1. Coping with Hope 2016 Medical Update
Derrick Butler MD,MPH
Associate Medical Director
To Help Everyone Health and Wellness Centers
Assistant Professor
Charles Drew University
Los Angeles, CA

2. Medical Update Big Picture Antiretroviral Treatment Prevention
Mental Health Review
Epidemiology

3. Coping with….

4. Hope

5. Mortality and HAART Over Time
90%
Deaths per 100 Person-Years 8 7 6 5 4 3 2 1
80%
70%
60%
50%
Patients on HAART
40%
30%
20%
Objective
Communicate the efficacy of HAART by examining its relationship to mortality over time
Support
In 1996, after the introduction of HAART, the rate of deaths from AIDS in the United States began to drop
Transition
We’ve seen what HAART does on a cumulative level; now let’s look at an example of how it might affect an individual’s disease progression
10%
% of patients on HAART
Deaths per 100 person-years
1996
1997
1998
1999
2000
2001
2002
2003
2004
Time
Reference: Palella FJ Jr, Baker RK, Moorman AC, et al; and HIV Outpatient Study Investigators. Mortality in the highly active antiretroviral therapy era: changing causes of death and disease in the HIV outpatient study.
J Acquir Immune Defic Syndr. 2006;43:27-34. 5 5 5

6. Narrowing the Gap in Life Expectancy Between HIV-Positive and Uninfected Persons
Average Life Expectancy Remaining At Age 20 Years
HIV positive 62 62 54 49
Life Expectancy (years) 36
Slide: Narrowing the Gap in Life Expectancy Between HIV-Positive and Uninfected Persons
Marcus and colleagues conducted a cohort study of HIV-infected adults who were members of Kaiser Permanente California during and HIV-uninfected members matched 10:1 on age, gender, medical center, and year. Deaths were comprehensively ascertained through 2011 from the electronic health record, California death certificates, and Social Security Administration datasets. Abridged life tables were used to estimate the average number of years of life remaining at age 20 years (“life expectancy at age 20”) in HIV-infected and HIV-uninfected individuals in and For the recent era, we estimated life expectancy at age 20 years by demographics and HIV risk group.1
Overall, life expectancy remaining after an HIV diagnosis at age 20 years increased from 36 to 49 years from to HIV-infected patients who had the largest gains in life expectancy were those who initiated ART with CD4 >500 cells/mm3.1
Reference
Marcus JL, Chao C, Leyden W, et al. Narrowing the gap in life expectancy for HIV+ compared with HIV- individuals. Program and abstracts from the 23rd Conference on Retroviruses and Opportunistic Infection; February 22-25, 2016; Boston, MA. Abstract 54.
Overall
HIV Negative
Overall
CD4 >500*
HIV Negative
*CD4 (cells/mm3) at time of starting ART.
Kaiser Permanente Northern California (1996 to 2011):
HIV-positive (n=25,768) and matched non-HIV-infected adults (n=257,600). Males (91%) and MSM (75%).
Marcus JL, et al. 23rd CROI. Boston, Abstract 54.

7. KP: Factors Contributing to Reduced Life Expectancy With HIV (2008-11)
Expected Yrs of Life Remaining at Age 20 Yrs
HIV Infected and Began ART With CD4+ ≥ 500 cells/mm3
HIV Uninfected
Difference
(95% CI)
Overall
54.5
62.3
7.9 ( )
No HBV or HCV
55.4
62.6
7.2 ( )
No drug or alcohol abuse
57.2
63.8
6.6 ( )
No smoking
58.9
64.3
5.4 ( )
None of the above
59.2
65.0
5.7 ( )
ART, antiretroviral therapy; HBV, hepatitis B virus; HCV, hepatitis C virus; KP, Kaiser Permanente.
The next slide looks at life expectancy at age 20 for people who began ART with CD4+ cell counts > 500. If you get rid of factors, like if there's no HBV or HCV, then life expectancy is a little longer. Then if you get rid of drug and alcohol abuse, it's a little bit longer, and if you don’t smoke it’s even longer. And if you have none of the above, although it doesn't quite reach the same as HIV-uninfected people, it does get quite a bit closer, arguing for healthy lifestyle and starting therapy earlier.
Slide credit: clinicaloptions.com
Marcus JL, et al. CROI Abstract 54. Reproduced with permission.

8. Antiretroviral Treatment
DHHS Guidelines
New Safer Regimens-TAF
Investigational Agents

9. START: Immediate vs Deferred Therapy for Asymptomatic, ART-Naive Pts
International, randomized phase IV study involving 215 sites in 35 countries
Serious AIDS and Non-AIDS Events, n
Treatment-naive
pts with CD4+ count > 500 cells/mm³
(N = 4685)
Immediate ART
(n = 2326) 42
Delayed ART (until CD4+ ≤ 350 cells/mm³)
(n = 2359) 96
Study stopped by DSMB following results of interim analysis
Overall HR: 0.43 (P < .001)
HR for serious AIDS-related events: 0.28 (P < .001) HR for non-AIDS–related events: 0.61 (P = .04)
Similar HIV-1 RNA suppression rates 12 mos after starting ART in both arms (immediate: 98%; delayed: 97%)
ART, antiretroviral therapy; DSMB, data and safety monitoring board.
Slide credit: clinicaloptions.com
Lundgren JD, et al. N Engl J Med. 2015;373:

10. DHHS GUIDELINES

11. DHHS Treatment Guidelines

12. New DHHS Recommendations

13. Reducing Toxicity, increasing Long Term Safety
tenofovir alafenamide (TAF)
New pro drug of Tenofovir
Co– formulated in multiple combination tablets
Multiple analyses vs. pro-drug Tenofovir Disoproxil Fumarate (TDF)

14. No HBV or HCV coinfection
Study 1089: Switch to F/TAF From F/TDF-Based Regimen in Virologically Suppressed Patients
Phase 3
(Double-Blind,
Double-Dummy)
TDF-based regimen*
HIV RNA <50 copies/mL
eGFR >50 mL/min
No HBV or HCV coinfection
Randomization
1:1
Switch to F/TAF qd +
Continue 3rd Agent (n=333)
F/TDF qd +
Continue 3rd Agent (n=330)
Week 48
Primary Endpoint
HIV RNA <50 copies/mL
Slide: Study 1089: Switch to F/TAF From F/TDF-Based Regimen in Virologically Suppressed Patients
Gallant and colleagues conducted a 96-week randomized, double-blind, phase 3 study in virologically suppressed HIV-1 infected patients receiving emtricitabine/tenofovir DF (F/TDF)-containing ART to evaluate the efficacy and safety of switching from F/TDF to emtricitabine/tenofovir AF (F/TAF) versus continuing F/TDF while remaining on the same third agent.1
The primary endpoint was virologic success at week 48 by ITT FDA snapshot algorithm with a pre-specified noninferiority margin of 10%.1
Reference
Gallant JE, Daar E, Raffi F, et al. Switching tenofovir DF to tenofovir alafenamide in virologically suppressed adults. Program and abstracts from the 23rd Conference on Retroviruses and Opportunistic Infection; February 22-25, 2016; Boston, MA. Abstract 29.
*Includes boosted PI or unboosted 3rd agents.
F: emtricitabine; TAF: emtricitabine/tenofovir alafenamide; TDF: tenofovir DF.
Dose of F/TAF: with boosted PIs (200/10 mg), unboosted 3rd agent (200/25 mg).
Non-inferiority margin: 10% (based on week 48 FDA snapshot analysis of percentage of patients with HIV RNA <50 copies/mL).
Baseline characteristics:
Median age: 48 years.
Male: 85%.
Black race/ethnicity: 21%.
Median CD4 count: cells/mm3.
Median eGFR: mL/min.
Boosted PI: 46%.
Unboosted 3rd agent: 54%.
Gallant JE, et al. 23rd CROI. Boston, Abstract 29.

