Professor of Medicine
David Geffen School of Medicine at University of California Los Angeles
From ES Daar, MD, at Los Angeles, Ca: April 22, 2013, IAS-USA. IAS –USA

Slide 2 of 42
When to Start: Case 1
– 30 yo white man
– Diagnosed on routine insurance examination
– PMHx remarkable for HTN, diet controlled
– No medications
– Understands treatment issues and wants to begin therapy if you think it is appropriate
From ES Daar, MD, at Los Angeles, Ca: April 22, 2013, IAS-USA. Adapted from Mike Saag

Slide 3 of 42
When to Start: Case 1b
– 30 yo white man
– Diagnosed on admission to jail for disorderly conduct
– PMHx remarkable for HTN, diet controlled and paranoid schizophrenia
– Doesn ’t take any medications and doesn’t want to
From ES Daar, MD, at Los Angeles, Ca: April 22, 2013, IAS-USA.

Slide 4 of 42
Effect on inflammation in predicting mortality higher in
HIV disease than the general population (SOCA/SCOPE)
From ES Daar, MD, at Los Angeles, Ca: April 22, 2013, IAS-USA. Hunt et al CROI 12

Slide 5 of 42
T cell “ activation ” is lower in treated than untreated adults, but consistently higher than “ normal ”
P < 0.001
P < 0.001
80
60
40
20
0
HAART –
Hunt et al JID 2003, PLoS ONE 2011 and unpublished
From ES Daar, MD, at Los Angeles, Ca: April 22, 2013, IAS-USA.

Slide 6 of 42
Permanent Loss of CD4 if Wait to Start
• CD4 count increases on sustained suppressive
(<400 c/mL) ARV treatment
(n=655) by baseline count
– >350 cells/mm 3 :
CD4 counts return to near-normal levels
– ≤350 cells/mm 3 : CD4 counts significantly increased but plateau after 4 years below normal range
• Differences in CD4 counts associated with differences in morbidity and mortality
Moore RD, Keruly JC. Clin Infect Dis 2007;44:441-446.
From ES Daar, MD, at Los Angeles, Ca: April 22, 2013, IAS-USA.
400
300
200
100
0
Median CD4 Counts Over 6 Years
Stratified by Baseline CD 4 Count
900
800
700
740
500
<200 201 –350 >350
0 1 2 3 4 5 6
Years After Starting HAART

Slide 7 of 42
Reasons to Start Early:
• The Biology
• Association of Inflammation and Disease
• Better Tolerated/Easier to Take
Medications
• Randomized Controlled Trial Data
• Cohort Data
• Irreversible Damage
• Public Health
From ES Daar, MD, at Los Angeles, Ca: April 22, 2013, IAS-USA.

Slide 8 of 42
Most New Infections Transmitted by
Persons Who Do Not Know Their
Status account for…
~25%
Unaware of
Infection
~54%
New
Infections
~42%
Aware of
Infection
~46% of New
Infections
Source : G. Marks et al. AIDS 2006
From ES Daar, MD, at Los Angeles, Ca: April 22, 2013, IAS-USA.

Slide 9 of 42
HPTN 052
1763 HIV discordant couples
(HIV+ partner CD4 350-550)
886 immediate
HAART
874 delayed
HAART (CD4 250)
All receiving HIV prevention services
1 transmission*
& 3 cases of extrapulmonary TB
27 transmissions*
& 17 cases of extrapulmonary TB
*96% reduction in HIV transmission to HIV-negative partner median follow-up 2 years
From ES Daar, MD, at Los Angeles, Ca: April 22, 2013, IAS-USA.

So ….what is the harm?
Slide 10 of 42
• Destruction of lymphoid tissue
• Inflammation
• Increased cardiovascular events
• Increased incidence of certain malignancies
• Increased ‘ aging ’
• Accelerated cognitive decline
From ES Daar, MD, at Los Angeles, Ca: April 22, 2013, IAS-USA.

