1. Integrating Recent Data When Selecting First-line Antiretroviral Therapy
This activity is supported by an educational grant from Merck.

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3. Faculty
Joseph J. Eron, Jr., MD Professor of Medicine and Epidemiology University of North Carolina School of Medicine
Director, AIDS Clinical Trials Unit
University of North Carolina
Chapel Hill, North Carolina
W. David Hardy, MD Clinical Professor of Medicine David Geffen School of Medicine at UCLA
Los Angeles, California
Paul E. Sax, MD Clinical Director HIV Program and Division of Infectious Diseases
Brigham and Women’s Hospital
Professor of Medicine
Harvard Medical School
Boston, Massachusetts
This slide lists the faculty who were involved in the production of these slides.

4. Disclosures
Joseph J. Eron, Jr., MD, has disclosed that he has received consulting fees from AbbVie, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline/ViiV, Merck, Tibotec/Janssen, and Tobira; has served on data and safety monitoring boards for Vertex; and has received funds for research support from AbbVie and GlaxoSmithKline/ViiV. W. David Hardy, MD, has disclosed that he has received consulting fees from Gilead Sciences, GlaxoSmithKline/ViiV, and Janssen; has received funds for research support from Gilead Sciences, GlaxoSmithKline/ViiV, Janssen, and Vertex; and has ownership interest (stocks, stock options or other ownership interest) in Merck. Paul E. Sax, MD, has disclosed that he has received consulting fees from AbbVie, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline/ViiV, Janssen, and Merck and funds for research support (paid to Brigham and Women’s Hospital) from Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline/ViiV, and Merck.
This slide lists the disclosure information of the faculty and staff involved in the development of these slides.

5. Overview of First-line Antiretroviral Therapy

6. Regardless of BL VL or CD4+ Count
DHHS and IAS-USA Guidelines: 2014 Recommended Regimens for First-line ART
Class
DHHS[1]
IAS-USA[2]
Regardless of BL VL or CD4+ Count
Pts With Pre-ART
VL < 100,000 c/mL
NNRTI
EFV/TDF/FTC
EFV + ABC/3TC*
RPV/TDF/FTC
EFV/TDF/FTC or
EFV + ABC/3TC*‡ or
RPV/TDF/FTC‡
Boosted PI
ATV/RTV + TDF/FTC
DRV/RTV + TDF/FTC
ATV/RTV + ABC/3TC*
ATV/RTV + TDF/FTC or
ATV/RTV + ABC/3TC*‡
INSTI
RAL + TDF/FTC
EVG/COBI/TDF/FTC║
DTG + ABC/3TC*§
DTG + TDF/FTC
3TC, lamivudine; ABC, abacavir; ART, antiretroviral therapy; ATV, atazanavir; BL, baseline; COBI, cobicistat; CrCl, creatinine clearance; DHHS, Department of Health and Human Services; DRV, darunavir; DTG, dolutegravir; EFV, efavirenz; EVG, elvitegravir; FTC, emtricitabine; IAS, International Antiviral Society; RAL, raltegravir; RPV, rilpivirine; RTV, ritonavir; TDF, tenofovir; VL, viral load.
EVG and DTG: Avoid simultaneous administration with antacids or other medications with divalent cations (Ca2+, Mg++, Al++, Fe++), as chelation of the integrase strand transfer inhibitor may reduce absorption.
EFV: Efavirenz should be taken preferably at bedtime and on an empty stomach.
ABC: Abacavir has been associated with an increased risk of cardiovascular complications; use caution in patients at high cardiovascular risk. Should only be administered to HLA-B*5701–negative patients.
ABC/3TC: When administered with efavirenz or ritonavir-boosted atazanavir, abacavir/lamivudine was less efficacious with baseline HIV-1 RNA level > copies/mL vs tenofovir/emtricitabine.
RPV: Rilpivirine should be taken with a full meal and should not be given with proton pump inhibitors.
ATV and DRV: Atazanavir and darunavir should be taken with food.
ATV: Avoid coadministration with H2-blockers or proton pump inhibitors or seek specific doses and dose separation schedules in the full prescribing information.
RAL: Coadministration of raltegravir with aluminum and/or magnesium-containing antacids can reduce absorption of raltegravir and is not recommended. Raltegravir may be co-administered with calcium carbonate-containing antacids.
*Only for pts who are HLA-B*5701 negative.
Only for those with CD4+ cell counts > 200 cells/mm3.
‡Not recommended in pts with baseline HIV-1 RNA > 100,000 copies/mL.
║Only for pts with pre-ART CrCl > 70 mL/min.
§Publication of these guidelines preceded the availability of DTG/ABC/3TC as a single-tablet regimen.
1. DHHS Guidelines. May Günthard HF, et al. JAMA. 2014;312:

7. DHHS Guidelines: 2015 Recommended Regimens for First-line ART
Class
DHHS Recommended Therapy
Regardless of BL VL or CD4+ Count
Alternative Regimens
INSTI
RAL + TDF/FTC
EVG/COBI/TDF/FTC*
DTG/ABC/3TC†
DTG + TDF/FTC
Boosted PI
DRV/RTV + TDF/FTC
ATV/RTV + TDF/FTC
ATV/COBI + TDF/FTC*
DRV/RTV + ABC/3TC†
DRV/COBI + ABC/3TC*†
DRV/COBI + TDF/FTC*
NNRTI
EFV/TDF/FTC
RPV/TDF/FTC‡
3TC, lamivudine; ABC, abacavir; ART, antiretroviral therapy; BL, baseline; COBI, cobicistat; CrCl, creatinine clearance; DHHS, Department of Health and Human Services; DRV, darunavir; EVG, elvitegravir; FTC, emtricitabine; RAL, raltegravir; RPV, rilpivirine; RTV, ritonavir; TDF, tenofovir; VL, viral load
*Only for pts with pre-ART CrCl ≥ 70 mL/min.
†Only for pts who are HLA-B*5701 negative.
‡Not recommended in pts with baseline HIV-1 RNA > 100,000 copies/mL and CD4+ cell counts < 200 cells/mm3.
DHHS Guidelines. April 2015.

8. Selecting Initial Antiretroviral Therapy

9. Selected Drug–Drug Interactions of INSTIs
Agent
Potential Drug–Drug Interactions
Raltegravir[1]
Metabolized by UGT1A
ATV increases RAL concentrations; dose adjustment not recommended
Avoid aluminum- and/or magnesium-containing antacids
Rifampin decreases RAL levels; double RAL dose if coadministered with rifampin
Elvitegravir/ cobicistat[2]
Metabolized by CYP3A, CYP2D6
COBI increases levels of drugs metabolized by CYP3A
Separate dosing with aluminum- and/or magnesium-containing antacids
Not recommended for use with rifamycins
Dolutegravir[3]
Metabolized by UGT1A, with contribution from CYP3A
Avoid use with ETR unless coadministered with boosted PI; avoid dosing with NVP
DTG may increase metformin concentrations; metformin dose adjustment may be needed; monitor clinically when starting or stopping DTG
ATV, atazanavir; COBI, cobicistat; DTG, dolutegravir; ETR, etravirine; NVP, nevirapine; RAL, raltegravir.
1. Raltegravir [package insert]. 2. EVG/COBI/TDF/FTC [package insert]. 3. Dolutegravir [package insert].

10. DHHS Guidelines, April 2015: What to Start
Alternative Regimens
NNRTI based
EFV/TDF/FTC
RPV/TDF/FTC*
PI based
ATV/COBI + TDF/FTC†
ATV/r + TDF/FTC
DRV/COBI + ABC/3TC‡
DRV/r + ABC/3TC‡
DRV/COBI + TDF/FTC†
*Only for pts with pre-ART HIV RNA < 100,000 copies/mL and CD4 > 200 cells mm3.
†Only for pts with pre-ART CrCl ≥ 70 mL/min.
‡Only for pts who are HLA-B*5701 negative.
3TC, lamivudine; ABC, abacavir; ART, antiretroviral therapy; ATV, atazanavir; COBI, cobicistat; CrCl, creatinine clearance; DHHS, Department of Health and Human Services; DRV, darunavir; EFV, efavirenz; FTC, emtricitabine; RPV, rilpivirine; RTV, ritonavir; TDF, tenofovir.
An alternative regimen may be the preferred regimen for some pts
DHHS Guidelines. April 2015.