15. Virologic Outcomes (Week 48) Treatment Difference:
Study 1089: Switch to F/TAF From F/TDF-Based Regimen in Virologically Suppressed Patients
HIV RNA <50 copies/mL at week 48
Switching to F/TAF met non-inferiority criteria versus F/TDF
Similar results regardless of 3rd agent in regimen, age (<50 and >50 years of age), sex, and race (black and non- black)
Safety following switch to F/TAF
Similar rates of discontinuations due to adverse events (1%-2%)
Significant and rapid improvements compared with F/TDF in
Proteinuria and tubular proteinuria (P<0.001)
Median change in eGFR (+8.4 versus mL/min; P<0.001)
Virologic Outcomes (Week 48)
Treatment Difference:
1.3% (-2.5, 5.1)
94%
93%
F/TAF (n=333)
F/TDF (n=330)
Slide: Study 1089: Switch to F/TAF From F/TDF-Based Regimen in Virologically Suppressed Patients
At week 48, switching to F/TAF met non-inferiority criteria versus F/TDF with regard to achieving HIV RNA <50 copies/mL. Similar results were seen regardless of 3rd agent in regimen, age (< and >50 years of age), sex, and race (black and non-black).1
Switch to F/TAF was generally well tolerated with similar rates of discontinuations due to adverse events compared with the F/TDF arm (1%-2%). In the F/TAF switch arm, there was a significant and rapid improvement compared with F/TDF in proteinuria and tubular proteinuria (P<0.001) as well as median change in eGFR (+8.4 versus +2.8 mL/min; P<0.001).1
Reference
Gallant JE, Daar E, Raffi F, et al. Switching tenofovir DF to tenofovir alafenamide in virologically suppressed adults. Program and abstracts from the 23rd Conference on Retroviruses and Opportunistic Infection; February 22-25, 2016; Boston, MA. Abstract 29.
Patients (%)
5.4%
5.5%
0.3%
1.5%
HIV RNA
<50 Copies/mL
Failure
No Data
All patients also received either a boosted PI or an unboosted 3rd agent.
Gallant JE, et al. 23rd CROI. Boston, Abstract 29.

16. GS-1089: Renal Outcomes With Switch From TDF- to TAF-Containing ART
No proximal renal tubulopathy or Fanconi syndrome in either arm
TAF
TDF
TAF
TDF
Urine Protein-to-Creatinine Ratio 40 20
Protein
Albumin
RBP
β2-M
P < .001
22.0
18.2 20
8.4
12.3 10
7.7
Median eGFR Change (mL/min)
Median % Change at Wk 48
β2-M, β2-microglobulin; eGFR, estimated glomerular filtration rate; RBP, retinol-binding protein; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil.
And then, this is the renal outcomes. You can see, with TAF, these patients actually had a significant but modest increase in eGFR vs continuing on TDF. This is not percent change but actual change in mLs per minute of 8.4 vs 2.8. And then, if you look at the urine protein excretion, you can see, with TAF, there's improvement in proteinuria, albuminuria, and retinal binding protein and β2-microglobulin that are specifically absorbed by the proximal tubule, while on tenofovir there's a continued increase in the proteinuria.
2.8
-7.7
-20
-14.6
-16.3
P < .001
P < .001
P < .001
-10
-40 12 24 36 48
-39.6
P < .001 Wk
Slide credit: clinicaloptions.com
Gallant JE, et al. CROI Abstract 29. Reproduced with permission.

17. Study 1089: Changes in Spine and Hip BMD Following Switch to F/TAF in Virologically Suppressed Patients
Spine BMD
Hip BMD
F/TAF (n=321)
F/TDF (n=320)
F/TAF (n=321)
F/TDF (n=317)
1.5
1.1
P<0.001
P<0.001
Mean Change (%)
Mean Change (%)
-0.2
Slide: Study 1089: Changes in Spine and Hip BMD Following Switch to F/TAF in Virologically Suppressed Patients
Bone mineral density increased in the F/TAF group but declined in the F/TDF group:1
Spine: 1.5% versus -0.2% (P<0.001).
Hip: 1.1% versus -0.2% (P<0.001).
Reference
Gallant JE, Daar E, Raffi F, et al. Switching tenofovir DF to tenofovir alafenamide in virologically suppressed adults. Program and abstracts from the 23rd Conference on Retroviruses and Opportunistic Infection; February 22-25, 2016; Boston, MA. Abstract 29.
-0.2
Treatment Week
Treatment Week
All patients also received either a boosted PI or an unboosted 3rd agent.
Gallant JE, et al. 23rd CROI. Boston, Abstract 29.

18. Study 112: Switch to E/C/F/TAF in Patients With Renal Impairment
Phase 3 study
(144 weeks)
Treatment-experienced
Open-label
HIV RNA <50 copies/mL
eGFR mL/min
Switch to E/C/F/TAF
(n=242)
Primary Endpoint
Week 24
Change From
Baseline in eGFR
Week 96 Analysis
E/C/F/TAF: elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide.
TAF 10 mg.
Pre-switch ART regimens:
NRTI: tenofovir DF (65%), abacavir (22%), other (7%), none (5%).
Third agent (some regimens included >1 third agent): PI (44%), NNRTI (42%), INSTI (24%), CCR5 antagonist (3%).
Baseline characteristics (GFR:<50/>50 mL/min):
Median age: 59/58 years.
Hypertension: 50%/34%.
Diabetes: 15%/13%.
Median CD4: 622/635 cells/mm3.
Median eGFR: 43/60 mL/min.
Dipstick proteinuria grade:
1+: 29%/20%
2+-3+: 15%/7%.
4+: none.
Slide: Study 112: Switch to E/C/F/TAF in Patients With Renal Impairment
Post and colleagues evaluated the safety and efficacy of a once-daily single tablet regimen of elvitegravir/cobicistat/emtricitabine/TAF in HIV-infected patients with mild to moderate renal impairment. Virologically suppressed adults with stable renal impairment (eGFR mL/min) had their treatment switched from both TDF- and non-TDF-containing regimens to open-label elvitegravir/cobicistat/emtricitabine/TAF.1,2
The primary endpoint was the week 24 change in eGFR.1,2
References
Pozniak A, Arribas JR, Gathe J, et al. Switching to tenofovir alafenamide, coformulated with elvitegravir, cobicistat, and emtricitabine, in HIV-infected patients with renal impairment: 48 week results from a single-arm, multi-center, open-label, Phase 3 study. J Acquir Immune Defic Syndr. 2015;Nov 30. [Epub ahead of print].
Post FA, Tebas P, Clarke A, et al. Longer-term safety of tenofovir alafenamide in renal impairment. Program and abstracts from the 23rd Conference on Retroviruses and Opportunistic Infection; February 22-25, 2016; Boston, MA. Abstract 680.
Pozniak A, et al. JAIDS. 2015;Nov 30. [Epub ahead of print].
Post FA, et al. 23rd CROI. Boston, Abstract 680.

19. Median Change in eGFR (CKD-EPI Cr) Median Change in eGFR (mL/min)
Study 112: Week 96 Changes After Switch to E/C/F/TAF in Patients With Renal Impairment
Median eGFR change after E/C/F/TAF switch
CKD-EPI Cr: 1.0 mL/min (n=158)
CKD-EPI CysC: 3.9 mL/min (n=157)
Significant improvements after E/C/F/TAF switch (P<0.05)
Proteinuria
Renal tubular function
Spine and hip bone mineral density
Maintained HIV RNA <50 copies/mL: 88%
Virologic failure: 2% (5/242)
No virologic data: 10% (23/242)
These 96-week data support the renal and bone safety of E/C/F/TAF in HIV patients with renal impairment (eGFR mL/min)
Median Change in eGFR (CKD-EPI Cr)
Baseline eGFR (mL/min)
>60 (n=76) (n=24)
51-60 (n=78) <30 (n=10)
41-50 (n=54)
Median Change in eGFR (mL/min)
Slide: Study 112: Week 96 Changes After Switch to E/C/F/TAF in Patients With Renal Impairment
At week 96, switching to E/C/F/TAF maintained viral suppression and was associated with stable eGFR and significant improvements in proteinuria, renal tubular function, and spine and hip BMD.1
Reference
Post FA, Tebas P, Clarke A, et al. Longer-term safety of tenofovir alafenamide in renal impairment. Program and abstracts from the 23rd Conference on Retroviruses and Opportunistic Infection; February 22-25, 2016; Boston, MA. Abstract 680.
Week
Post FA, et al. 23rd CROI. Boston, Abstract 680.