Slide 11 of 42
When to Start Treatment
Clinical Category
AIDS-defining illness or severe symptoms
CD4 Count
(cells/mm 3 )
Any value
HIV RNA
(copies/mL)
Any value
2/13/13
DHHS
Guidelines
Treat
2012
IAS-USA
Guidelines
Asymptomatic <500 Any value Treat
>500 Any value Treat
Pregnant women
HIV-associated nephropathy
HIV/HBV coinfection when HBV treatment is indicated
Any value
Any value
Any value
Any value
Any value
Any value
Treat
Treat
Treat
*Unless elite controller (HIV RNA <50 copies/mL) or has stable CD4 cell count and low-level viremia in absence of therapy. The IAS-USA guidelines also recommend initiating antiretroviral therapy in HIV-infected patients with active hepatitis C virus infection, active or high risk for cardiovascular disease, and symptomatic primary HIV infection.
DHHS. Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.
Revision February 2013; Thompson MA, et al. JAMA. 2012;308:387-402.
From ES Daar, MD, at Los Angeles, Ca: April 22, 2013, IAS-USA.

Slide 12 of 42
• 34 yo woman is diagnosed with TB
• As part of evaluation she is found to be HIV+
• Initial lab values
– CD4 82 cells/µL
– VL 76,000 c/mL
• No other significant medical condition
• She is started on 4-drug anti-TB therapy
(including INH and rifabutin)
• Virus is wild-type virus
From ES Daar, MD, at Los Angeles, Ca: April 22, 2013, IAS-USA.

Slide 13 of 42
When to Start ARV with Complications
• ARVs within 0-2 weeks of diagnosis
– Infections for which there is no specific treatment (e.g. dementia, cryptosporidium, microsporidium, PML) (AIII)
– Other OIs, e.g. PCP (AI)
• Consider deferring therapy for crypto meningitis
• Tuberculosis
– Within 2 weeks for CD4 <50 cells/uL (AI)
– Within 2-4 weeks for severe symptoms with CD4 50-200
(BI) and >200 cells/uL (BIII)
– Within 8-12 weeks for mild symptoms and 50-500 cells/uL (AI) and >500 cells/uL (BIII)
– Meningitis 2 months (AI) in RLS, perhaps earlier in other settings (CIII)
DHHS. Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.
Revision February 2013; Thompson MA, et al. JAMA. 2012;308:387-402.
From ES Daar, MD, at Los Angeles, Ca: April 22, 2013, IAS-USA.

Slide 14 of 42
A 49 year old asymptomatic man presents to your clinic after recently being diagnosed with HIV
• History of HTN with CrCl ~42 mL/min
• HBsAb+, HCV antibody negative
• CD4 cells repeatedly 700-420 cells/uL
• Plasma HIV RNA 30-50,000 copies/mL
• Not anxious to start antiretrovirals but willing if you think it is necessary
From ES Daar, MD, at Los Angeles, Ca: April 22, 2013, IAS-USA.

Slide 15 of 42
• Patient’s willingness to commit to therapy
• Baseline resistance
• Efficacy data
• Tolerability
• Convenience
• Comorbid conditions
• Consequences of failure (resistance)
• Since the introduction of potent ARV therapy preferred regimens all include NRTIs + third drug
From ES Daar, MD, at Los Angeles, Ca: April 22, 2013, IAS-USA.

Boosted-Protease Inhibitors
Slide 16 of 42
KLEAN 1
(ITT-E, TLOVR)
48 weeks
ARTEMIS 2
(ITT, TLOVR)
96 weeks
CASTLE 3
(ITT, NC=F)
96 weeks
100
80
74
65
66
100
80
74
71
79
100
80
74
68
74
40 40 40
20 20 20 n=434 N=444 n=346 n=343 n=443 n=440
0 0 0
LPV/r
400/100
BID
FPV/r
700/100
BID
LPV/r
QD or
BID
DRV/r
800/100
QD
LPV/r
400/100
BID
ATV/r
300/100
QD
Adapted from: 1. Eron J, et al. Lancet 2006; 368:476-482; 2. Mills A, et al. AIDS May 29, 2009
3. Molina J-M, et al. 48 th ICAAC/46 th IDSA , Washington, DC, 2008. Abst. H-1250d
From ES Daar, MD, at Los Angeles, Ca: April 22, 2013, IAS-USA.

