavir
Cimetidine
Trimethoprim
ATP-Binding
Cassette
BCRP
H+
MATE2-K
Solute Carrier
OCTN1
OCTN2
Blood
(Basolateral)
Active Tubular Secretion
Lepist et al. Presented at: 51st ICAAC, Sep 17-20, 2011, Chicago, IL.
Urine
(Apical)
No apparent
effect on actual
GFR
Phase III Studies of TDF/FTC/COB/EVG
vs PI/r
vs NNRTI
• Non-inferior to Efavirenz/TDF/FTC
Through Wk 144
– Consistent across subgroups
– Resistance at VF detected in 10 pts per arm
•
In EVG/COB, 9/10 pts had primary integrase
and 10/10 had NRTI resistance mutations
•
In EFV, 10/10 had NNRTI and 3/10 had NRTI
resistance mutations
• Renal safety
– 13/701 discontinuation (1.9%), including 4 due to
proximal renal tubulopathy in EVG/COB
– No discontinuation in EFV
• Non-inferior to ATV/RTV +
TDF/FTC Through Wk 144
– Consistent across subgroups
– In EVG/COB, resistance at VF detected in
6 pts through Wk 96 vs 0 pts in ATV/RTV
arm
•
5/6 had primary integrase and 5/6 had NRTI
resistance mutations
• Renal safety
– 13/701 discontinuation (1.9%), including 4
due to proximal renal tubulopathy in
EVG/COB
– 8/355 discontinuation (2.3%), including 3 due
to proximal renal tubulopathy in ATV/RTV
Zolopa A et al. J Acquir Immune Defic Syndr. 2013;63:96-100.
Sax PE et al. Lancet. 2012;379:2439-2448.
Wohl D et al. ICAAC 2013. Abstract H-672a.
Rockstroh J et al. J Acquir Immune Defic Syndr. 2013 63:77-85.
De Jesus E et al. Lancet. 2012; 30:2429-2438.
Cohen C et al. IAC 2014; Melbourne, Australia. Poster WEPE063.
Summary of Results from Tx-Naïve
Phase III Studies of EVG/COB/TDF/FTC
• Virologic outcomes noninferior to EFV/TDF/FTC and ATV/RTV +
TDF/FTC
– Activity sustained in high VL stratum
• 2% failed with resistance, usually to both NRTIs and EVG
• Adverse events
– vs EFV: fewer CNS, rash events; better lipids; more nausea
– vs ATV/RTV: less jaundice
• Small, rapid increase in serum creatinine related to cobicistat’s
inhibition of tubular secretion of creatinine from inhibition of MATE-1
transporter
Important NRTI-sparing or NRTI-limiting Studies
Study
Design
Outcome
ACTG 5142
LPV/r + 2NRTIs vs EFV + 2NRTIs vs
LPV/r + EFV
More resistance on failure and lipid abnormalities
with LPV/r + EFV
PROGRESS RAL vs TDF/FTC, both with LPV/r
RAL non-inferior to TDF/FTC; baseline HIV RNA low
in study population
ACTG 5262
DRV/r + RAL
High rates of virologic failure in those with baseline
HIV RNA > 100K
SPARTAN
ATV BID + RAL BID vs TDF/FTC + ATV/r
More virologic failure and jaundice in ATV + RAL arm
RADAR
RAL vs TDF/FTC, both with DRV/r
Higher rates of virologic failure with RAL + DRV/r
NEAT
RAL vs TDF/FTC, both with DRV/r
Overall non-inferior, but higher rates of virologic
failure with RAL + DRV/r if baseline high HIV RNA or
low CD4
GARDEL*
3TC vs 2 NRTIs, both with LPV/r
3TC non-inferior to 2 NRTIs, even at high HIV RNA
MODERN
MVC vs TDF/FTC, both with DRV/r
MVC inferior to TDF/FTC
*Only fully powered NRTI-limiting study to date demonstrating comparable efficacy and tolerability to standard-of-care regimens.
Riddler SA et al. N Engl J Med. 2008;358:2095-106. Reynes J1 et al. HIV Clin Trials. 2011;12:255-267. Taiwo B1, et al. AIDS. 2011;25:2113-2122.
Kozal MJ et al. HIV Clin Trials. 2012;13:119-130. Bedimo RJ et al. PLoS One. 2014;9:e106221. Raffi F et al. Lancet. 2014. [Epub ahead of print].
Cahn P et al. Lancet Infect Dis. 2014;14:572-580. Stellbrink et al. IAC 2014; Melbourne, Australia. Abstract TUAB0101.
First-line Therapy: Special Situations
Patient Scenario
Recommended Regimen
Comment
Suboptimal
adherence likely or
possible
• Emtricitabine/tenofovir DF +
atazanavir/ritonavir or darunavir/ritonavir
Lower risk of resistance at
treatment failure with boosted Pls
vs NNRTI- and RAL-based
strategies.
