1. HIV Medicine Update: Where are we in 2014
Calvin Cohen MD
CRI New England
Harvard Vanguard Medical Assoc
Boston MA
Slide: Post Conference Update: 21st Conference on Retroviruses and Opportunistic Infections

2. Disclosures Grants/Research Support: Gilead, Viiv, Merck, Janssen, BMS
Consultant: Gilead, Viiv, Merck, Janssen, BMS, Splicos
Speakers’ Bureau: none
Stock Shareholder: none
Other Support: Expert Testimony - Gilead
Slide: Educator 2

3. Rates of Diagnosis of HIV Infection Among Adults and Adolescents, 2011
United States and 6 Dependent Areas
9.5
N = 50,007
Total Rate = 19.1
3.0
2.6
5.2
VT 2.3
2.6
7.2
8.0
5.7 NT
4.5 MA
22.5 RI
14.0 CT
14.2 NJ
21.1 DE
16.7 MD
36.4 DC
177.9
30.1
3.8
9.6
3.4
19.2
17.7
5.0
14.3
4.3
5.1
20.0
12.6
9.5
9.6
6.6
11.2
16.2
6.2
9.4
13.3
20.8
8.6
17.3
10.7
24.5
10.0
22.0
25.3
20.9
31.4
Rates per 100,000 population
36.6
4.6
< 10.0
33.2
10.0 – 19.9
6.8
American Samoa
Guam
Northern Mariana Islands
Puerto Rico
Republic of Palau
U.S. Virgin Islands
0.0
5.3
28.6
39.5
20.0 – 29.9
≥ 30.0
Note. Data include persons with a diagnosis of HIV infection regardless of stage of disease at diagnosis. All displayed data have been statistically adjusted to account for reporting delays, but not for incomplete reporting.

4. Preventing HIV Transmission Safer Sex: the HOT Study
Cohort study of MSM
N = 439
Six month observation period
Oral sex: No HIV infections observed despite lack of condom use (94%)
Conclusions:
Rate of transmission via oral sex is lowest
Not zero: <0.8%
* HIV incidence determined in repeat testers
** RAI = receptive anal intercourse
Adapted from Page-Shafer K, et al. XIV Intl AIDS Conference, Barcelona 2002, #4872; Balls et al. We PpC2072, Bangkok 2004

5. HIV Prevention – What Else Can we do?
Treatment as Prevention
PrEP
Slide: Program Overview

6. When to Start ART: Global Consensus and Diversity
CD4 Count (cells/mm3)
AIDS or
HIV-Related Symptoms
<200
>500
United States
DHHS (2013)
Yes
IAS-USA (2012)
British HIV Association (2013)
Consider
Defer
European AIDS Society (2013)
WHO (2013)
Slide: When to Start ART: Global Consensus and Diversity
This slide provides a list of the different global guidelines on when to start ART.1-5
References
Panel on Antiretroviral Guidelines for Adult and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. February 12, 2013; Available at:
Thompson MA, Aberg JA, Hoy JF, et al. Antiretroviral treatment of adult HIV infection: 2012 recommendations of the International AIDS Society-USA panel. JAMA. 2012;308:
European AIDS Clinical Society. Guidelines. Version 7.0. October Available at:
BHIVA Treatment Guidelines Writing Group. Guidelines for the treatment of HIV-1 positive adults with antiretroviral therapy. Updated November Available at:
WHO. Available at:
The IAS-USA guidelines also recommend initiating ART in HIV-infected patients with active HCV infection, active or high risk for cardiovascular disease, and symptomatic primary HIV infection.
DHHS. Available at:
Revision February 12, 2013; Thompson MA, et al. JAMA. 2012;308: ; EACS. Available at:
Version 7.0 October 2013; BHIVA. Available at:
WHO. Available at:

7. HPTN 052: HIV Prevention in “Stable” Heterosexual Couples
Linked HIV Transmission
DSMB halts trial
Median follow-up: 1.7 years
HIV RNA <400 copies/mL
Early ART: 90%
Delayed ART: 93%
Linked HIV transmissions to HIV-negative partner
Early therapy (n=1)
0.1 per 100 person-years
Delayed therapy (n=27)
1.7 per 100 person-years
HR: 0.04
(95% CI )
(P<0.001)
Delayed
ART
Cumulative Probability
Slide: HPTN 052: HIV Prevention in Stable Heterosexual Couples
On April 28, 2011, the NIAID Multinational Data Safety and Monitoring Board recommended the results be reported. As shown in this slide, the majority of patients in either treatment arm achieved HIV RNA <400 copies/mL.1
There were a total of 28 linked HIV transmissions to HIV-negative partner.1
Early therapy (n=1): 0.1 per 100 person-years.
Delayed therapy (n=27): 1.7 per 100 person-years.
Early ART that suppressed HIV RNA led to a 96% reduction of sexual transmission of HIV in serodiscordant couples.1
Reference
Cohen MS, Chen YQ, McCauley M, et al. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med. 2011;365:
96%
Early
ART
Years
Cohen MS, et al. N Engl J Med. 2011;365:

8. Rate of Couple Transmission (per 100 Couple-Years Follow-Up)
PARTNER Study: HIV Transmission Risk Through Condomless Sex - Serodiscordant Couples
HIV transmission rate
None – despite condomless sexual activity with a partner on suppressive ART
Uncertainty over the upper limit of risk remains
Particularly with receptive anal sex with ejaculation
Duration of prior ART without transmission may have selected for lowest risk discordant couples
Rate of Couple Transmission
(per 100 Couple-Years Follow-Up)
Heterosexual (Male)
Vaginal sex with ejaculation
(192 CYFU)
Heterosexual (Female)
Vaginal sex (272 CYFU)
MSM
Receptive anal sex:
With ejaculation (93 CYFU)
Without ejaculation (157 CYFU)
Insertive anal sex (262 CYFU)
Slide: HIV Transmission According to Sexual Behavior Reported by HIV-Negative Partner
Although some negative partners became HIV positive during follow-up, no phylogenetically linked transmissions occurred, giving a rate of within-couple HIV transmission during eligible couple-years of zero for both MSMs and heterosexuals.1
Uncertainty over the upper limit of risk remains, particularly with receptive anal sex with ejaculation.1
Additional follow-up needed to provide more precise estimates for transmission risk. Duration of prior ART without transmission may have selected for lowest risk discordant couples.1
Reference
Rodger A, Bruun T, Cambiano V, et al. HIV transmission risk through condomless sex if HIV+ partner on suppressive ART: PARTNER study. Program and abstracts of the 21st Conference on Retroviruses and Opportunistic Infections; March 3-6, 2013; Boston, MA. Abstract 153LB.
Rate (95% CI)
Rodger A, et al. 21st CROI. Boston, Abstract 153LB.

9. Continuum of HIV Care in United States
100%
75%
50%
25%
66%
77%
80%
89%
Of all with HIV infection, 850,000 individuals do not have suppressed HIV RNA (72%)
MMWR (60), 2011.

10. Until there is a Vaccine…
Treating HIV Negative Persons: Pre-Exposure Prophylaxis (PrEP)

11. CDC Advocates PrEP

12. iPrex Open Label Extension: HIV Incidence and Drug Concentrations
<2 Tablets/Week
2-3 Tablets/Week
4-6 Tablets/Week
7 Tablets/Week
Off PrEP
On PrEP I
0 LLOQ
350
500
700
1000
1250
1500
Risk Reduction
44%
84%
100%
95% CI
-31 to 77%
21 to 99%
86 to 100%
(combined)
Grant R, et al. 20th IAC; Melbourne, Australia; July 20-25, 2014; Abst. TUAC0105LB; Grant R, et al, Lancet ID, published online July 22, 2014.

13. iPrex: Drug Concentrations over Time
First Evidence of HIV Infection
TFV-DP:
Control
Case
Control
Case
Weeks Pre-Infection
Weeks Post-Infection N=
Control:
380
1306
1647
1396
1489
1441
1338
768
386
266
171 44
Case: 8 22 24 26 28 7
Grant R, et al. 20th IAC; Melbourne, Australia; July 20-25, 2014; Abst. TUAC0105LB; Grant R, et al, Lancet ID, published online July 22, 2014.

14. iPrex: Correlates of TDF Drug Concentration
Predictor of Drug Concentration
Adjusted OR
P Value
Non-condom Receptive Anal Intercourse at Entry
1.69
<0.0001
>=5 Sexual Partners in the Past 3 Months
1.57
Known HIV Positive Partner
1.40
0.03
Age
Ref
<0.0001
Education
Less than Secondary Secondary Post-secondary
Ref
Transgender
0.72
0.02
Alcohol and Substance Use and Drug Concentrations in Dried Blood Spots
Adjusted OR
P Value
Alcohol >=5 Drinks a Day on Drinking Days
0.81
0.07
Cocaine use in the past 30 days
1.07
0.60
Methamphetamine Use in the Past 30 Days
0.78
0.42
Grant R, et al. 20th IAC; Melbourne, Australia; July 20-25, 2014; Abst. TUAC0105LB; Grant R, et al, Lancet ID, published online July 22, 2014.

15. Ipergay: Effectiveness of “On-Demand” PrEP
Randomized placebo-controlled trial
Full prevention services + TDF/FTC before and after sex (n=950)
High risk MSM
Condomless anal sex with >2 partners within 6 months
eGFR >60 mL/mn
Full prevention services + placebo before and after sex (n=950)
Main messages:
The Caprisa study was conducted in KwaZulu-Natal, South Africa in a population of women yo, that were sexually active and at high risk for contracting HIV. Sero-status, safety, sexual behaviour, gel and condom use were assessed monthly for 30 months.
Women were requested to insert one dose of gel within 12 hours before sex and as soon as possible within 12 hours after sex. This dosing strategy was based on the data from monkey challenge studies and perinatal transmission studies.
Background:
Tenofovir (PMPA) was studied due to the effectiveness, safety, and long half life, along with the protective data in the monkey challenge studies.
Regimen – Two doses 2-24 hours before sex, one dose for two days after
Counseling, testing for STI, condoms, vaccination, Post Exp Prophylaxis
Primary endpoint : HIV infection
Power - Incidence of HIV-infection: 3% PY, 50% efficacy, 64 events
N ~ 2000 pts
Fonsart J, et al. 20th IAC; Melbourne, Australia; July 20-25, 2014; Abst. LBPE28. 15

16. Ipergay: Detection of TFV in Plasma
% of Participants with TFV Detected in Plasma (548 samples from 113 Participants) 46 44 40 33 23 8
Overall detection:
- 86% TDF/FTC - 4% placebo
(56) (57)
(51) (56)
(49) (52)
(42) (44)
(37) (40)
(22) (26)
(8) (8) 3 2
Fonsart J, et al. 20th IAC; Melbourne, Australia; July 20-25, 2014; Abst. LBPE28.