ATV/r vs. EFV
Primary Endpoint
Slide 17 of 42
Daar ES, et al. Ann Intern Med 2011; 154:445-456.
From ES Daar, MD, at Los Angeles, Ca: April 22, 2013, IAS-USA.

Slide 18 of 42
ITT, NC=F
100
86
81
42 76
80
71
82
79
74
69
67
61
40
20 CD4 Change: RAL +374 vs. EFV +312
Weeks
0
0 12 24 48 72 96 120 144 168 192 216 240
Number of Contributing Patients
Raltegravir 400 mg BID 281 278 279 280 281 281 274 280 281 281 274 279
Efavirenz 740 mg QHS 282 282 282 281 282 282 281 281 282 282 282 279
Rockstroh J, et al, 19th IAC; Washington, DC; July 22-27, 2012; Abst. LBPE19.
From ES Daar, MD, at Los Angeles, Ca: April 22, 2013, IAS-USA.

Slide 19 of 42
Pooled ECHO and THRIVE: Virologic
Response (ITT-TLOVR)
84.3%
82.3%
Rimsky L, et al. 50 th ICAAC 2010, Boston, MA. Abst. H-1810
From ES Daar, MD, at Los Angeles, Ca: April 22, 2013, IAS-USA.

Slide 20 of 42
Rimsky L, et al. 50 th ICAAC 2010, Boston, MA. Abst. H-1810
From ES Daar, MD, at Los Angeles, Ca: April 22, 2013, IAS-USA.

Slide 21 of 42
GS102 & GS103: EVG/COBI/TDF/FTC vs.
EFV/TDF/FTC or ATV/RTV + TDF/FTC
Randomized, Phase III, Double-blind, Double Dummy,
Active-controlled, International Studies
GS 102
~89% men
33% >10 5 c/mL
CD4= ~385 c/uL
Quad QD
EFV/FTC/TDF Placebo QD
EFV/FTC/TDF QD
Treatment Naïve
HIV-1 RNA ≥5,000 c/mL
Any CD4 cell count eGFR ≥70 mL/min
Quad Placebo QD
Quad QD
ATV/r +TDF/FTC Placebo QD
GS 103
~90% men
~41% >10 5 c/mL
CD4= ~370 c/uL
QUAD Placebo QD
ATV/r +TD/FTC QD
48 weeks
Sax P, et al, Lancet 2012: 3 79::2439-48; D eJesus E, et al, Lancet 2012; 379: 2429-38
From ES Daar, MD, at Los Angeles, Ca: April 22, 2013, IAS-USA.
192 weeks

Slide 22 of 42
Study 236-102: Primary Endpoint:
HIV-1 RNA < 50 copies/mL
+3.6%, 95% CI 3.6 (-1.6% to +8.8%)
CD4+ change: Quad +239 vs. EFV +206 c/mm 3 (p=0.009)
No difference by baseline characteristics
Sax P, et al. 19th CROI; Seattle, WA; March 5-8, 2012. Abst. 101.
From ES Daar, MD, at Los Angeles, Ca: April 22, 2013, IAS-USA.