20. Studies 104 and 111: Post-Hoc Analysis E/C/F/TAF in Patients at High Risk for Chronic Kidney Disease
Randomization
1:1
E/C/F/TAF qd
CKD Risk: High (n=246); Low (n=620)
Phase 3
(2 trials combined)
Treatment-naive
HIV RNA >1000 copies/mL
eGFR >50 mL/min
No HBV or HCV coinfection
E/C/F/TDF qd
CKD Risk: High (n=274); Low (n=593)
Week
E/C/F: elvitegravir/cobicistat/emtricitabine.
TAF: tenofovir alafenamide 10 mg; TDF: tenofovir DF 300 mg.
High risk of CKD (>2 risk factors). Low risk of CKD (<1 risk factor).
Baseline risk factors:
Black race: 25%-26%.
Female sex: 15%.
Any NSAID use: 16%-17%.
Hypertension: 14%-17%.
CD4 <200 cells/mm3: 13%-14%.
Hyperlipidemia: 11%-12%.
Age >50 years: 10%-13%.
Diabetes: 3%-5%.
Slide: Studies 104 and 111: Post-Hoc Analysis E/C/F/TAF in Patients at High-Risk for Chronic Kidney Disease
Studies 104 and 111 are 2 phase 3 studies of identical design comparing 2 single-tablet regimens, elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) and E/C/F/tenofovir DF (E/C/F/TDF), in treatment-naïve HIV-positive adults. Patients were randomized 1:1 to receive a single-tablet regimen of E/C/F/TAF or E/C/F/TDF once daily.1,2
The primary endpoint was week 48 virologic response by FDA snapshot algorithm in a pre-specified analysis of the combined studies.1,2
References
Sax PE, Saag MS, Yin MT, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate, coformulated with elvitegravir, cobicistat, and emtricitabine, for initial treatment of HIV-1 infection: two randomised, double-blind, phase 3, non-inferiority trials. Lancet. 2015;385:
Wohl D, Thalme A, Finlayson R, et al. Renal safety of tenofovir alafenamide in patients at high risk of kidney disease. Program and abstracts from the 23rd Conference on Retroviruses and Opportunistic Infection; February 22-25, 2016; Boston, MA. Abstract 681.
Sax PE, et al. Lancet. 2015;385:
Wohl D, et al. 23rd CROI. Boston, Abstract 681.

21. Studies 104 and 111: Long-Term Renal Safety of E/C/F/TAF
TAF versus TDF
Significantly smaller decreases in eGFR (P<0.001)
Significantly less proteinuria, albuminuria, and tubular proteinuria (P<0.001)
Acute kidney injury (>50% decline in eGFR)
TAF versus TDF: 0.3% versus 1.3% (P=0.06)
No cases of tubulopathy/Fanconi syndrome in either arm
Fewer discontinuations due to renal adverse events in the TAF arm
TAF versus TDF: 0 (0%) versus 6 (0.7%)
Week 96 Change in eGFR
-2.0
P<0.001
Median Change (mL/min)
Slide: Studies 104 and 111: Long-Term Renal Safety of E/C/F/TAF
Rijnders and colleagues used data from studies 104 and 111 to assess renal biomarkers of renal function and clinically significant renal events among patients receiving E/C/F/TAF and E/C/F/TDF.
There was a significantly smaller decrease from baseline at week 96 in eGFR in the TAF arm compared with the TDF arm (P<0.001). In addition, the TAF arm had significantly less proteinuria, albuminuria, and tubular proteinuria (P<0.001).1
There were no cases of tubulopathy/Fanconi syndrome in either arm. There were no discontinuations due to renal adverse events in the TAF arm compared with 0.7% (6 cases) in the TDF arm.1
Reference
Rijnders BJ, Post FA, Rieger A, et al. Longer-term renal safety of tenofovir alafenamide vs tenofovir disoproxil fumarate. Program and abstracts from the 23rd Conference on Retroviruses and Opportunistic Infection; February 22-25, 2016; Boston, MA. Abstract 682.
-7.5
E/C/F/TAF
(n=866)
E/C/F/TDF
(n=867)
E/C/F: elvitegravir/cobicistat/emtricitabine.
TAF: tenofovir alafenamide; TDF: tenofovir DF.
Rijnders BJ, et al. 23rd CROI. Boston, Abstract 682.

22. The new pro drug Tenofovir Alafenamide (TAF) is less toxic to :
The liver
The brain
The bones
The kidneys
Both c and d
All of the above

23. Investigational Therapies
New Antiretrovirals
Doravirine
Cabotegravir

24. Doravirine NNRTI Potent Activity
Active against common NNRTI Resistance mutations
Once daily Dosing
No interaction with PPI
Less CNS effects than efavirenz

25. MK-1439-007: Doravirine + TDF/FTC vs EFV + TDF/FTC In Treatment-Naive Pts
Doravirine: investigational NNRTI with potent activity against common NNRTI resistance mutations, QD dosing, no PPI drug–drug interactions, improved CNS safety vs EFV in early studies
Part 2 of 2-part randomized, double-blind phase II study
Primary endpoint: HIV-1 RNA < 40 copies/mL at Wk 48
Wk 48
Wk 96
ART-naive HIV-infected pts with HIV-1 RNA ≥ 1000 copies/mL,
CD4+ cell count
≥ 100 cells/mm3
(N = 132)*
Doravirine 100 mg QD + TDF/FTC
(n = 66)
ART, antiretroviral therapy; CNS, central nervous system; EFV, efavirenz; FTC, emtricitabine; TDF, tenofovir disoproxil; PPI, proton pump inhibitor; QD, once daily.
This the phase IIb study of doravirine with TDF/FTC. This is a look at the dose that has gone forward in the phase III trials—so doravirine 100 mg with TDF/FTC compared to efavirenz 600 mg with TDF/FTC. And it's a double-blind, randomized phase II trial. The thing that's a little tricky on this slide is n = 66 in both arms, but in part 1 of the study, there were also 42 and 43 patients that had received doravirine at the 100-mg dose and efavirenz at the 600 mg (ie, the standard efavirenz dose), respectively, which will get included in the analysis.
Efavirenz 600 mg QD + TDF/FTC
(n = 66)
*42 pts receiving doravirine 100 mg QD + TDF/FTC and 43 pts receiving efavirenz 600 mg QD + TDF/FTC
in part 1 of this study were included in this analysis.
Slide credit: clinicaloptions.com
Gatell JM, et al. CROI Abstract 470.

26. HIV RNA <40 Copies/mL (Week 48) Baseline HIV RNA (copies/mL)
Study 007 (Parts 1 and 2 Combined): Doravirine Versus Efavirenz in ART-Naïve Patients
Phase 2b study (n=216)
HIV RNA >1000 copies/mL
CD4 >100 cells/mm3
Randomized arms
Doravirine 100 mg or efavirenz 600 mg + FTC/TDF
Non-success at week 48
Doravirine arm (n=18)
Efavirenz arm (n=14)
Discontinuations due to adverse events
Doravirine arm: 3%
Efavirenz arm: 6%
HIV RNA <40 Copies/mL (Week 48)
Doravirine
Efavirenz
87%
87%
84%
78%
79%
74%
Slide: Study 007 (Parts 1 and 2 Combined): Doravirine Versus Efavirenz in ART-Naïve Patients
Gatell and colleagues reported the week 48 efficacy and safety results from Study 007 for all patients who received doravirine 100 mg or efavirenz in part 1 (n=42 per group) and part 2 (n=66 per group) combined.1
Part 1 (dose selection): doravirine 25, 50, 100, and 200 mg.
Part 2 enrolled additional patients to receive doravirine 100 mg.
Doravirine 100 mg qd demonstrated antiretroviral activity and immunological effect similar to efavirenz (each with emtricitabine/tenofovir DF) and was generally safe and well tolerated during 48 weeks in treatment-naïve patients. There were significantly less discontinuations due to adverse events in the doravirine arm compared with the efavirenz arm.1
Reference
Gatell J-M, Raffi F, Plettenberg A, et al. Doravirine 100mg QD vs efavirenz +TDF/FTC in ART-naive HIV+ patients: week 48 results. Program and abstracts from the 23rd Conference on Retroviruses and Opportunistic Infection; February 22-25, 2016; Boston, MA. Abstract 470.
Patients (%)
Overall
(NC=F)
<100K
(OF)
>100K
(OF)
Baseline HIV RNA (copies/mL)
NC=F: non-completer=failure; OF: observed failure.
Gatell J-M, et al. 23rd CROI. Boston, Abstract 470.