11. The International Antiviral Society–USA Recommended Treatment Regimens
Class
IAS-USA[1]
NNRTI
EFV/TDF/FTC or
EFV + ABC/3TC*†
RPV/TDF/FTC†
Boosted PI
ATV/RTV + TDF/FTC or
ATV/RTV + ABC/3TC*†
DRV/RTV + TDF/FTC
INSTI
RAL + TDF/FTC
EVG/COBI/TDF/FTC‡
DTG + ABC/3TC*§
DTG + TDF/FTC
3TC, lamivudine; ABC, abacavir; ART, antiretroviral therapy; ATV, atazanavir; COBI, cobicistat; CrCl, creatinine clearance; DRV, darunavir; DTG, dolutegravir; EFV, efavirenz; FTC, emtricitabine; IAS, International Antiviral Society; RAL, raltegravir; RPV, rilpivirine; RTV, ritonavir; TDF, tenofovir; WHO, World Health Organization.
*Only for pts who are HLA-B*5701 negative.
Not recommended in pts with baseline HIV-1 RNA > 100,000 copies/mL.
‡Only for pts with pre-ART CrCl ≥ 70 mL/min.
§Publication of these guidelines preceded the availability of DTG/ABC/3TC as a single-tablet regimen.
Currently preferred WHO regimens: EFV/TDF/FTC or EFV/TDF/3TC due to efficacy and cost of treatment[2]
1. Günthard HF, et al. JAMA. 2014;312: WHO. The strategic use of antiretrovirals to help end the HIV epidemic

12. Comparing Integrase Inhibitor Regimens

13. FLAMINGO: Wk 96 Subgroup Efficacy Analysis
DTG + NRTIs (n = 242)
DRV/RTV + NRTIs (n = 242)
100 82 82 80 80 79 80 73 75 68 64 60 52
HIV-1 RNA < 50 c/mL (%) 40
3TC, lamivudine; ABC, abacavir; BL, baseline; DRV, darunavir; DTG, dolutegravir; FTC, emtricitabine; RTV, ritonavir; TDF, tenofovir.
Joseph J. Eron, Jr., MD:
A subgroup analysis of Week 96 data from FLAMINGO study showed that the difference in efficacy between the 2 treatment arms was magnified among patients with high baseline HIV-1 RNA levels.[5] Among patients with baseline HIV-1 RNA > 100,000 copies/mL, 82% treated with dolutegravir achieved HIV-1 RNA levels < 50 copies/mL vs 52% for patients treated with darunavir/ritonavir. However, it is important to note that the number of patients in the high HIV-1 RNA subgroup was relatively small, constituting only one fourth of the total study population (122/484). A subgroup analysis of virologic response according to background NRTIs showed similar efficacy between dolutegravir plus abacavir/lamivudine and dolutegravir plus emtricitabine/tenofovir disoproxil fumarate, although this was not a randomized comparison controlled for other factors such as baseline HIV-1 RNA or CD4+ cell count because investigators selected the NRTI pairs. Therefore, it is difficult to draw definitive conclusions from this analysis.
Jürgen K. Rockstroh, MD:
Regarding the difference in virologic response rates among patients with high baseline HIV-1 RNA, it is useful to consider that viral kinetics differ between integrase inhibitors and boosted PIs such that the decline in HIV-1 RNA is more rapid with integrase inhibitors and, therefore, undetectable HIV-1 RNA is reached more quickly. This difference becomes more pronounced in patients with baseline HIV-1 RNA > 100,000 copies/mL because it takes longer for this group to reach HIV-1 RNA < 50 copies/mL. The slower decline in HIV-1 RNA with PIs may mean that some patients are classified as having virologic failure at a given time point, despite the fact that they may achieve HIV-1 RNA < 50 copies/mL at a later time. Because there is no emergence of drug resistance, there is no adverse clinical consequence from the delay in achieving undetectable HIV-1 RNA.
I agree. The decline in HIV-1 RNA is slower with PIs, especially in patients with very high HIV-1 RNA, but this likely is of little clinical consequence. 20
Overall
≤ 100,000
(n = 362)
> 100,000
(n = 122)
ABC/3TC
(n = 159)
TDF/FTC
(n = 325)
BL HIV-1 RNA (c/mL)
Background NRTI
Molina JM, et al. Glasgow HIV Abstract O153.