17. PrEP: Are Long Acting Agents the Answer
PrEP: Are Long Acting Agents the Answer? GSK : Macaque Model with SHIV
50 mg/kg GSK744 LAP
IM (n=8)
Week
Rectal challenges
(50 TCID50 SHIV162P3)
Results
GSK 744
P<0.0001
Based on very long parenteral (IM or IV) half life – protective effect of 744 will be assessed with q1-3 month dosing
Andrews C, et al. 20th CROI; Atlanta, GA; March 3-6, Abst. 24LB.

18. iPrex: Rates of Non-Condom Receptive Anal Intercourse (ncRAI)
PrEP Started Later
Immediate PrEP*
No PrEP˄
*P = 0.006
˄P = 0.03
Grant R, et al. 20th IAC; Melbourne, Australia; July 20-25, 2014; Abst. TUAC0105LB; Grant R, et al, Lancet ID, published online July 22, 2014.

19. Antiretroviral Trials – Where are we?
Slide: Program Overview

20. DHHS Guidelines: Preferred Regimens – Early 2013
NNRTI
Efavirenz1/emtricitabine2/tenofovir DF3 PI
Atazanavir4 + ritonavir + emtricitabine2/tenofovir DF3
Darunavir + ritonavir (qd) + emtricitabine2/tenofovir DF3
INSTI
Raltegravir + emtricitabine2/tenofovir DF3
Slide: DHHS Guidelines: Preferred Regimens
On February 12, 2013, the DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents updated its recommendations and made specific regimen recommendations for treatment-naïve HIV-infected patients.1
- Preferred regimens provide optimal and durable efficacy, a favorable tolerability and toxicity profile, and ease of use.
Preferred regimens include:1
NNRTI: efavirenz/emtricitabine/tenofovir DF.
Boosted PI: atazanavir + ritonavir + emtricitabine/tenofovir DF, or darunavir + ritonavir (qd) + emtricitabine/tenofovir DF.
Integrase strand transfer inhibitors (ISTI): raltegravir + emtricitabine/tenofovir DF.
Pregnant women: lopinavir/r bid + zidovudine/lamivudine.
On October 30, 2013, the DHHS panel expanded the preferred regimen options to include elvitegravir- and dolutegravir-based regimens based on the results of phase 3 studies demonstrating these regimens were non-inferior to existing preferred regimens.2
References
Panel on Antiretroviral Guidelines for Adult and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. February 12, 2013; Available at:
Panel on Antiretroviral Guidelines for Adult and Adolescents. Recommendation on integrase inhibitor use in antiretroviral treatment-naïve HIV-infected individuals. October 30, Available at: Available at:
INSTI: Integrase strand transfer inhibitors.
1Efavirenz should not be used during the first trimester of pregnancy or in women trying to conceive or not using effective and
consistent contraception.
2Lamivudine may substitute for emtricitabine or visa versa.
3Tenofovir DF should be used with caution in patients with renal insufficiency.
4Atazanavir + RTV should not be used in patients who require >20 mg omeprazole equivalent/day.
5Patients with creatinine clearance >70 mL/min.
6Patients who are HLA-B*5701 negative.
DHHS. Available at:
Revision February 12, 2013.
DHHS. Available at:
Update October 30,2013.