27. MK-1439-007: Clinical Adverse Events
Clinical AEs, %
DOR + TDF/FTC
(n = 108)
EFV + TDF/FTC
Difference,
DOR–EFV (95% CI)
≥ 1 AE
87.0
88.9
-1.9 (-10.9 to 7.1)
Serious AEs
6.5
8.3
-1.9 (-9.5 to 5.6)
Death
D/c for AEs
2.8
5.6
-2.8 (-9.2 to 3.0)
Drug-related AEs*
31.5
56.5
-25.0 (-37.3 to 11.8)
Diarrhea
0.9
Nausea
7.4
Dizziness
25.9
Headache
Abnormal dreams
14.8
Insomnia
Nightmares
Sleep disorder
4.6
AE, adverse event; D/c, discontinuation; DOR, doravirine; EFV, efavirenz; FTC, emtricitabine; TDF, tenofovir disoproxil.
The next slide looks at adverse events for doravirine vs efavirenz, both with TDF/FTC. Not surprisingly, there are more drug-related adverse events with efavirenz. Interestingly, there was less diarrhea with doravirine. Diarrhea is not a side effect I think about from efavirenz, but the data are there for you to look at.
And then, in a separate in vitro analysis, they looked at doravirine in vitro activity against a variety of NNRTI-containing viruses and showed that doravirine was very active against 103N, 181C, and viruses with both mutations. And then, they did a selection experiment, and again for those 3 variants, which are the most common transmitted variants, you didn't see any breakthrough in a serial passage study, whereas, if you use rilpivirine or efavirenz at clinically relevant concentrations, obviously you saw evolution of further resistance.
*Specific AEs occurring in ≥ 5% of pts included.
Slide credit: clinicaloptions.com
Gatell JM, et al. CROI Abstract 470. Reproduced with permission.

28. Cabotegravir Integrase Inhibitor Potent Activity Oral preparation
Nanosuspension (long acting) IM Preparation
Does not require boosting
Side effects: injection site reaction and headache

29. LATTE-2: Cabotegravir + Rilpivirine as Long-Term Maintenance Therapy
Maintenance Phase
Cabotegravir 400 mg + Rilpivirine 600 mg
IM every 4 weeks (n=115)
Phase 2a
Open-label
>18 years of age
ART-naïve
CD4 >200 cells/mm3
Creatinine clearance
>50 mL/min
No HBV, ALT >5x ULN
Induction Phase
Cabotegravir 30 mg
+ ABC/3TC for
20 Weeks (n=309)
Cabotegravir 600 mg + Rilpivirine 900 mg
IM every 8 weeks (n=115)
Oral Cabotegravir 30 mg + ABC/3TC qd (n=56)
Slide: LATTE-2: Cabotegravir + Rilpivirine as Long-Term Maintenance Therapy
LATTE-2 was a phase 2a, open-label dose-ranging study of cabotegravir LA as maintenance therapy in virologically suppressed patients.1
Induction phase: patients received oral cabotegravir 30 mg + abacavir/lamivudine for 20 weeks.
Maintenance phase: virologically suppressed patients were randomized to either cabotegravir 400 mg + rilpivirine 600 mg IM every 4 weeks, cabotegravir 600 mg + rilpivirine 900 mg IM every 8 weeks, or continue with oral therapy (cabotegravir 30 mg + abacavir/lamivudine).
The primary endpoint was HIV RNA <50 copies/mL at week 32 of the maintenance phase.1
Reference
Margolis DA, González-García J, Stellbrink H-J, et al. Cabotegravir+rilpivirine as long-acting maintenance therapy: LATTE-2 week 32 results. Program and abstracts from the 23rd Conference on Retroviruses and Opportunistic Infection; February 22-25, 2016; Boston, MA. Abstract 31LB.
Week
Primary Endpoint
HIV RNA <50 copies/mL
Cabotegravir: INSTI.
Baseline characteristics:
Median age: 35 years.
Male: 92%.
Black race/ethnicity: 15%.
CDC class C: 1%.
Median HIV RNA: 4.4 log10 copies/mL.
HIV RNA >100K copies/mL: 18%.
Median CD4: 489 cells/mm3.
Margolis DA, et al. 23rd CROI. Boston, Abstract 31LB.

30. LATTE-2: Cabotegravir + Rilpivirine as Long-Term Maintenance Therapy
Week 32 Maintenance Therapy
94%*
95%*
91%
Oral cabotegravir + ABC/3TC daily (n=56)
Cabotegravir IM + IM rilpivirine
Every 4 weeks (n=115)
Every 8 weeks (n=115)
HIV RNA <50 Copies/mL
Slide: LATTE-2: Cabotegravir + Rilpivirine as Long-Term Maintenance Therapy
Cabotegravir LA maintenance therapy at both dosage arms met non-inferiority criteria to oral cabotegravir with regard to achieving HIV RNA <50 copies/mL.1
Reference
Margolis DA, González-García J, Stellbrink H-J, et al. Cabotegravir+rilpivirine as long-acting maintenance therapy: LATTE-2 week 32 results. Program and abstracts from the 23rd Conference on Retroviruses and Opportunistic Infection; February 22-25, 2016; Boston, MA. Abstract 31LB. 4% 5% 5% 4%
<1%
<1%
Success
Failure
No Data
*Met non-inferiority criteria (treatment difference with oral):
Every 4 weeks: +2.8 (-5.8, 11.5); every 8 weeks: +3.2 (-4.8, 12.2).
Margolis DA, et al. 23rd CROI. Boston, Abstract 31LB.

31. Cabotegravir IM + Rilpivirine IM
LATTE-2: Protocol-Defined Virologic Failure With Cabotegravir + Rilpivirine as Long-Term Maintenance Therapy
Cabotegravir IM + Rilpivirine IM
Every
4 Weeks
(n=115)
8 Weeks
Oral Cabotegravir
+ 3TC/ABC
(n=56)
Protocol-defined
virologic failure (%) 1 2
INI mutations (%)
NRTI mutations (%)
NNRTI mutations (%)
Slide: LATTE-2: Protocol-Defined Virologic Failure With Cabotegravir + Rilpivirine as Long-Term Maintenance Therapy
No emergent resistant mutations were detected among patients who met the criteria for virologic failure and had available genotype data.1
Reference
Margolis DA, González-García J, Stellbrink H-J, et al. Cabotegravir+rilpivirine as long-acting maintenance therapy: LATTE-2 week 32 results. Program and abstracts from the 23rd Conference on Retroviruses and Opportunistic Infection; February 22-25, 2016; Boston, MA. Abstract 31LB.
Protocol-defined virologic failure: <1.0 log10 copies/mL decrease in plasma HIV RNA by week 4 or confirmed HIV RNA >200 copies/mL
after prior suppression to <200 copies/mL or >0.5 log10 copies/mL increase from nadir HIV RNA >200 copies/mL.
Margolis DA, et al. 23rd CROI. Boston, Abstract 31LB.