Slide 23 of 42
EFV/FTC/TDF
(n=352)
Quad
(n=348)
Treatment Emergent Adverse Events in ≥ 10% of subjects (%)
Diarrhea
Nausea *
Abnormal Dreams
Fatigue
Insomnia *
^
Upper Respiratory Infection
Headache
23%
21%
15%
14%
14%
12%
9%
Depression
Dizziness ^
Rash #
9%
7%
6%
* p<0.05; ^ p<0.001; # p=0.009
Sax P, et al, Lancet 2012: 3 79::2439-48
From ES Daar, MD, at Los Angeles, Ca: April 22, 2013, IAS-USA.
19%
14%
27%
11%
9%
13%
14%
11%
24%
12%

Slide 24 of 42
Study 236-103: ATV/r vs.
TDF/FTC/COBI/EVG HIV-1 RNA < 50 c/mL
100 92%
90
88%
80
70 Diff: 3.5% (95% CI: -1.0 to 8.0)
74
50
QUAD
ATV/r
40
30
20
10
0
BL 2 4 8 12 16 24
Week
32 40 48
Changes in CD4+ count: Quad +207 vs. ATV/r +211 cells/mm 3 (p=0.61)
No difference by baseline characteristics
D eJesus E, et al, Lancet 2012; 379: 2429-38
From ES Daar, MD, at Los Angeles, Ca: April 22, 2013, IAS-USA.

Slide 25 of 42
Diarrhea
Nausea
Upper respiratory infection
Headache
Fatigue
Ocular icterus
Adverse Events > 10% in Either Group
Quad
(n=353)
22%
20%
15%
15%
14%
1%
ATV/r + FTC/TDF
(n=355)
27%
19%
16%
12%
13%
14%
Discontinuation rates due to renal events were identical in both arms (0.3%)
D eJesus E, et al, Lancet 2012; 379: 2429-38
From ES Daar, MD, at Los Angeles, Ca: April 22, 2013, IAS-USA.

Slide 26 of 42
TDF/FTC/EVG/COBI vs. EFV or
ATV/r: Lipid changes
P =0.006
P <0.001
P= 0.001
P =0.001
P =0.44
Conclusion: While some lipid fractions better with Quad than EFV or ATV/r, overall differences were modest and unlikely to be of clinical significance.
Sax P, et al, Lancet 2012: 3 79::2439-48; D eJesus E, et al, Lancet 2012; 379: 2429-38
From ES Daar, MD, at Los Angeles, Ca: April 22, 2013, IAS-USA.

Slide 27 of 42
EVG/COBI/TDF/FTC vs. EFV or ATV/r:
Creatinine Changes
Conclusion: Cobicistat is associated with reduced active secretion of creatinine in the renal tubules leading to initial rises in creatinine levels.
Sax P, et al, Lancet 2012: 3 79::2439-48; D eJesus E, et al, Lancet 2012; 379: 2429-38
From ES Daar, MD, at Los Angeles, Ca: April 22, 2013, IAS-USA.

Slide 28 of 42
Arm
A
ABC/3TC Placebo QD
HIV-1 RNA ≥1000 c/mL
Any CD4+ count
> 16 years of age
B
C
Stratified by screening HIV-1 RNA
(< or ≥ 100,000 c/mL)
Enrolled 2005-2007 last pt enrolled
D
Followed through Sept 2009, 96 wks after
From ES Daar, MD, at Los Angeles, Ca: April 22, 2013, IAS-USA.

Slide 29 of 42
A5202: Time to Virologic Failure in
Patients with HIV RNA >100,000 c/mL
Probability of No Virologic Failure
100
TDF-FTC (26 events)
80
ABC-3TC (57 events)
60
40
20
P<0.001, log-rank test
Hazard ratio, 2.33 (95% CI, 1.46-3.72)
0
0 12 24 36 48 60 72 84 96 108
Weeks since Randomization
No. at Risk
ABC-3TC 398
TDF-FTC 399
363 313
361 321
267
284
222
236
188
204
Sax PE, et al. NEJM 2009;361:2230-2240.
From ES Daar, MD, at Los Angeles, Ca: April 22, 2013, IAS-USA.
137
174
87
104
49
65
20
23

ABC/3TC vs. TDF/FTC
Low Viral Load Stratum
Slide 30 of 42
Sax PE, et al. JID 2011: 204:1191-1201.
From ES Daar, MD, at Los Angeles, Ca: April 22, 2013, IAS-USA.