21. DHHS Guidelines: Preferred Regimens – Oct 30 2013
NNRTI
Efavirenz1/emtricitabine2/tenofovir DF3 PI
Atazanavir4 + ritonavir + emtricitabine2/tenofovir DF3
Darunavir + ritonavir (qd) + emtricitabine2/tenofovir DF3
INSTI
Raltegravir + emtricitabine2/tenofovir DF3
Elvitegravir/cobicistat/emtricitabine/tenofovir DF5
Dolutegravir + abacavir/lamivudine6
Dolutegravir + emtricitabine/tenofovir DF
Slide: DHHS Guidelines: Preferred Regimens
On February 12, 2013, the DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents updated its recommendations and made specific regimen recommendations for treatment-naïve HIV-infected patients.1
- Preferred regimens provide optimal and durable efficacy, a favorable tolerability and toxicity profile, and ease of use.
Preferred regimens include:1
NNRTI: efavirenz/emtricitabine/tenofovir DF.
Boosted PI: atazanavir + ritonavir + emtricitabine/tenofovir DF, or darunavir + ritonavir (qd) + emtricitabine/tenofovir DF.
Integrase strand transfer inhibitors (ISTI): raltegravir + emtricitabine/tenofovir DF.
Pregnant women: lopinavir/r bid + zidovudine/lamivudine.
On October 30, 2013, the DHHS panel expanded the preferred regimen options to include elvitegravir- and dolutegravir-based regimens based on the results of phase 3 studies demonstrating these regimens were non-inferior to existing preferred regimens.2
References
Panel on Antiretroviral Guidelines for Adult and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. February 12, 2013; Available at:
Panel on Antiretroviral Guidelines for Adult and Adolescents. Recommendation on integrase inhibitor use in antiretroviral treatment-naïve HIV-infected individuals. October 30, Available at: Available at:
INSTI: Integrase strand transfer inhibitors.
1Efavirenz should not be used during the first trimester of pregnancy or in women trying to conceive or not using effective and
consistent contraception.
2Lamivudine may substitute for emtricitabine or visa versa.
3Tenofovir DF should be used with caution in patients with renal insufficiency.
4Atazanavir + RTV should not be used in patients who require >20 mg omeprazole equivalent/day.
5Patients with creatinine clearance >70 mL/min.
6Patients who are HLA-B*5701 negative.
DHHS. Available at:
Revision February 12, 2013.
DHHS. Available at:
Update October 30,2013.

22. DHHS Guidelines May 2014: Ten Recommended Regimens
NNRTI
Efavirenz/emtricitabine/tenofovir DF PI
Atazanavir + ritonavir + emtricitabine/tenofovir DF
Darunavir + ritonavir (QD) + emtricitabine/tenofovir DF
INSTI
Raltegravir + emtricitabine/tenofovir DF
Elvitegravir/cobicistat/emtricitabine/tenofovir DF
Dolutegravir + abacavir/lamivudine
Dolutegravir + emtricitabine/tenofovir DF
Additional options if the VL < 5 log:
Efavirenz + abacavir/lamivudine
Atazanavir + ritonavir + abacavir/lamivudine
Rilpivirine/tenofovir DF/emtricitabine (if CD4 count > 200/mm3)
INSTI: Integrase strand transfer inhibitors.
1Efavirenz should not be used during the first trimester of pregnancy or in women trying to conceive or not using effective and
consistent contraception.
2Lamivudine may substitute for emtricitabine or visa versa.
3Tenofovir DF should be used with caution in patients with renal insufficiency.
4Atazanavir + RTV should not be used in patients who require >20 mg omeprazole equivalent/day.
5Patients with creatinine clearance >70 mL/min.
6Patients who are HLA-B*5701 negative.
Slide: DHHS Guidelines: Preferred Regimens
On February 12, 2013, the DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents updated its recommendations and made specific regimen recommendations for treatment-naïve HIV-infected patients.1
- Preferred regimens provide optimal and durable efficacy, a favorable tolerability and toxicity profile, and ease of use.
Preferred regimens include:1
NNRTI: efavirenz/emtricitabine/tenofovir DF.
Boosted PI: atazanavir + ritonavir + emtricitabine/tenofovir DF, or darunavir + ritonavir (qd) + emtricitabine/tenofovir DF.
Integrase strand transfer inhibitors (ISTI): raltegravir + emtricitabine/tenofovir DF.
Pregnant women: lopinavir/r bid + zidovudine/lamivudine.
On October 30, 2013, the DHHS panel expanded the preferred regimen options to include elvitegravir- and dolutegravir-based regimens based on the results of phase 3 studies demonstrating these regimens were non-inferior to existing preferred regimens.2
References
Panel on Antiretroviral Guidelines for Adult and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. February 12, 2013; Available at:
Panel on Antiretroviral Guidelines for Adult and Adolescents. Recommendation on integrase inhibitor use in antiretroviral treatment-naïve HIV-infected individuals. October 30, Available at: Available at:
IAS-USA 2014 Guidelines concur on all ten Recommended Regimens
DHHS. Available at: Update May 2014

23. How Do We Choose from Among these Ten Options?
Drug Characteristics:
BID vs. QD (or less?)
Efficacy at any pre-treatment viral load and CD4 count
Food requirements
Number of pills per day (range 1-3)
Potential drug-drug interactions
Years of experience
Barrier to resistance if viremic
These could me minor and non-serious (bilirubin)

24. How Do We Choose from Among these Ten Options?
Patient Characteristics:
Pre-treatment virus resistance
Predicted Medication Adherence
Risk of Adverse Events
The rate of - and type of - adverse events
Type of evidence demonstrating the adverse event
Other medical comorbidities
CV, diabetes, renal, bone, psychological, and others
Financial Concerns
Patient copays, formulary restrictions, generics
Other?