14. Difference in 96-Wk Cumulative Incidence (97.5% CI)
ACTG 5257: Cumulative Incidence of Virologic or Tolerability Failure at Wk 96
Difference in 96-Wk Cumulative Incidence (97.5% CI)
1.00
ATV/RTV + TDF/FTC RAL + TDF/FTC DRV/RTV + TDF/FTC
Favors RAL
ATV/RTV vs RAL 15% (10.2% to 19.6%)
0.75
Favors RAL
DRV/RTV vs RAL 7.5% (3.2% to 11.8%)
Favors DRV/RTV
ATV/RTV vs DRV/RTV 7.5% (2.3% to 12.7%)
Cumulative Incidence
0.50
-20
-10 10 20
ATV, atazanavir; DRV, darunavir; FTC, emtricitabine; RAL, raltegravir; RTV, ritonavir.
0.25 24 48 64 80 96
112
128
144
Wks Since Study Entry
Lennox JL, et al. Ann Intern Med. 2014;161:

15. STARTMRK: Drug-Related Adverse Events
5-Yr Drug-Related AEs in ≥ 5% of Pts, %
RAL + TDF/FTC (n = 281)
EFV + TDF/FTC (n = 282)
Gastrointestinal
21.7
29.4
Diarrhea
5.3
9.9
Flatulence
3.6
5.0
Nausea
8.9
11.0
General disorders
10.0
16.7
Fatigue
4.3
Nervous system disorders
18.5
49.6
Dizziness
7.8
35.1
Headache
9.3
14.2
Somnolence
1.1
7.4
Psychiatric disorders
30.9
Abnormal dreams
6.8
13.1
Insomnia
7.5
8.2
Nightmares
2.8
Skin and subcutaneous tissue disorders
6.0
22.3
Rash
AEs, adverse events; EFV, efavirenz; FTC, emtricitabine; RAL, raltegravir; TDF, tenofovir.
Rockstroh JK, et al. J Acquir Immune Defic Syndr. 2013;63:77-85.

16. HIV-1 RNA < 50 copies/mL (%) HIV-1 RNA < 50 copies/mL (%)
EVG/COBI Noninferior to EFV and to ATV/RTV, With TDF/FTC, Through Wk 144
Study 102[1]
Study 103[2]
EVG/COBI/TDF/FTC (n = 348)
EFV/TDF/FTC (n = 352)
EVG/COBI/TDF/FTC (n = 353)
ATV/RTV + TDF/FTC (n = 355)
Δ: 3.6%
(-1.6 to 8.8)
Δ: 2.7%
(-2.1 to 7.5)
Δ: 1.1%
(-4.5 to 6.7)
Δ: 2.7%
(-2.9 to 8.3)
Δ: 4.9%
(-1.3 to 11.1)
Δ: 3.1%
(-3.2 to 9.4)
HIV-1 RNA < 50 copies/mL (%)
100 88
HIV-1 RNA < 50 copies/mL (%)
100 90 84 87 84 82 83 80 82 78 80 75 80 75 60 60
ATV, atazanavir; BL, baseline; COBI, cobicistat; EFV, efavirenz; EVG, elvitegravir; FTC, emtricitabine; RTV, ritonavir; TDF, tenofovir. 40 40 20 20
Wk 48
Wk 96
Wk 144
Wk 48
Wk 96
Wk 144
1. Wohl DA, et al. J Acquir Immune Defic Syndr. 2014;65:e118-e Clumeck N, et al. J Acquir Immune Defic Syndr. 2014;65:e121-e124.

17. Treatment Difference (95% CI)
Studies 104 and 111: HIV-1 RNA < 50 c/mL at Wk 48 (Primary Endpoint)
Virologic Outcome
Treatment Difference (95% CI)
100 92
Favors E/C/F/TDF
Favors E/C/F/TAF 90
E/C/F/TAF (n = 866) E/C/F/TDF (n = 867) 80 60
4.7%
‒0.7%
2.0%
HIV-1 RNA <50 c/mL (%) 40 20 4 4 4 6
C, cobicistat; D/C, discontinued; E, elvitegravir; F, emtricitabine; TAF, tenofovir alafenamide fumarate; TDF, tenofovir disoproxil.
Success
Failure
No Data
‒12%
+12%
CD4+ significantly higher for TAF than TDF (P = .024)
D/C for adverse events: TAF 0.9%, TDF 1.5%
Resistance with failure: TAF 7/866 (0.8%), TDF 5/867 (0.6%)
Wohl D, et al. CROI Abstract 113LB.