Slide 31 of 42
HEAT: Virologic Failure by Baseline
HIV-1 RNA (A5202 Efficacy Endpoint)
100
80
60
90
87 87
90 100%
80%
74%
22%
18% ~59%
15%
4%
19%
~37%
18%
40 40%
63%
20 20% 41%
0 0%
<100,000 ≥100,000
ABC/3TC n = 188 205 155 140
≥500,000 c/mL
ABC/3TC
250,000 - <500,000 c/mL
Pappa K, et al. 17th IAC, Mexico City, 2008. Abst. THAB0304.
Young B, et al. 48th ICAAC/46th IDSA, Washington, DC, 2008. Abst. H-1233.
From ES Daar, MD, at Los Angeles, Ca: April 22, 2013, IAS-USA.
TDF/FTC
100,000 - <250,000 c/mL
<100,000 c/mL

Slide 32 of 42
• Conflicting results regarding relationship between ABC and CV events
• TDF-associated with greater decline in bone mineral density
• TDF-associated with variable decline in renal function
From ES Daar, MD, at Los Angeles, Ca: April 22, 2013, IAS-USA.

Slide 33 of 42
D HHS Guidelines for Adolescents/Adults:What to Start
Preferred
Regimens
Alternative
Regimens
• EFV/TDF/FTC
• ATV/r + TDF/FTC
• DRV/r (once daily) + TDF/FTC
• RAL + TDF/FTC
[Pregnant Women Only: LPV/r (twice daily) + ZDV/3TC]
• EFV + ABC/3TC
• RPV + (TDF or ABC)/(FTC or 3TC)
• ATV/r or DRV/r + ABC/3TC
• FPV/r or LPV/r (qd or bid) ABC/3TC or TDF/FTC
• RAL + ABC/3TC
• EVG/COBI/TDF/FTC (9/18/12)
Acceptable
Regimens
• EFV or RPV + ZDV/3TC
• NVP + TDF/FTC or ZDV/3TC or ABC/3TC
• ATV + (ABC or ZDV)/3TC
• ATV/r, DRV/r, LPV/r, FPV/r , RAL + ZDV/3TC
• MVC + ZDV or ABC/3TC
• SQV/r + TDF/FTC or ABC/3TC or ZDV/3TC (with caution)
DHHS Guidelines. Available at: http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf
. Revision March 27, 2012.
From ES Daar, MD, at Los Angeles, Ca: April 22, 2013, IAS-USA.

Slide 34 of 42
ART: What to Start
IAS –USA Recommendations, 2012
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)
Thompson MA, et al. JAMA. 2012;308(4):387-402
From ES Daar, MD, at Los Angeles, Ca: April 22, 2013, IAS-USA.

Slide 35 of 42
A 45 year old African American woman presents to your clinic having been diagnosed with HIV and severe thrush/onychomycosis
• Clinically stable on fluconazole
• History mild depression, diabetes, HTN and dyslipidemia on ACE, metformin, atorvastatin
• Laboratories
– HBsAg and HCV antibody negative
– AST/ALT- 42/82 IU/mL, CrCl~70 mL/min (relatively stable),
HgbA1C=7.1%, UA- 3+ proteinuria
– CD4= 78 cells/uL, HIV-RNA= 219,000 copies/mL
– HIV genotype- WT
• Ready to start antiretrovirals if recommended with no specific concerns regarding various adverse events but would prefer simple regimen
From ES Daar, MD, at Los Angeles, Ca: April 22, 2013, IAS-USA.

Slide 36 of 42
Patient starts TDF/FTC/EFV, TMP/SMX and continues other meds. At 2 months CD4 190 cells/uL, HIV RNA 220 copies/mL, but patient has increasing depression and persistent neurologic symptoms thought to be associated with EFV. CrCl is repeatedly ~70 mL/min. She is seeing psych and on antidepressants.
A 45 year old African American woman
• H/O depression, DM, HTN, dyslipidemia, CKD
• CrCl- 70 mL/min with proteinuria
• CD4 nadir= 78 cells/uL and BL HIV RNA 212,000 copies/mL
From ES Daar, MD, at Los Angeles, Ca: April 22, 2013, IAS-USA.