32. How satisfied are you with your current treatment?
LATTE-2: Wk 32 Pt Satisfaction With Maintenance Therapy vs Oral Induction
How satisfied are you with your current treatment?
How satisfied would you be to continue with your present form of treatment?
More
Neutral
Less
More
Neutral
Less 3 1 2 1
100
100 3 1 80 29 80 29 60 60
Pts (%) 40 40
CAB, cabotegravir; Q4W, every 4 weeks; Q8W, every 8 weeks.
Finally, this is looking at patient satisfaction in the LATTE-2 study. How satisfied are you with your current treatment? You can see that patients were actually quite satisfied. And how happy were they to continue? And again, almost all patients were happy to continue. Again, this is a questionnaire outcome. 20 20 97 96 71 98 98 71
Q8W (n = 106)
Q4W (n = 100)
Oral CAB (n = 49)
Q8W (n = 106)
Q4W (n = 100)
Oral CAB (n = 49)
Margolis DA, et al. CROI Abstract 31LB. Reproduced with permission.
Slide credit: clinicaloptions.com

33. Approximately what percentage of your pts do you think would be interested in long-acting injectable therapy administered every 8 wks?
< 5%
10%
25%
50%
75%

34. Coping with Hope Prevention PrEP Real Experience PreP Safety
Investigational Agents

35. Boston Community Based Health Center: PrEP Experience
Fenway Health: largest primary care center for MSM in Massachusetts
Account for 14.2% of newly diagnosed HIV cases in Massachusetts in 2014
In 2014
Start new ART (n=121)
Start PrEP (n=537)
PrEP at Fenway Health ( )
HIV seroconversion: <1% (5/664)
Recent bacterial STI: 36%
80% of gonorrhea and chlamydia infections at Fenway Health in HIV- negative MSM on PrEP
Highlights the need for ongoing STI screening
Number of New PrEP Starts at Fenway Health, Boston
960
537
Slide: Boston Community Based Health Center: PrEP Experience
Fenway Community Health is the largest primary care center for MSM in Massachusetts and cared for 14.2% of newly diagnosed HIV cases in Massachusetts in
In 2014, there were 121 and 537 new ART and PrEP starts, respectively.1
From 2011 to 2015, the rate of HIV seroconversions among PrEP patients was <1% (5/664). Recent bacterial STIs were diagnosed in 36% of patients, with 80% of gonorrhea and chlamydia infections at Fenway Health in HIV-negative MSM on PrEP.1
These data highlight the need for ongoing STI screening among PrEP patients.1
Reference
Mayer KH, Levine K, Maloney KM, et al. Increasing HIV Suppression, PrEP use, and STDs in Boston MSM accessing primary care. Program and abstracts from the 23rd Conference on Retroviruses and Opportunistic Infection; February 22-25, 2016; Boston, MA. Abstract 890.
Number of New PrEP Starts
102 20 5
2011
2012
2013
2014
2015
Mayer KH, et al. 23rd CROI. Boston, Abstract 890.

36. Cohort Characteristics
Kaiser Permanente-Northern California: Adherence and Discontinuation of PrEP
Cohort of plan members initiating PrEP (n=972, )
Data sources: electronic health records, HIV registry, US census
Follow-up: 850 person-years
Mean 0.9 years/person
Outcomes
Adherence (pharmacy refill)
Low adherence (<60%, consistent with fewer than 4 of 7 doses/week)
Discontinuation
>120 days without emtricitabine/tenofovir DF
HIV seroconversion
Cohort Characteristics
Participants
(n=972)
Age (years) 36
Race/ethnicity (%)
White/black/Hispanic/Asian
70/4/12/10
Male (%) 98
Any STI/rectal STI, prior 2 years (%)
33/12
Smoker (%) 23
Baseline eGFR <80 mL/min (%) 15
Drug/alcohol abuse (%) 6
Hypertension (%) 11
Diabetes (%) 3
Median
PrEP copay/month (USD)
Household income (USD) 77
Slide: Kaiser Permanente-Northern California: Adherence and Discontinuation of PrEP
Marcus and colleagues assessed adherence and discontinuation of PrEP use in a cohort study of Kaiser Permanente Northern California members initiating PrEP between July 2012 and December Follow-up was defined as days from PrEP initiation until earliest time of discontinuation, health plan disenrollment, HIV seroconversion, death, or June 30, Data sources included electronic health records, HIV registry, and US census data.1
Outcomes included adherence based on pharmacy refill with low adherence defined as <60%, consistent with fewer than 4 of 7 doses/week. Discontinuation of PrEP was defined as >120 days without emtricitabine/tenofovir DF. HIV seroconversion was also assessed.1
Reference
Marcus JL, Hurley LB, Hare B, et al. HIV Preexposure prophylaxis: adherence and discontinuation in clinical practice. Program and abstracts from the 23rd Conference on Retroviruses and Opportunistic Infection; February 22-25, 2016; Boston, MA. Abstract 894.
Follow-up: from first PrEP until the earliest of PrEP discontinuation,
health plan disenrollment, HIV seroconversion, death,
or end of study.
Marcus JL, et al. 23rd CROI. Boston, Abstract 894.

37. Significant Factors Associated With PrEP Adherence and Discontinuation
Kaiser Permanente-Northern California: Adherence and Discontinuation of PrEP
High adherence: 97%
HIV seroconversion
On PrEP: 0% (0/753)
Discontinued PrEP: 0.9% (2/219)
1 black and 1 Hispanic man (both <30 years of age)
Critical need for strategies to support continuation of PrEP throughout periods of HIV risk
Significant Factors Associated With PrEP Adherence and Discontinuation
P Value
Adherence <60%*
Younger age
Black/Hispanic ethnicity
Smoking
0.005
0.007
0.009
Discontinuation of PrEP
Women
Drug/alcohol abuse
Copay >$50/month
<0.001
0.045
Slide: Kaiser Permanente-Northern California: Adherence and Discontinuation of PrEP
Adherence was very high, which is consistent with the lack of HIV seroconversions among those who continued to use PrEP.1
Younger age, black or Hispanic race/ethnicity, and smoking were associated with <60% adherence, while women, individuals with drug/alcohol abuse, and individuals with higher copays for PrEP were more likely to discontinue.1
Given 2 seroconversions after PrEP discontinuation, there is a critical need for strategies to support continuation of PrEP throughout periods of HIV risk.1
Reference
Marcus JL, Hurley LB, Hare B. et al. HIV Preexposure prophylaxis: adherence and discontinuation in clinical practice. Program and abstracts from the 23rd Conference on Retroviruses and Opportunistic Infection; February 22-25, 2016; Boston, MA. Abstract 894.
*Rare outcome of low adherence (3%) precluded multivariate analysis.
Marcus JL, et al. 23rd CROI. Boston, Abstract 894.

38. iPrEx DXA Substudy: Recovery of BMD After Stopping PrEP
7 study sites in 5 cities (Cape Town, Chiang Mai, Lima, Rio de Janeiro, San Francisco)
DXA of hip and spine
Every 24 weeks during iPrEx
Week 24 after stopping PrEP
At OLE enrollment
Exposure to PrEP (retained cohort): 1.5 years
Baseline Characteristics
(Retained Through OLE Enrollment)
Patients
(n=289)
Mean age (years) 26
Transgender (%) 12
Smoker (%) 46
Drink alcohol (%) 82
Height (cm)
170
Weight (kg) 66
Z-score
Hip
Spine
-0.19
-0.66
Slide: iPrEx DXA Substudy: Recovery of BMD After Stopping PrEP
Grant and colleagues conducted a DXA substudy of BMD in consecutively enrolled iPrEx trial participants.1
7 study sites in 5 cities (Cape Town, Chiang Mai, Lima, Rio de Janeiro, San Francisco).
DXA of hip and spine were performed every 24 weeks during iPrEx, at week 24 after stopping PrEP, and at enrollment into the open-label extension study for iPrEx.1
Overall exposure to PrEP (retained cohort) was 1.5 years.1
Reference
Grant R, Mulligan K, McMahan V, et al. Recovery of bone mineral density after stopping oral HIV preexposure prophylaxis. Program and abstracts from the 23rd Conference on Retroviruses and Opportunistic Infection; February 22-25, 2016; Boston, MA. Abstract 48LB.
OLE: open-label extension.
Baseline at start of iPrEx.
Z-score: comparing BMD with healthy individuals matched by age, gender, and race.
Grant R, et al. 23rd CROI. Boston, Abstract 48LB.