18. Integrase Inhibitor Options for First-line Antiretroviral Therapy
Drug
Dosing
STR
Boosting Required
Any Resistance in Pts With Failure
Cross- Resistance
Raltegravir
Twice daily No
Yes
Elvitegravir
Once daily
Dolutegravir
None so far
Partial
STR, single-tablet regimen.

19. DHHS Recommended Therapy Regardless of BL VL or CD4+ Count
DHHS Guidelines: 2015 Recommended and Alternative Regimens for First-line ART
Class
DHHS Recommended Therapy
Regardless of BL VL or CD4+ Count
Alternative Regimens
INSTI
RAL + TDF/FTC
EVG/COBI/TDF/FTC*
DTG/ABC/3TC†
DTG + TDF/FTC
Boosted PI
DRV/RTV + TDF/FTC
ATV/RTV + TDF/FTC
ATV/COBI + TDF/FTC*
DRV/RTV + ABC/3TC†
DRV/COBI + ABC/3TC†
DRV/COBI + TDF/FTC*
NNRTI
EFV/TDF/FTC
RPV/TDF/FTC‡
3TC, lamivudine; ABC, abacavir; ART, antiretroviral therapy; ATV, atazanavir; BL, baseline; COBI, cobicistat; CrCl, creatinine clearance; DHHS, Department of Health and Human Services; DRV, darunavir; DTG, dolutegravir; EFV, efavirenz; FTC, emtricitabine; RAL, raltegravir; RPV, rilpivirine; RTV, ritonavir; TDF, tenofovir; VL, viral load.
*Only for pts with pre-ART CrCl ≥ 70 mL/min.
†Only for pts who are HLA-B*5701 negative.
‡Not recommended in pts with baseline HIV-1 RNA > 100,000 copies/mL and CD4+ cell counts < 200 cells/mm3.
An alternative regimen may be the preferred regimen for some pts
DHHS Guidelines. April 2015.

20. Virologic Nonresponse
SINGLE: DTG + ABC/3TC Superior to EFV/TDF/FTC in Tx-Naive Pts To Wk 144
Emergent resistance in those with VF: 0/39 (DTG) vs 7/33 (EFV)
DTG + ABC/3TC QD (n = 414)
EFV/TDF/FTC QD (n = 419)
95% CI for Difference
100 80 60 40 20
Favors
EFV/TDF/FTC
Favors
DTG + ABC/3TC 88 81 80 72 71 63
Wk 48
7.4%
Pts (%)
2.5%
12.3%
Wk 96
8.0% 30
2.3%
13.8%
3TC, lamivudine; ABC, abacavir; DTG, dolutegravir; EFV, efavirenz; FTC, emtricitabine; HBV, hepatitis B virus; TDF, tenofovir; QD, once daily.
Randomized, blinded phase III study of DTG + ABC/3TC vs EFV/TDF/FTC
Outcomes at Wk 144:
HIV-1 RNA < 50 c/mL: 71% (DTG) vs 63% (EFV)
Virologic failure: 9% (DTG) vs 8% (EFV)
No virologic data available: 18% (DTG) vs 30% (EFV)
Emergent resistance in those with VF: 0/39 (DTG) vs 7/33 (EFV)
CD4 cell count increase: +379 (DTG) vs (EFV) cells/mm3 (P = .003) 20 18
Wk 144
8.3% 13 10 12 5 6 7 8 7 7
2.0%
14.6%
Wk 48 96
144
Wk 48 96
144
Wk 48 96
144
15%
15%
Virologic Success*
Virologic Nonresponse
No Virologic Data
*HIV-1 RNA < 50 copies/mL as defined by FDA Snapshot algorithm.
-10% noninferiority margin.
Pts with HBV infection were excluded from this study.
Pappa K, et al. ICAAC Abstract H-647a.