Slide 37 of 42
RPV mean C trough in ECHO/THRIVE
Mills A, et al. 51 st ICAAC; Chicago, IL; September 17-20, 2011. Abst. H2-794c.
From ES Daar, MD, at Los Angeles, Ca: April 22, 2013, IAS-USA.

Slide 38 of 42
Patient switched to TDF/FTC + ATV/r and continued other meds. After 4 months neurologic symptoms resolved, CD4 250 cells/uL, HIV RNA <40 copies/mL but patient
CrCl has gradually declined (now off TMP/SMX) to 40-45 mL/min with no change in other labs or
UA (glucosuria and proteinuria).
A 45 year old African American woman
• H/O depression, DM, HTN, dyslipidemia, CKD
• CrCl- 40-45 mL/min with proteinuria (HLA-B5701-negative)
• CD4 nadir= 78 cells/uL and BL HIV RNA 212,000 copies/mL
From ES Daar, MD, at Los Angeles, Ca: April 22, 2013, IAS-USA.

Slide 39 of 42
D:A:D Study: NRTIs and Risk of MI
1.9
1.5
1.2
1
**
0.8
0.6
Recent Exposure*: yes/no
Cumulative Exposure: per year
ZDV ddI
#PYFU: 138,109 74,407
#MI: 533 331 ddC d4T 3TC ABC
29,676 95,320 153,009 53,300
148 405 554 221
Adjusting for eGFR does not change ABC MI finding:
Adjusted RR 1.89; 95% CI (1.46 – 2.44; P=0.0001)
TDF
39,157
139
* Recent use=current or within the last 6 months.
**Not shown (low number of patients currently on ddC)
Lundgren J, et al. 16th CROI, Montreal, Canada, 2009. Abst. 44LB. Sabin C, et al. Lancet
2008;371:1417-26.
From ES Daar, MD, at Los Angeles, Ca: April 22, 2013, IAS-USA.

Slide 40 of 42
VA Case Registry: Use of ABC or
TDF in Last Regimen and Risk of MI
2.2
2.0
1.8
1.6
Unadjusted HR of AMI for each PY of exposure to each one of the categories
Adjusted for estimated GFR prior to regimen onset (by MDRD method)
1.4
1.2
1.0
0.8
0.6
0.4
0.2
ABC TDF Both ABC and TDF
NRTI in Last Regimen During Observation Period
Bedimo R, et al. Clin Inf Dis. 2011;53:84-91.
From ES Daar, MD, at Los Angeles, Ca: April 22, 2013, IAS-USA.

Slide 41 of 42
Cumulative Exposure to ARVs and Risk of CKD
Tenofovir
Indinavir
Cockcroft-Gault (n=225)
MDRD (n=274)
CKD-EPI (n=258)
INSIGHT def (n=129)
Censoring ATV
Censoring TDF
Censoring boosted PI
Atazanavir
Lopinavir/r
0.9
Mocroft A, et al. AIDS. 2010; 53:1667-78
1.4
From ES Daar, MD, at Los Angeles, Ca: April 22, 2013, IAS-USA.

A5202: ABC/3TC vs. TDF/FTC
Slide 42 of 42
Median Change in Creatinine Clearance p-values: ABC/3TC vs.
TDF/FTC
Wk 48, p=0.83
Wk 96, p=0.14
Wk 48, p<0.001
Wk 96, p<0.001
Week 48
Week 96
TDF/FTC
ABC/3TC ABC/3TC TDF/FTC
N= 191 173
ATV/r
217 191 186 157
EFV
200 178
>25% decr(%): 3 2 7 6 2 3 1 3
Daar ES, et al. Ann Intern Med 2011; 154:445-456.
From ES Daar, MD, at Los Angeles, Ca: April 22, 2013, IAS-USA.