39. iPrEx DXA Substudy: Recovery of BMD After Stopping PrEP
Hip BMD
Spine BMD
Placebo
TFV-DP concentration at week 24
>16 fmol/M
<16 fmol/M
Placebo
TFV-DP concentration at week 24
>16 fmol/M
<16 fmol/M
Change in BMD (%)
Change in BMD (%)
Slide: iPrEx DXA Substudy: Recovery of BMD After Stopping PrEP
Among participants with protective PrEP drug concentrations at week 24, average BMD in the spine and hip increased after PrEP was stopped.1
Reference
Grant R, Mulligan K, McMahan V, et al. Recovery of bone mineral density after stopping oral HIV preexposure prophylaxis. Program and abstracts from the 23rd Conference on Retroviruses and Opportunistic Infection; February 22-25, 2016; Boston, MA. Abstract 48LB. * * *
*P<0.001
*P<0.001 *
Week 24
Stop
PrEP
Week 24
After Stop
OLE
Entry
Week 24
Stop
PrEP
Week 24
After Stop
OLE
Entry
Average annualized recovery after stopping PrEP: 1.13% (P=0.002 versus placebo)
Average annualized recovery after stopping PrEP: 1.81% (P=0.01 versus placebo)
<25 years of age: full recovery of hip and spine BMD within 24 weeks of stopping PrEP.
>25 years of age: full recovery of spine BMD within 24 weeks of stopping PrEP; hip BMD recovered by OLE entry.
Grant R, et al. 23rd CROI. Boston, Abstract 48LB.

40. Hair Drug Levels and eGFR Quartile of Hair Drug Concentrations
iPrEx OLE (Baseline eGFR <90 mL/min): Probability of eGFR Decreasing to <70 mL/min Within a Year
Odds ratio of decreasing to <70 mL/min if hair drug levels in 4th quartile
Tenofovir DF: 4.4 (P=0.45)
Emtricitabine: 4.5 (P=0.027)
Probability of decreasing to <70 mL/min if hair drug levels in 3rd or 4th quartiles
<40 years of age: <4%
40-50 years of age: 19% to 21%
>50 years of age: 23% to 24%
Potential implications for patients starting PrEP
Monitor renal function if >40 years of age and a baseline eGFR <90 mL/min
Hair Drug Levels and eGFR
Years of age
<40
40-49
>50 ~7
doses/week ~4
doses/week
24%
23%
Probability of eGFR Falling <70 mL/min
21% ~2
doses/week
19%
Slide: iPrEx OLE (Baseline eGFR <90 mL/min): Probability of eGFR Decreasing to <70 mL/min Within a Year
Clinically significant reductions in eGFR below 70 mL/min were uncommon. When it did occur, it was more common if hair drug levels were in the 4th quartile (tenofovir DF: OR 4.4; P=0.45 and emtricitabine: OR 4.5; P=0.027).1
These data suggest that careful monitoring of renal function may be helpful for patients >40 years of age and with a pre-PrEP eGFR <90 mL/min.1
Reference
Gandhi M, Glidden DV, Liu AY, et al. Higher cumulative TFV/FTC levels in PrEP associated with decline in renal function. Program and abstracts from the 23rd Conference on Retroviruses and Opportunistic Infection; February 22-25, 2016; Boston, MA. Abstract 866.
12% 6%
10% 5%
1st
2nd
3rd
4th
Quartile of Hair Drug Concentrations
Gandhi M, et al. 23rd CROI. Boston, Abstract 866.

41. US DEMO Project: Changes in Renal Function With PrEP
HIV-negative MSM and transgender women (n=557)
Mean change in eGFR
Declined 2.8% (-3.6 mL/min) during first 12 weeks (P=0.005)
Remained stable through week 48 (P=0.91)
2 consecutive visits with a >10% decline in eGFR and a >0.2 mg/dL increase in creatinine: 2.4%
Baseline Characteristics
Participants
(n=557)
Age (years) 33
Race/ethnicity (%)
White/black/Latino/Asian
48/35/7/5
Geographic origin (%)
San Francisco
Miami
Washington, DC 54 28 18
Hypertension (%) 11
Diabetes (%) 2
Baseline
eGFR (mL/min)
eGFR <70 mL/min (%)
97.1 6
Slide: US DEMO Project: Changes in Renal Function With PrEP
Liu and colleagues evaluated changes in renal function among participants enrolled in the open-label US PrEP Demonstration project.1
HIV-negative MSM and transgender women (n=557).
The mean change in eGFR was a decline of 2.8% (-3.6 mL/min) during first 12 weeks (P=0.005), which remained stable through week 48 (P=0.91).1
Only 2.4% of patients experienced a >10% decline in eGFR and a creatinine increase >0.2 mg/dL.1
Reference
Liu AY, Vittinghoff E, Anderson PL, et al. Changes in renal function associated with TDF/FTC PrEP use in the US demo project. Program and abstracts from the 23rd Conference on Retroviruses and Opportunistic Infection; February 22-25, 2016; Boston, MA. Abstract 867.
Liu AY, et al. 23rd CROI. Boston, Abstract 867.

42. US DEMO Project: Changes in Renal Function With PrEP
New-onset eGFR <70 mL/min: 13%
Factors associated with new-onset eGFR <70 mL/min
Older age (P=0.02)
Baseline eGFR <90 mL/min (P<0.001)
Tenofovir diphosphate levels were not associated with eGFR <70 mL/min (P=0.38)
PrEP discontinuation due to elevated creatinine (>1.5x ULN) (0.5%, 3/557)
eGFR <70 mL/min
Within 1 Year of PrEP
Baseline eGFR (mL/min)
<90
>90
Prevalence (%)
Slide: US DEMO Project: Changes in Renal Function With PrEP
New-onset eGFR <70 mL/min was detected in 13% during follow-up. Factors associated with new onset eGFR <70 mL/min included older age (P=0.02) and baseline eGFR <90 mL/min (P<0.001).1
Tenofovir diphosphate levels were not associated with eGFR <70 mL/min (P=0.38).1
PrEP discontinuation due to elevated creatinine (>1.5x ULN) occurred in 0.5% (3/557) of patients.1
Reference
Liu AY, Vittinghoff E, Anderson PL, et al. Changes in renal function associated with TDF/FTC PrEP use in the US demo project. Program and abstracts from the 23rd Conference on Retroviruses and Opportunistic Infection; February 22-25, 2016; Boston, MA. Abstract 867.
18-25
26-35
36-45
>45
Age Group (years)
Liu AY, et al. 23rd CROI. Boston, Abstract 867.

43. Case Report: Multiclass Resistant HIV Infection Despite High Adherence to PrEP
43-yr-old MSM acquired multiclass resistant HIV-1 infection following 24 mos of oral once-daily TDF/FTC PrEP
Pharmacy records, blood concentration analyses, and clinical history support recent and long-term adherence to PrEP
PrEP failure likely result of exposure to PrEP-resistant, multiclass resistant HIV-1 strain
Drug Class
Mutations Detected on Day 7 Following p24-Positive Test
Estimated Fold-Change in IC50 or Change in Response (Drug)
NRTI
41L, 67G, 69D, 70R, 184V, 215E
1.9x (ABC), 61x (3TC), 38x (FTC), 1.3x (TDF)
NNRTI
181C
43x (NVP) PI
10I
No relevant change
INSTI
51Y, 92Q
Reduced (RAL), resistant (EVG), reduced (DTG)
3TC, lamivudine; ABC, abacavir; DTG, dolutegravir; EVG, elvitegravir; FTC, emtricitabine; MSM, men who have sex with men; NVP, nevirapine; PrEP, pre-exposure prophylaxis; RAL, raltegravir; TDF, tenofovir disoproxil.
This is a very well characterized example of a PrEP failure. A 43-year-old man who has sex with men was on oral once-daily TDF/FTC and, by pharmacy records, blood analysis, and clinical history, appeared to be quite adherent but became infected anyway. Unfortunately, he was exposed to a very highly drug–resistant variant that included multiple nucleoside mutations, a classical NNRTI mutation, and a known integrase mutation. Hopefully, this will be an uncommon scenario.
Slide credit: clinicaloptions.com
Knox DC, et al. CROI Abstract 169aLB.