21. Virologic Nonresponse Nonresponse Due to Other Reasons
FLAMINGO: DTG + 2 NRTIs Superior to DRV/RTV + 2 NRTIs in Tx-Naive Pts at Wk 96
Randomized, open-label phase III study of DTG NRTIs vs DRV/RTV NRTIs
Protocol defined VF: <1% (2/242) with DTG vs 2% (4/242) with DRV/RTV
No treatment-emergent resistance in either arm
DTG + 2 NRTIs (n = 242)
DRV/RTV + 2 NRTIs (n = 242)
100 80 80 68 60
Adjusted difference at Wk 96: 12.4% (95% CI: ; P = .002)
Pts (%) 40 21 20 12 12 8
DRV, darunavir; DTG, dolutegravir; RTV, ritonavir; TDF, tenofovir; Tx, treatment; VF, virologic failure.
Randomized, open-label phase III study of DTG + 2 NRTIs vs DRV/RTV + 2 NRTIs
Treatment-related d/c: 2% (DTG) vs 4% (DRV/RTV)
VF: < 1% (n = 2) in each arm
No treatment-emergent resistance in either arm
Similar CD4+ count increase at Wk 48: +210 cells/mm³
Virologic Success*
Virologic Nonresponse
Nonresponse Due to Other Reasons
Wk 96
*HIV-1 RNA < 50 copies/mL as defined by FDA Snapshot algorithm.
Molina JM, et al. Glasgow HIV Abstract O153.

22. Studies Addressing Abacavir and MI
Study
Association
Description
D:A:D[1] 
Cohort collaboration (prospective)
Danish HIV Cohort[2]
Cohort (linked with registries)
Montreal study[3]
Nested case-control study
SMART[4]
Post hoc subgroup analysis of RCT (use of ABC not randomized)
STEAL[5]
Preplanned secondary analysis of RCT (use of ABC randomized)
Swiss HIV Cohort[6]
Cohort (retrospective)
FHDH ANRS CO4[7] ?
NA-ACCORD[8]
VA Clinical Case Registry[9] X
Brothers et al. analysis[10]
Post hoc meta-analysis of RCTs
ACTG A5001/ALLRT[11]
FDA meta-analysis[12]
ABC, abacavir; MI, myocardial infarction; RCT, randomized controlled trial.
1. Friis-Møller N, et al. N Engl J Med. 2003;349: Obel N, et al. HIV Med. 2010;11: Durand M, et al. J Acquir Immune Defic Syndr. 2011;57: Phillips AN, et al. Antiviral Ther. 2008;13: Martin A, et al. AIDS. 2010;24: Young J, et al. J Acquir Immune Defic Syndr [Epub ahead of print] 7. Lang S, et al. AIDS. 2010;24: Palella F, et al. CROI Abstract 749LB. 9. Bedimo RJ, et al. Clin Infect Dis. 2011;53: Brothers CH, et al. J Acquir Immune Defic Syndr ;51: Ribaudo HJ, et al. Clin Infect Dis. 2011;52: Ding X, et al. J Acquir Immune Defic Syndr. 2012;61:

23. NA-ACCORD: Recent Abacavir Use and Risk of MI
Retrospective analysis of pts in 7 clinical cohorts with recent ABC use from 1/1/1995 to 12/31/2010
“Recent” ABC initiation: prescribed within previous 6 mos
ABC initiators (n = 1948) vs non-ABC initiators (n = 14,785):
“Full” study population: all ART users excluding persons on ABC at study entry
“Restricted” population: ART-naive persons who initiated ART in the cohort
Endpoint of incident MIs: presence of clinical diagnosis or elevation of cardiac enzymes
All MIs independently adjudicated
Adjusted HRs for MI in Those With Recent ABC Use
D:A:D Replication
1.33
Full Study
1.95
Restricted Study
1.00
2.00
3.00
4.00
Recent ABC use significant in restricted population and D:A:D replication
Association diminished after adjusting for additional CVD risk factors in multivariate analysis
Significant factors
Both: age 60+ yrs, HTN, eGFR < 30, AIDS
Full: smoking, DM
ABC, abacavir; ART, antiretroviral therapy; CVD, cardiovascular disease; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; HTN, hypertension; MI, myocardial infarction.
For more information about this study, go to
Palella F, et al. CROI Abstract 749LB.