25. Criteria that Are Not Considered when selecting a Regimen
Age
Beyond specific co-morbidity concerns
Gender
Race
Weight / BMI

26. D:A:D Study: Update on MI Risk and Abacavir Use
Prospective cohort ( )
N= >49,000 patients 11 cohorts in Europe, Australia, US
Abacavir use was associated with a 98% increase in rate of MI
No difference pre vs. post-2008
Results stable after stratifying by Framingham risk group, and other factors (eg, renal function, dyslipidemia, hypertension)
Current findings argue against channeling bias
Adjusted Relative MI Rate
and Current Abacavir Use
Pre
3/2008
Post
3/2008
Overall 5 4 3 2 1
0.7
1.98
1.97
1.97
Reference
No Abacavir
Slide: D:A:D Study: Update on MI Risk and Abacavir Exposure
Sabin and colleagues provided an update on the potential impact of abacavir exposure on MI risk on the prospective D:A:D cohort ( ), which includes over 49,000 HIV-positive patients from 11 cohorts in Europe, Australia, US.1
They found that from March 2008 to 2014, current abacavir use was associated with a 98% increase in MI rate, with no difference in MI risk that was detected prior to March These results remained unchanged after stratifying by Framingham risk group, as well as by other factors (eg, renal function, dyslipidemia, hypertension).1
The authors concluded that the current findings argue against channeling bias since one would expect MI risk to decline among patients who had CVD risk being provided ART options that did not include abacavir.1
Reference
Sabin C, Reiss P, Ryom L, et al. Is there continued evidence for an association between abacavir and myocardial infarction risk?. Program and abstracts of the 21st Conference on Retroviruses and Opportunistic Infections; March 3-6, 2013; Boston, MA. Abstract 747LB.
Not on abacavir
Events/PYs
Rate/PYs (95% CI)
600/2,95,642
0.20
(0.19, 0.22)
425/169,417
0.25
(0.23, 0.28)
175/126,225
0.14
(0.12, 0.16)
On abacavir
341/71,917
0.47
(0.42, 0.52)
247/40,833
0.61
(0.53, 0.68)
94/31,084
0.30
(0.24, 0.36)
PY: person-years.
Sabin CA, et al. 21st CROI. Boston, Abstract 747LB.

27. STaR Adverse Events Leading to Discontinuation of EFV/FTC/FTC through Weeks 48 & 96
EFV/FTC/TDF
(n=392)
Baseline-
Week 48
Week 48-
Week 96
Discontinuations* Due to AE, n (%)
34 (9%)
+9 (2.3%)
AE leading to discontinuation in >1 subject in either arm
Nervous System Disorders
7 (1.8%)
+1 (0.3%)
Dizziness
5 (1.3%)
Psychiatric Disorders
18 (5%)
+6 (1.5%)
Abnormal Dreams/Nightmares
6 (1.5%)
Insomnia
3 (0.8%)
Depression
+4 (1%)
Anxiety
2 (0.5%) +0
Suicidal Ideation
GI, General, Skin Disorders
15 (4%)
Diarrhea
Fatigue
Pyrexia
Toxic Skin Eruption
Table \
Note: depression contains depressed mood category as well
Cohen C, et al. EACS Brussels 2013, LBPE7/17

28. Efavirenz and Time to Suicidality Primary Analysis
Hazard ratio (95% CI)
2.28 (1.27 to 4.10), p=0.006
EFV: 47 events/5817 PY*
(8.08/1000 PY)
No EFV: 15 events/4099 PY*
(3.66/1000 PY)
As-treated HR
2.16 ( )
*Person Years, sum of at-risk follow-up
Mollan K, et al. IDWeek San Francisco, CA. #670.

29. ACTG 5257: Study Design
HIV-infected patients, ≥18 yr, with no previous ART,
VL ≥ 1,000 c/mL at U.S. Sites
(N=1,809)
Randomized 1:1:1 to Open Label Therapy
Stratified by screening HIV-1 RNA level (≥ vs. <100,000 c/mL),
A5260s metabolic substudy participation, cardiovascular risk
RAL 400 mg BID + FTC/TDF QD (N=603)
ATV 300 mg QD + RTV 100 mg QD + FTC/TDF QD (N=605)
DRV 800 mg QD + RTV 100 mg QD + FTC/TDF QD (N=601)
Primary Endpoints*
Time to HIV-1 RNA >1000 c/mL wk 16 to before wk 24, or >200 c/mL at or after wk 24 (VF)
Time to discontinuation of randomized component for toxicity (TF)
Pre-planned Composite Endpoint
The earlier occurrence of either VF or TF in a given participant
Landovitz L, et al. 21st CROI; Boston, MA; March 3-6, Abst. 85.

30. ACTG 5257: Toxicity Associated Discontinuation
RAL (N=603)
DRV/r (N=601)
ATV/r (N=605)
Any Toxicity Discontinuation
8 (1%)
32 (5%)
95 (16%)
Gastrointestinal Toxicity 2 14 25
Jaundice/Hyperbilirubinemia 47
Other Hepatic Toxicity 1 5 4
Skin Toxicity 7
Metabolic Toxicity 6
Renal Toxicity (All Nephrolithiasis)
Abnormal Chem/Heme (Excl. LFTs)
Other Toxicity 3
Landovitz L, et al. 21st CROI; Boston, MA; March 3-6, Abst. 85.