44. Prophylactic Efficacy of Emtricitabine/Tenofovir AF Against Rectal SHIV Infection
Macaque model to simulate populations at high risk for HIV infection
Weekly rectal exposure with R5 virus inoculum (SHIV162p3) for up to 19 weeks
Identical design used to demonstrate efficacy of FTC/TDF after 14 challenges
Dosing groups (n=6 per arm)
FTC/TAF (20/1.5 mg/kg) or placebo given orally by gavage (under anesthesia)
1 day before and 2 hours after SHIV exposure
Single-dose pharmacokinetics (1.5 mg/kg of TAF)
~90% lower plasma TFV exposure
PBMC TFV-DP levels within range of 25 mg dose in humans
Lower rectal TFV-DP exposure compared with TDF (via rectal biopsy)
Slide: Prophylactic Efficacy of Emtricitabine/Tenofovir AF Against Rectal SHIV Infection
Massud and colleagues used the macaque model to simulate populations at high risk for HIV infection by weekly rectal exposure to R5 virus inoculum (SHIV162p3) for up to 19 weeks. This was the identical design used to demonstrate efficacy of emtricitabine/tenofovir DF after 14 challenges.1
The dosing groups (n=6 per arm) included:1
Emtricitabine/tenofovir AF (20/1.5 mg/kg) or placebo given orally by gavage (under anesthesia) 1 day before and 2 hours after SHIV exposure.
Single-dose pharmacokinetics (1.5 mg/kg of TAF) found 90% lower plasma tenofovir exposure, PBMC tenofovir diphosphate levels within range of 25-mg dose in humans, and lower rectal tenofovir diphosphate exposure compared with tenofovir DF (via rectal biopsy).1
Reference
Massud I, Mitchell J, Babusis D, et al. Chemoprophylaxis with oral FTC/TAF protects macaques from rectal SHIV infection. Program and abstracts from the 23rd Conference on Retroviruses and Opportunistic Infection; February 22-25, 2016; Boston, MA. Abstract 107.
DP: diphosphate.
Massud I, et al. 23rd CROI. Boston, Abstract 107.

45. Protection Against SHIV
Prophylactic Efficacy of Emtricitabine/Tenofovir AF Against Rectal SHIV Infection
Protection Against SHIV
FTC/TAF (n=6)
100%
Placebo (n=6)
Protected (%)
Slide: Prophylactic Efficacy of Emtricitabine/Tenofovir AF Against Rectal SHIV Infection
Emtricitabine/tenofovir AF prevented SHIV infection in all 6 macaque compared with SHIV infection in all 6 placebo macaques.1
Reference
Massud I, Mitchell J, Babusis D, et al. Chemoprophylaxis with oral FTC/TAF protects macaques from rectal SHIV infection. Program and abstracts from the 23rd Conference on Retroviruses and Opportunistic Infection; February 22-25, 2016; Boston, MA. Abstract 107. 0%
SHIV Challenges
Massud I, et al. 23rd CROI. Boston, Abstract 107.

46. RING STUDIES

47. Dapivirine Vaginal Ring for HIV Prevention in Women at High Risk: 2 Phase 3 Trials
ASPIRE (MTN-020)
RING STUDY (IMP 027)
Malawi, South Africa, Uganda, Zimbabwe
Malawi, South Africa, Uganda, Zimbabwe
Women
18 to 45 Years of Age
(n=2629)
Women
18 to 45 Years of Age
(n=1959)
Dapivirine Ring
(n=1313)
Placebo Ring
(n=1316)
Dapivirine Ring
(n=1307)
Placebo Ring
(n=652)
Slide: Dapivirine Vaginal Ring for HIV Prevention in Women at High Risk: 2 Phase 3 Trials
The safety and efficacy of the dapivirine vaginal ring for HIV prevention in women at high risk for HIV infection was evaluated in 2 phase 3 trials conducted in Africa.1-3
ASPIRE (n=2629).
RING study (n=1959).
References
Baeten JM, Palanee-Phillips T, Brown ER, et al. A phase III trial of the dapivirine vaginal ring for HIV-1 prevention in women. Program and abstracts from the 23rd Conference on Retroviruses and Opportunistic Infection; February 22-25, 2016; Boston, MA. Abstract 109LB.
Baeten JM, Palanee-Phillips T, Brown ER, et al. Use of a vaginal ring containing dapivirine for HIV-1 prevention in women. N Engl J Med Feb 22. [Epub ahead of print].
Nel A, Kapiga S, Bekker L-G, et al. Safety and efficacy of dapivirine vaginal ring for HIV-1 prevention in African women. Program and abstracts from the 23rd Conference on Retroviruses and Opportunistic Infection; February 22-25, 2016; Boston, MA. Abstract 110LB.
Dapivirine: NNRTI.
Women self-inserted and removed ring at 4-week intervals.
All women received a comprehensive package of HIV prevention services.
Baeten JM, et al. 23rd CROI. Boston, Abstract 109LB.
Baeten JM, et al. N Engl J Med. 2016;Feb 22. [Epub ahead of print].
Nel A, et al. 23rd CROI. Boston, Abstract 110LB.

48. Dapivirine Vaginal Ring: Reduction in HIV Seroconversion
ASPIRE (MTN-020)
RING STUDY (IMP 027)
Dapivirine
(n=1313)
Placebo
(n=1316)
HIV infections
(number) 71 97
HIV incidence
(person-years)
3.3
4.5
HIV protection effectiveness (%) 27
(95% CI: 1, 46)
P=0.04
Dapivirine
(n=1300)
Placebo
(n=650)
HIV infections
(number) 77 56
HIV incidence
(person-years)
4.1
6.1
HIV protection effectiveness (%) 31
(95% CI: 0.9, 52)
P=0.04
Slide: Dapivirine Vaginal Ring: Reduction in HIV Seroconversion
In the ASPIRE study, HIV incidence decreased 27% from 4.5 to 3.3 HIV infections/person-years in the placebo and dapivirine arms, respectively. In the RING study, there was a 31% reduction in HIV seroconversions.1-3
References
Baeten JM, Palanee-Phillips T, Brown ER, et al. A phase III trial of the dapivirine vaginal ring for HIV-1 prevention in women. Program and abstracts from the 23rd Conference on Retroviruses and Opportunistic Infection; February 22-25, 2016; Boston, MA. Abstract 109LB.
Baeten JM, Palanee-Phillips T, Brown ER, et al. Use of a vaginal ring containing dapivirine for HIV-1 prevention in women. N Engl J Med Feb 22. [Epub ahead of print].
Nel A, Kapiga S, Bekker L-G, et al. Safety and efficacy of dapivirine vaginal ring for HIV-1 prevention in African women. Program and abstracts from the 23rd Conference on Retroviruses and Opportunistic Infection; February 22-25, 2016; Boston, MA. Abstract 110LB.
Baeten JM, et al. 23rd CROI. Boston, Abstract 109LB.
Baeten JM, et al. N Engl J Med. 2016;Feb 22. [Epub ahead of print].
Nel A, et al. 23rd CROI. Boston, Abstract 110LB.