24. DHHS Recommended Therapy Regardless of BL VL or CD4+ Count
DHHS Guidelines: 2015 Recommended and Other Regimens for First-line ART
Class
DHHS Recommended Therapy
Regardless of BL VL or CD4+ Count
Other Regimens
INSTI
RAL + TDF/FTC
EVG/COBI/TDF/FTC*
DTG/ABC/3TC†
DTG + TDF/FTC
RAL + ABC/3TC†
Boosted PI
DRV/RTV + TDF/FTC
ATV/RTV or COBI + ABC/3TC†‡
LPR/RTV + ABC/3TC†
LPR/RTV + TDF/FTC
NNRTI
EFV + ABC/3TC†‡
When TDF or ABC cannot be used
DRV/RTV + RAL§
LPV/RTV + 3TC
3TC, lamivudine; ABC, abacavir; ART, antiretroviral therapy; ATV, atazanavir; BL, baseline; COBI, cobicistat; CrCl, creatinine clearance; DHHS, Department of Health and Human Services; DRV, darunavir; DTG, dolutegravir; EFV, efavirenz; FTC, emtricitabine; RAL, raltegravir; RTV, ritonavir; TDF, tenofovir; VL, viral load.
*Only for pts with pre-ART CrCl ≥ 70 mL/min.
†Only for pts who are HLA-B*5701 negative.
‡Not recommended in pts with baseline HIV-1 RNA > 100,000 copies/mL.
§Not recommended in pts with baseline HIV-1 RNA > 100,000 copies/mL and CD4+ cell counts < 200 cells/mm3.
DHHS Guidelines. April 2015.

25. DHHS Recommended Therapy Regardless of BL VL or CD4+ Count
DHHS Guidelines: 2015 Recommended and Alternative Regimens for First-line ART
Class
DHHS Recommended Therapy
Regardless of BL VL or CD4+ Count
Alternative Regimens
INSTI
RAL + TDF/FTC
EVG/COBI/TDF/FTC*
DTG/ABC/3TC†
DTG + TDF/FTC
Boosted PI
DRV/RTV + TDF/FTC
ATV/RTV + TDF/FTC
ATV/COBI + TDF/FTC*
DRV/RTV + ABC/3TC†
DRV/COBI + ABC/3TC†
DRV/COBI + TDF/FTC*
NNRTI
EFV/TDF/FTC
RPV/TDF/FTC‡
3TC, lamivudine; ABC, abacavir; ART, antiretroviral therapy; ATV, atazanavir; BL, baseline; COBI, cobicistat; CrCl, creatinine clearance; DHHS, Department of Health and Human Services; DRV, darunavir; DTG, dolutegravir; EFV, efavirenz; FTC, emtricitabine; RAL, raltegravir; RPV, rilpivirine; RTV, ritonavir; TDF, tenofovir; VL, viral load.
*Only for pts with pre-ART CrCl ≥ 70 mL/min.
†Only for pts who are HLA-B*5701 negative.
‡Not recommended in pts with baseline HIV-1 RNA > 100,000 copies/mL and CD4+ cell counts < 200 cells/mm3.
An alternative regimen may be the preferred regimen for some pts
DHHS Guidelines. April 2015.

26. Evolving Options for First-line Antiretroviral Therapy

27. Treatment Difference (95% CI)
Studies 104 and 111: HIV-1 RNA < 50 c/mL at Wk 48 (Primary Endpoint)
Virologic Outcome
Treatment Difference (95% CI)
100 92
Favors E/C/F/TDF
Favors E/C/F/TAF 90
E/C/F/TAF (n = 866) E/C/F/TDF (n = 867) 80 60
4.7%
‒0.7%
2.0%
HIV-1 RNA <50 c/mL (%) 40 20 4 4 4 6
C, cobicistat; D/C, discontinued; E, elvitegravir; F, emtricitabine; TAF, tenofovir alafenamide fumarate; TDF, tenofovir disoproxil.
Success
Failure
No Data
‒12%
+12%
CD4 significantly higher for TAF than TDF (P = .024)
D/C for adverse events: TAF 0.9%, TDF 1.5%
Resistance with failure: TAF 7/866 (0.8%), TDF 5/867 (0.6%)
Wohl D, et al. CROI Abstract 113LB.