31. All patients received emtricitabine/tenofovir DF.
ACTG A5257 Study: Outcomes
All patients received emtricitabine/tenofovir DF.
RAL
(n=603)
DRV/r
(n=601)
ATV/r
(n=605)
Combined virologic or tolerability endpoint (%) 1 5 16
Week 96
HIV RNA
<50 copies/mL (%)
CD4 gain (cells/mm3) 94
288 89
256 88
284
Any resistance(%) 3
<1
1.5
Slide: ACTG A5257 Study: Comparison of Non-Efavirenz ART
All 3 arms had equivalent virologic efficacy, however the atazanavir/r arm was less well tolerated, largely due to cosmetic hyperbilirubinemia.1
Raltegravir was superior to both PI/r regimens for combined tolerability + virologic efficacy and darunavir/r was superior to atazanavir/r.1
The mergence of virologic failure with resistance was rare, but when it did happen it was more frequent with raltegravir.1
Reference
Landovitz RJ, Ribaudo HJ, Ofotokun I, et al. Efficacy and tolerability of atazanavir, raltegravir, or darunavir with FTC/tenofovir: ACTG Program and abstracts of the 21st Conference on Retroviruses and Opportunistic Infections; March 3-6, 2013; Boston, MA. Abstract 85.
Landovitz RJ, et al. 21st CROI. Boston, Abstract 85.

32. DHHS Guidelines: Preferred Regimens
NNRTI
Efavirenz1/emtricitabine2/tenofovir DF3 PI
Atazanavir4 + ritonavir + emtricitabine2/tenofovir DF3
Darunavir + ritonavir (qd) + emtricitabine2/tenofovir DF3
INSTI
Raltegravir + emtricitabine2/tenofovir DF3
Elvitegravir/cobicistat/emtricitabine/tenofovir DF5
Dolutegravir + abacavir/lamivudine6
Dolutegravir + emtricitabine/tenofovir DF
Which Integrase Inhibitor?
Slide: DHHS Guidelines: Preferred Regimens
On February 12, 2013, the DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents updated its recommendations and made specific regimen recommendations for treatment-naïve HIV-infected patients.1
- Preferred regimens provide optimal and durable efficacy, a favorable tolerability and toxicity profile, and ease of use.
Preferred regimens include:1
NNRTI: efavirenz/emtricitabine/tenofovir DF.
Boosted PI: atazanavir + ritonavir + emtricitabine/tenofovir DF, or darunavir + ritonavir (qd) + emtricitabine/tenofovir DF.
Integrase strand transfer inhibitors (ISTI): raltegravir + emtricitabine/tenofovir DF.
Pregnant women: lopinavir/r bid + zidovudine/lamivudine.
On October 30, 2013, the DHHS panel expanded the preferred regimen options to include elvitegravir- and dolutegravir-based regimens based on the results of phase 3 studies demonstrating these regimens were non-inferior to existing preferred regimens.2
References
Panel on Antiretroviral Guidelines for Adult and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. February 12, 2013; Available at:
Panel on Antiretroviral Guidelines for Adult and Adolescents. Recommendation on integrase inhibitor use in antiretroviral treatment-naïve HIV-infected individuals. October 30, Available at: Available at:
INSTI: Integrase strand transfer inhibitors.
1Efavirenz should not be used during the first trimester of pregnancy or in women trying to conceive or not using effective and
consistent contraception.
2Lamivudine may substitute for emtricitabine or visa versa.
3Tenofovir DF should be used with caution in patients with renal insufficiency.
4Atazanavir + RTV should not be used in patients who require >20 mg omeprazole equivalent/day.
5Patients with creatinine clearance >70 mL/min.
6Patients who are HLA-B*5701 negative.
DHHS. Available at:
Revision February 12, 2013.
DHHS. Available at:
Update October 30,2013.

33. DHHS Guidelines May 2014: Ten Recommended Regimens
NNRTI
Efavirenz/emtricitabine/tenofovir DF PI
Atazanavir + ritonavir + emtricitabine/tenofovir DF
Darunavir + ritonavir (QD) + emtricitabine/tenofovir DF
INSTI
Raltegravir + emtricitabine/tenofovir DF
Elvitegravir/cobicistat/emtricitabine/tenofovir DF
Dolutegravir + abacavir/lamivudine
Dolutegravir + emtricitabine/tenofovir DF
Additional options if the VL < 5 log:
Efavirenz + abacavir/lamivudine
Atazanavir + ritonavir + abacavir/lamivudine
Rilpivirine/tenofovir DF/emtricitabine (if CD4 count > 200/mm3)
INSTI: Integrase strand transfer inhibitors.
1Efavirenz should not be used during the first trimester of pregnancy or in women trying to conceive or not using effective and
consistent contraception.
2Lamivudine may substitute for emtricitabine or visa versa.
3Tenofovir DF should be used with caution in patients with renal insufficiency.
4Atazanavir + RTV should not be used in patients who require >20 mg omeprazole equivalent/day.
5Patients with creatinine clearance >70 mL/min.
6Patients who are HLA-B*5701 negative.
Slide: DHHS Guidelines: Preferred Regimens
On February 12, 2013, the DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents updated its recommendations and made specific regimen recommendations for treatment-naïve HIV-infected patients.1
- Preferred regimens provide optimal and durable efficacy, a favorable tolerability and toxicity profile, and ease of use.
Preferred regimens include:1
NNRTI: efavirenz/emtricitabine/tenofovir DF.
Boosted PI: atazanavir + ritonavir + emtricitabine/tenofovir DF, or darunavir + ritonavir (qd) + emtricitabine/tenofovir DF.
Integrase strand transfer inhibitors (ISTI): raltegravir + emtricitabine/tenofovir DF.
Pregnant women: lopinavir/r bid + zidovudine/lamivudine.
On October 30, 2013, the DHHS panel expanded the preferred regimen options to include elvitegravir- and dolutegravir-based regimens based on the results of phase 3 studies demonstrating these regimens were non-inferior to existing preferred regimens.2
References
Panel on Antiretroviral Guidelines for Adult and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. February 12, 2013; Available at:
Panel on Antiretroviral Guidelines for Adult and Adolescents. Recommendation on integrase inhibitor use in antiretroviral treatment-naïve HIV-infected individuals. October 30, Available at: Available at:
Alternatives to TDF/FTC or ABC/3TC?
IAS-USA 2014 Guidelines concur on all ten Recommended Regimens
DHHS. Available at: Update May 2014