HIV-1 RNA >100,000
copies/mL or CD4+
cell count <50
cells/mm3
• Efavirenz/emtricitabine/tenofovir DF
• Emtricitabine/tenofovir DF +
atazanavir/ritonavir or darunavir/ritonavir
• Emtricitabine/tenofovir DF + raltegravir
• Cobicistat/elvitegravir/emtricitabine/tenofov
ir DF
• Emtricitabine/tenofovir DF + dolutegravir
• Abacavir/lamivudine + dolutegravir
Specific regimens to avoid due to
higher rates of virologic failure:
• Abacavir/lamivudine +
efavirenz
• Abacavir/lamivudine +
atazamavor/ritonavir
• Abacavir/lamivudine +
rilpivirine
• Emtricitabinetenofovir DF +
rilpivirine
Sax PE. Key Principles and Recommended Regimens for First-line Antiretroviral Therapy. In “InPractice HIV” Eron JJ, Jr., MD;
Kuritzkes DR; Squires, KE Editors; http://www.inpractice.com/Textbooks/HIV.aspx; Revised 9/8/14.
First-line Therapy: Special Situations
Hepatitis B
co-infection
Hepatitis C
co-infection
• Emtricitabine/tenofovir DF + any third drug
listed as recommended
• Emtricitabine/tenofovir DF + raltegravir
• Emtricitabine/tenofovir DF + dolutegravir
• Abacavir/lamividine/dolutegravir
TDF/FTC provides 2 drugs active
against hepatitis B, whereas
other NRTI options (ABC/3TC
and ZDV/3TC) have only 1,
risking hepatitis B resistance to
3TC or FTC.
No significant drug-drug
interactions between these
agents and the HCV Pls
telaprevir, boceprevir, and
simeprevir. Note that sofosbuvir
does not have significant drugdrug interactions with any HIV
medication.
Sax PE. Key Principles and Recommended Regimens for First-line Antiretroviral Therapy. In “InPractice HIV” Eron JJ, Jr., MD;
Kuritzkes DR; Squires, KE Editors; http://www.inpractice.com/Textbooks/HIV.aspx; Revised 9/8/14.
First-line Therapy: Special Situations
Sexually active
• Emtricitabine/tenofovir DF +
women of
boosted PI
childbearing potential
not using reliable
birth control
Alternative antiretroviral regimens that do not
include EFV should be strongly considered in
women who 1) are planning to become
pregnant or 2) are sexually active and not
using effective contraception, assuming
these alternative regimens are acceptable to
the provider and are not thought to
compromise the health of the woman. EFV
may be continued in pregnant women
receiving an EFV-based regimen who
present for antenatal care in the first
trimester, provided there is virologic
suppression on the regimen.
Pregnancy
If patient becomes pregnant while on
antiretroviral therapy, continue current
regimen if virologic suppression has been
achieved and if regimen is well tolerated.
• Emtricitabine/tenofovir DF +
boosted PI
Sax PE. Key Principles and Recommended Regimens for First-line Antiretroviral Therapy. In “InPractice HIV” Eron JJ, Jr., MD;
Kuritzkes DR; Squires, KE Editors; http://www.inpractice.com/Textbooks/HIV.aspx; Revised 9/8/14.
First-line Therapy: Special Situations
Preexisting renal
disease
• Abacavir/lamivudine/
dolutegravir
Patients with renal disease appear to be at
greater risk of developing TDF-related renal
dysfunction. If patients have both renal
disease and are at high risk for
cardiovascular disease (see below), some
clinicians choose to use NRTI-sparing
regimens suh as RAL or DTG + a boosted PI
(several ongoing studies are evaluating
these combinations).
ABC and 3TC must be given as separate
agents in patients with eGFR < 50 mL/min as
3TC dose must be adjusted.
Low bone mineral
density
• Abacavir/lamivudine/
dolutegravir
In 2 head-to-head clinical trials, TDF/FTC
was associated with a greater decline in
bone mineral density than ABC/3TC.
Sax PE. Key Principles and Recommended Regimens for First-line Antiretroviral Therapy. In “InPractice HIV” Eron JJ, Jr., MD;
Kuritzkes DR; Squires, KE Editors; http://www.inpractice.com/Textbooks/HIV.aspx; Revised 9/8/14.
First-line Therapy: Special Situations
History of cardiac
disease or multiple
cardiac risk factors
• Efavirenz/emtricitabine/tenofovir
DF
• Emtricitabine/tenofovir DF +
atazanavir/ritonavir
• Emtricitabine/tenofovir DF +
raltegravir
• Emtricitabine/rilpivirine/tenofovir DF
• Emtricitabine/tenofovir DF +
dolutegravir
• Cobicistat/elvitegravir/emtricitabine/
tenofovir DF
Several studies have suggested an
increased risk of cardiovascular events
in ABC- treated subjects; some studies
have not found this association. A similar
association has been found with some
PIs (LPV/RTV, FpV/RTV, IDV).No
association was found between ATV and
MI risk; not enough data to date on
DRV/RTV. If use of a Pl is necessary,
ATV/RTV is preferred. RAL and DTG
have a relatively neutral effect on plasma
lipids. Among NNRTls, RPV has less
effect on lipids than EFV.