28. TAF vs TDF: Renal Outcomes
Significantly smaller decreases in eGFR (P < .001)
Significantly less proteinuria, albuminuria, and tubular proteinuria (P < .001)
No cases of tubulopathy/Fanconi syndrome in either arm
Discontinuations due to renal adverse events
E/C/F/TAF: 0 (0%)
E/C/F/TDF: 4 (0.5%) 10
Mean Change in eGFR
E/C/F/TAF (n = 866)
E/C/F/TDF (n = 867) 5
Mean Change (mL/min) -5
-6.6
P < .001
-10
C, cobicistat; E, elvitegravir; eGFR, eGFR, estimated glomerular filtration rate; F, emtricitabine; TAF, tenofovir alafenamide fumarate; TDF, tenofovir disoproxil.
-11.2
-15
-20
Treatment Wk
Sax PE, et al. CROI Abstract 143LB.

29. TAF vs TDF: Changes in Spine and Hip BMD2
P < .001 2
P < .001
‒0.66
‒1.30
Mean (SD) % Change
From Baseline -2 -2
‒2.86
‒2.95 -4 -4
BMD, bone mineral density; C, cobicistat; E, elvitegravir; F, emtricitabine; TAF, tenofovir alafenamide fumarate; TDF, tenofovir disoproxil. -6 -6 24 48 Wk 24 48 Wk
E/C/F/TAF, n
845
E/C/F/TDF, n
850
797
816
784
773
836
848
789
815
780
767
Sax PE, et al. CROI Abstract 143LB.

30. TAF-Based Therapies in Development
Studies all under way or completed
EVG/COBI/FTC/TAF
TAF/FTC
RPV/TAF/FTC
Darunavir/COBI/FTC/TAF
TAF for HBV
TAF/FTC for PrEP: studies planned
COBI, cobicistat; EFV, efavirenz; FTC, emtricitabine; HBV, hepatitis B virus; PrEP, pre-exposure prophylaxis; RPV, rilpivirine; TAF, tenofovir alafenamide fumarate.

31. DHHS Guidelines: 2015 Recommended Regimens for First-line ART
Class
DHHS Recommended Therapy
Regardless of BL VL or CD4+ Count
Alternative Regimens
INSTI
RAL + TDF/FTC
EVG/COBI/TDF/FTC*
DTG/ABC/3TC†
DTG + TDF/FTC
Boosted PI
DRV/RTV + TDF/FTC
ATV/RTV + TDF/FTC
ATV/COBI + TDF/FTC*
DRV/RTV + ABC/3TC†
DRV/COBI + ABC/3TC*†
DRV/COBI + TDF/FTC*
NNRTI
EFV/TDF/FTC
RPV/TDF/FTC‡
3TC, lamivudine; ABC, abacavir; ART, antiretroviral therapy; BL, baseline; COBI, cobicistat; CrCl, creatinine clearance; DHHS, Department of Health and Human Services; DRV, darunavir; EVG, elvitegravir; FTC, emtricitabine; RAL, raltegravir; RPV, rilpivirine; RTV, ritonavir; TDF, tenofovir; VL, viral load
*Only for pts with pre-ART CrCl ≥ 70 mL/min.
†Only for pts who are HLA-B*5701 negative.
‡Not recommended in pts with baseline HIV-1 RNA > 100,000 copies/mL and CD4+ cell counts < 200 cells/mm3.
DHHS Guidelines. April 2015.

32. Initial Factors that Influence Selection of Firstline ART
Pt preference
Single vs multi-pill regimens
Tolerability issues
Drug–drug interactions
Comorbidities
Potential adherence issues
Adherence to regimen
Adherence to follow-up care
ART, antiretroviral therapy.

33. Go Online to Register for an Interactive CME/CE-Certified Webinar!
Including case discussions on:
Considering stage of disease
Evaluating patient comorbidities
Appraising drug–drug interactions
Assessing potential adherence issues
Applying guideline recommendations
clinicaloptions.com/hiv/live events