34. GARDEL Study: Study Design
Stratified by Screening HIV RNA (≤ or > 100,000 copies/mL)
Week 48 Primary Endpoint
ARV- naive patients
≥18 years
HIV RNA >1,000 copies/mL No IAS-USA defined NRTI or PI resistance at screening
HB(s)Ag negative (N=426)
Dual Therapy (DT): LPV/r 400/100 mg BID
+ 3TC 150 mg BID (n=217)
Triple Therapy (TT): LPV/r 400/100 mg BID + 3TC or FTC and a third investigator-selected NRTI in fixed-dose combination (n=209)
Cahn P et al. 14th EACS; Brussels, Belgium; October 16-19, Abst. LBPS7/6.

35. GARDEL Study: Primary Efficacy Outcome
VL <50 copies/mL (ITTe)
88.3
83.7
P=0.171, difference +4.6% [Cl 95%: -2.2% to +11.8%]
Percent Patients
Week
Week 48 <50 copies/mL
Observed (n=373) DT
95.5% TT
96.6%
-1.1%;
[-5.6% to 3.4%]
P=0.777
Cahn P et al. 14th EACS; Brussels, Belgium; October 16-19, Abst. LBPS7/6.

36. So – How do we Pick?

37. Impacting Adherence A Role for Simplification
Three types of Supportive Data:
Pt. preference
Small Randomized Trials
Large cohort analyses of adherence and outcomes

38. Comparing Regimens: Copays and Numbers of Pills
Ordered by numbers of copays, then by pills per day
Alphabetically when identical in both
Regimen
Schedule
# Copays
Pills Per Day
TDF/FTC/EFV QD 1
TDF/FTC/EVG/cob
TDF/FTC/RPV
2 NRTI + DTG 2
2 NRTI + RAL
BID 3
2 NRTI + ATV/r
2 NRTI + DRV/r

39. Comparing Regimens: Copays and Numbers of Pills
Ordered by numbers of copays, then by pills per day
Alphabetically when identical in both
Regimen
Schedule
# Copays
Pills Per Day
$ per month AWP
TDF/FTC/EFV QD 1
2402
TDF/FTC/EVG/cob
2948
TDF/FTC/RPV
2463
2 NRTI + DTG 2
2900
2 NRTI + RAL
BID 3
2800
2 NRTI + ATV/r
3200
2 NRTI + DRV/r

40. Comparing Regimens: Copays and Numbers of Pills – End 2014?
Ordered by numbers of copays, then by pills per day
Alphabetically when identical in both
Regimen
Schedule
# Copays
Pills Per Day
TDF/FTC/EFV QD 1
TDF/FTC/EVG/cob
TDF/FTC/RPV
2 NRTI + DTG
2 NRTI + RAL
BID 2 3
2 NRTI + ATV/r
2 NRTI + DRV/r

41. Economics: Antiretroviral Drugs Available in U. S
Economics: Antiretroviral Drugs Available in U.S. as a Generic Formulation
Abacavir
Didanosine
Lamivudine
Nevirapine
Stavudine
Zidovudine
Zidovudine/lamivudine

42. HOPS Cohort: Frequency of VL Monitoring and Risk of Treatment Failure
For virological suppressed patients observed on stable cART ≥2 years, the association between frequency of VL monitoring in period 2 and VL non-suppression in period 3
Period 1 (1 Year)
Period 2 (1 Year)
Period 3 (1 Year)
cART regimen initiation
cd4 VL
INDEX DATE:
Outcome (yes/no): VL >200 copies/mL
1,607 patients starting ART
After virologic suppression, 1,002 with VL monitoring > 2x/year, remainder had it done less frequently
Multivariable models: No increased risk of treatment failure with less frequent VL monitoring
Cost savings estimated to be $ /person/year
Data support DHHS Guidelines to reduce frequency of VL monitoring in those with virologic suppression for >2 years
Young B, et al. 20th IAC; Melbourne, Australia; July 20-25, 2014; Abst. WEPE045