Sax PE. Key Principles and Recommended Regimens for First-line Antiretroviral Therapy. In “InPractice HIV” Eron JJ, Jr., MD;
Kuritzkes DR; Squires, KE Editors; http://www.inpractice.com/Textbooks/HIV.aspx; Revised 9/8/14.
First-line Therapy: Special Situations
Psychiatric
disease
• Emtricitabine/tenofovir DF +
atazanavir/ritonavir or darunavir/ritonavir
• Emtricitabine/tenofovir DF + raltegravir
• Emtricitabine/rilpivirine/tenofovir DF
• Cobicistat/elvitegravir/emtricitabine/tenofo
vir DF
• Emtricitabine/tenofovir DF + dolutegravir
• Abacavir/lamivudine/dolutegravir
In general, EFV-related
neuropsychiatric adverse effects are
more difficult to tolerate in patients with
active psychiatric disease, in particular
depression. RAL may rarely cause
psychiatric side effects, but does so
less commonly than EFV. There are
fewer CNS adverse effects with RPV,
EVG, RAL, and DTG than EFV in
clinical trials in treatment-naïve
patients.
Transmitted
NNRTI
resistance
• Emtricitabine/tenofovir DF +
atazanavir/ritonavir or darunavir/ritonavir
• Emtricitabine/tenofovir DF + raltegravir
• Cobicistat/elvitegravir/emtricitabine/tenofo
vir DF
• Emtricitabine/tenofovir DF + dolutegravir
• Abacavir/lamivudine/dolutegravir
Virologic response to NNRTI-based
regimens markedly reduced when
NNRTIs are used despite transmitted
NNRTI resistance.
Sax PE. Key Principles and Recommended Regimens for First-line Antiretroviral Therapy. In “InPractice HIV” Eron JJ, Jr., MD;
Kuritzkes DR; Squires, KE Editors; http://www.inpractice.com/Textbooks/HIV.aspx; Revised 9/8/14.
Case Study
• 54-year-old man
– Obesity
– GERD, on PPIs
– Diabetes
– Creatinine 1.6 (calculated GFR 50)
– Dyslipidemia, on statin
– Transaminitis due to hepatic steatosis
– CD4 780
– VL 45,000
– WT genotype
– HLA-B*5701 negative
Polling Question
Baseline Survey
The case study patient has researched the topic and
requests an integrase-based regimen with TDF/FTC. Your
response is:
A. Ok
B. You prefer ABC/3TC, given renal disease
C. You prefer an “NRTI-sparing” or “NRTI-limiting” approach
D. Other
NNRTI-based Regimens
Considered for This Case
Regimen Choices
Considerations
TDF/FTC/EFV
• May worsen dyslipidemia
• Many other choices now with fewer CNS side effects
TDF/FTC/RPV
• Contraindicated with pantoprazole
PI-based Regimens
Considered for This Case
Regimen
Considerations
TDF/FTC + DRV/r
• May worsen dyslipidemia
• No data yet on CV safety
• Interacts with amlodipine, simvastatin
TDF/FTC + ATV/r
• Combination of tenofovir with ATV/r may increase risk of
TDF/FTC-associated renal disease
• Interacts with amlodipine, simvastatin
• Must be dosed separately from pantoprazole
Integrase-based Regimens
Considered for This Case
Regimen
Considerations
TDF/FTC + RAL
• RAL must be dosed twice-daily
TDF/FTC /EVG/COBI • Should not be used if GFR < 70
• Interacts with amlodipine, simvastatin
TDF/FTC + DTG
• Will slightly increase serum creatinine from DTG’s inhibition of
tubular secretion of creatinine – could make monitoring of renal
function more difficult
• DTG may increase levels of metformin; use with caution
ABC/3TC + DTG
• Has several significant cardiac risk factors
• DTG may increase levels of metformin; use with caution
Case Outcome
• Selection of the optimal ART regimen in this case required careful
consideration of baseline cardiovascular, metabolic, and renal issues
• NRTI selection needed to balance possible nephrotoxicity of TDF with the
potential cardiac toxicity of ABC; given ability to monitor for the former,
TDF/FTC was selected
• For the key third drug, RAL and DTG were considered best – fewest drug
interactions and favorable metabolic profile
• Although DTG is dosed once-daily and has a higher resistance barrier than
RAL, its inhibition of creatinine secretion would make monitoring renal
function more difficult, and the potential drug-drug interaction with
metformin is a potential concern, particularly with impaired renal function
• Ultimately, TDF/FTC + RAL was selected
Conclusions
• HIV-infected patients are increasingly presenting for treatment with
multiple medical comorbidities
• Choice of ART is now driven by additional considerations
– No longer are virologic potency and tolerability sufficient
– Important additional considerations now include:
•
•
•
•
•
Cardiovascular risk
Drug-drug interactions
Effects on serum creatinine and nephrotoxicity
Pill burden/availability of STR formulations
Host genetics
• DHHS preferred regimens can be individualized based on traditional
and new considerations with a nuanced understanding of regimen
differences
Participant CME Evaluation
• Please take out the Participant CME Post-survey and
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• If you are not seeking credit, we ask that you fill out the
information pertaining to your degree and specialty, as well
as the few post-activity survey questions measuring the
knowledge and competence you have garnered from this
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