43. Hepatitis C – Profound Progress

44. LDV/SOF: Phase 3 - HCV Mono Infection - ION-1, ION-2, ION-3
Week 0
Week 8
Week 12
Week 24
LDV/SOF + RBV
LDV/SOF
ION-12
ION-23
LDV/SOF + RBV
LDV/SOF
LDV/SOF + RBV
ION-34
LDV/SOF
ION-1: GT-1 HCV treatment-naïve,16% with cirrhosis; N = 865
ION-2: GT-1 HCV treatment-experienced, 20% with cirrhosis; N = 440
ION-3: GT-1 HCV treatment-naïve, without cirrhosis; N = 647
Sulkowski M, et al. 20th IAC; Melbourne, Australia; July 20-25, 2014; Abst. LBPE15.

45. Efficacy Summary (ITT)
LDV/SOF
LDV/SOF+RBV 99 97 98 99 94 93 95 94 96 99 99
SVR12 (%)
211/ 214
211/ 217
212/ 217
215/ 217
202/ 215
201/ 216
206/ 216
102/ 109
107/ 111
108/ 109
110/ 111
12 Weeks
24 Weeks
8 Weeks
12 Weeks
12 Weeks
24 Weeks
ION-1
GT-1 Treatment-naïve
Including Cirrhotics
ION-3
GT-1 Treatment-naïve
Non-cirrhotic
ION-2
GT-1 treatment-experienced
Including Cirrhotics and PI Failures
97% (1885/1952) overall SVR rate
3% (67/1952) did not achieve SVR
1.8% (36) relapsed
1.2% (23) lost to follow-up
0.3% (6) withdrew consent
0.1% (2) virologic breakthrough (both due to non-adherence)
Error bars represent 95% confidence intervals.
Sulkowski M, et al. 20th IAC; Melbourne, Australia; July 20-25, 2014; Abst. LBPE15.

46. NIAID SYNERGY: Sofosbuvir/Ledipisvir FDC Alone or In Combination with GS-9451 or GS-9669
Treatment naïve, genotype 1 infected patients
African American, 88%
Virologic response:
SOF/LDV x 12 wks (n=20)
SVR12 100%
SOF/LDV/9669 x 6 wks (n=20)
SVR4 90%; Relapse, n=1
SOF/LDV/9451 x 6 wks (n=20)
SVR4 100%
No discontinuation or SAE
Kohli A, et al. 64th AASLD; Washington, DC; November 1-5, Abstract LB-8.

47. Standard of Care for Treatment of Chronic HCV Infection? – by End 2014
Genotype
Regimen
Duration
Considerations
GT 2
Sofosbuvir 400 mg QD + RBV 1000 or 1200 mg/day in 2 divided doses BID
12 weeks
GT 3
24 weeks
Some data to support addition of PegIFN
GT 1
Sofosbuvir 400 mg QD + Ledipasvir 90 mg QD (FDC) 12
Phase 3 trials are complete
[ABT-450/r + ABT-267] (FDC) QD + ABT-333 BID ± RBV BID
Jacobson IM et al. 64th AASLD; Washington, DC; November 1-5, 2013; Abstract LB-3. (B)

48. “…may HIV flow from our blood into our history books…”
Stalemate? Or a Cure?
“…may HIV flow from our blood into our history books…”
- William Jefferson Clinton
10th Retrovirus Conf.
Boston 2003 48

49. Summary and Conclusion

51. No virologic failures observed with FOTO schedule
QD plus PK Cushion in virologically suppressed Pts: FOTO: 48 Week Results
*FOTO = TDF/FTC/EFV - five days on / two days off treatment per week
N=60
On TDF / FTC / EFV
HIV RNA<50 X 6 months
All drugs fully active
Change to FOTO*
N=30
Continue FOTO*
N=23
TDF/FTC/EFV QD
N=30
Rollover to FOTO*
N=27
The FOTO (Five-days ON, Two-days Off) dosing schedule takes advantage of the long half-lives and overall phamacokinetics of a regimen consisting of tenofovir DF (TDF), emtricitabine (FTC) and efavirenz EFV).
In this study, 60 patients, all virologically controlled on TDF/FTC/EFV and without prior history of virologic failure were equally randomized to continue the same regimen once-daily or on a FOTO dosing schedule. At 24 weeks all patients in the FOTO dosing schedule were amble to maintain an undetectable viral load (<50 copies/mL). [Data presented at EACS 2008, Cohen C, et al. HIV-9 (2008), Abst. O214].
After 24 weeks, 23 of the 30 patients in the FOTO arm continued the extension phase of the study; and on the QD arm, 27 of the 30 rollover to the FOTO dosing schedule for an additional 24 weeks.
24 wk
Extension/rollover
48 wk
No virologic failures observed with FOTO schedule
Cohen C, et al. 5th IAS; Cape Town, South Africa; July 19-22, 2009; Abst. MOPEB063. 51 51

52. Rising Need for Polypharmacy
Projected Use of Co-medications
Smit M, et al. 20th IAC; Melbourne, Australia; July 20-25, 2014; Abst. MOPE107.