49. Dapivirine Vaginal Ring: Reduction in HIV Seroconversion
ASPIRE (MTN-020)
(Post-Hoc Analysis)
RING STUDY (IMP 027)
(Pre-Defined Analysis)
-15%
P=NS
-27%
-27%
Reduction in HIV Seroconversion (%)
P=0.04
P=NS
Reduction in HIV Seroconversion (%)
-31%
P=0.04
Slide: Dapivirine Vaginal Ring: Reduction in HIV Seroconversion
In a post-hoc analysis of the ASPIRE study and pre-defined analysis of the RING study, there was no impact of the dapivirine vaginal ring on HIV prevention among women <21 years of age. This was attributed to lower adherence rates in this group of women and reinforces the importance of adherence for PrEP to be effective.1-3
References
Baeten JM, Palanee-Phillips T, Brown ER, et al. A phase III trial of the dapivirine vaginal ring for HIV-1 prevention in women. Program and abstracts from the 23rd Conference on Retroviruses and Opportunistic Infection; February 22-25, 2016; Boston, MA. Abstract 109LB.
Baeten JM, Palanee-Phillips T, Brown ER, et al. Use of a vaginal ring containing dapivirine for HIV-1 prevention in women. N Engl J Med Feb 22. [Epub ahead of print].
Nel A, Kapiga S, Bekker L-G, et al. Safety and efficacy of dapivirine vaginal ring for HIV-1 prevention in African women. Program and abstracts from the 23rd Conference on Retroviruses and Opportunistic Infection; February 22-25, 2016; Boston, MA. Abstract 110LB.
-37%
P<0.001
-56%
P<0.001
Overall
<21
>21
Overall
<21
>21
Age (years)
Age (years)
Baeten JM, et al. 23rd CROI. Boston, Abstract 109LB.
Baeten JM, et al. N Engl J Med. 2016;Feb 22. [Epub ahead of print].
Nel A, et al. 23rd CROI. Boston, Abstract 110LB.

50. Injectable PrEP

51. ÉCLAIR Study: Cabotegravir LA for PrEP in Low-Risk, HIV-Uninfected Men
Oral Phase
Injection Phase
Cabotegravir
30 mg qd
(n=105)
Cabotegravir LA 800 mg
IM every 12 weeks
(n=94)
Phase 2a
Double-blind
Men 18 to 65 years of age
Low risk of acquiring HIV
No PEP or ART
No liver disease
5:1 randomization
Placebo
(n=21)
Saline Placebo
IM every 12 weeks
(n=21)
Slide: ÉCLAIR Study: Cabotegravir LA for PrEP in Low-Risk, HIV-Uninfected Men
Markowitz and colleagues conducted a phase 2a study to evaluate the use of cabotegravir maintenance therapy in men at low risk of acquiring HIV. Cabotegravir was first administered orally 30 mg/day for 4 weeks, then via IM infection of 800 mg once every 12 weeks.1
Reference
Markowitz M, Frank I, Grant R, et al. ÉCLAIR: Phase 2A safety and PK study of cabotegravir LA in HIV-uninfected men. Program and abstracts from the 23rd Conference on Retroviruses and Opportunistic Infection; February 22-25, 2016; Boston, MA. Abstract 106.
Week
Cabotegravir: INSTI.
Baseline characteristics (cabotegravir oral phase):
Median age: 31 years.
White/black race/ethnicity: 56%/31%.
Hispanic/Latino race/ethnicity: 15%.
Median height: 176 cm.
Median BMI: 26 kg/m2.
Risk of HIV acquisition:
Homosexual contact: 85%.
Heterosexual contact: 21%
Occupational exposure: 2%.
Markowitz M, et al. 23rd CROI. Boston, Abstract 106.

52. ÉCLAIR Study: Safety of Cabotegravir LA for PrEP in Low-Risk, HIV-Uninfected Men
Adverse events (%)
Placebo
(n=21)
Cabotegravir
(n=94)
Grade 1-4 (%) 90 98
Grade 2-4 (%) 48 80
Injection site pain
Pyrexia
Injection site pruritus
Injection site swelling 5 59 7 6
Serious adverse event (%)
<1
Slide: ÉCLAIR Study: Safety of Cabotegravir LA for PrEP in Low-Risk, HIV-Uninfected Men
Overall, maintenance dosing of once every 12 weeks of cabotegravir was safe, with the most common adverse events being related to injection site reactions.1
Pharmacokinetic analysis found that dosing once every 12 weeks produced peak and trough levels that were higher and lower, respectively, than expected during the study. The authors noted that IM dosing once every 8 weeks may be necessary in men.1
Reference
Markowitz M, Frank I, Grant R, et al. ÉCLAIR: Phase 2A safety and PK study of cabotegravir LA in HIV-uninfected men. Program and abstracts from the 23rd Conference on Retroviruses and Opportunistic Infection; February 22-25, 2016; Boston, MA. Abstract 106.
With dosing once every 12 weeks, cabotegravir peak and trough levels were higher and lower,
respectively, than expected during the study
IM dosing once every 8 weeks may be necessary in men
No laboratory adverse events led to study discontinuation.
Cabotegravir administered IM once every 12 weeks.
Markowitz M, et al. 23rd CROI. Boston, Abstract 106.

53. ÉCLAIR: Patient Satisfaction With IM Therapy vs Oral Phase
Pt satisfaction assessed by questionnaire at Wk 18 of IM treatment; asked pts to compare satisfaction of current IM vs past oral therapy[1]
In separate macaque study, CAB LA conferred 88% protection (21/24 animals) against IV exposure to SIVmac251; results may be relevant to humans who inject drugs[2]
How satisfied are you with your current treatment?
How satisfied would you be to continue with your present form of treatment?
More
Neutral
Less
100
100 81 80 71 29 80 74 62 60 60
Pts (%) 40 40 23 24
CAB, cabotegravir; IM, intramuscular; IV, intravenous; LA, long acting.
So this is looking at questionnaire-based satisfaction with IM therapy vs oral in the ÉCLAIR study. On the left-hand side is how satisfied patients were with their current treatment. What you can see is that about two thirds of the patients were more satisfied being on an injectable than a pill, 15% were less satisfied, and 23% were neutral. It was similar between placebo and cabotegravir. And then, they were asked how satisfied would you be to continue your current treatment? Again, you can see three quarters of the patients were positive about continuing and about 10% would not.
There was a separate study, which is the bullet on the bottom, looking at cabotegravir LA in a macaque model. It showed that 21 out of 24 monkeys were protected from IV exposure to SIV after getting cabotegravir long-acting, suggesting that perhaps this strategy could be used as PrEP in people who inject drugs. 19 15 20 20 15 11 5
CAB (n = 91)
Placebo (n = 21)
CAB (n = 91)
Placebo (n = 21)
Markowitz M, et al. CROI Abstract 106.
2. Andrews CD, et al. CROI Abstract 105. Reproduced with permission.
Slide credit: clinicaloptions.com

54. Cabotegravir LA: Prophylactic Efficacy Against IV Challenge of SIV in Macaques
IV SIV challenge model in macaques
Mimics blood transfusions based on the per-act probability of infection
IV challenge with 17 AID50 SIVmac251 on week 2
Untreated controls (n=5)
Cabotegravir LA IM groups
Group 1: 50 mg/kg at week 0 and 4 (mimic sexual transmission)
Group 2: 50 mg/kg at week 0 (determine need for second injection)
Group 3: 25 mg/kg at week 0 and 50 mg/kg on week 4 (correlate cabotegravir plasma concentrations at the time of challenge with protection)
Infection status by real-time PCR amplification of viral gag sequences from plasma obtained weekly
Plasma cabotegravir concentrations by HPLC-MS/MS
Slide: Cabotegravir LA: Prophylactic Efficacy Against IV Challenge of SIV in Macaques
Andrews and colleagues evaluated the effectiveness of cabotegravir LA as PrEP against IV SIV challenge in a model that mimics blood transfusions based on the per-act probability of infection. Three groups of rhesus macaques (n=8/group) were injected IM with cabotegravir LA and challenged IV with 17 AID50 SIVmac251 on week 2.
Group 1: 50 mg/kg on week 0 and 4 (mimic sexual transmission).
Group 2: 50 mg/kg on week 0 (determine need for second injection).
Group 3: 25 mg/kg on week 0 and 50 mg/kg on week 4 (correlate cabotegravir plasma concentrations at the time of challenge with protection).
Controls: 5 untreated macaques.
Reference
Andrews CD, St. Bernard L, Poon A. Cabotegravir long-acting injection protects macaques against intravenous challenge. Program and abstracts from the 23rd Conference on Retroviruses and Opportunistic Infection; February 22-25, 2016; Boston, MA. Abstract 105.
Andrews CD, et al. 23rd CROI. Boston, Abstract 105.

55. Protection Against SIV (IV Challenge)
Cabotegravir LA: Prophylactic Efficacy Against IV Challenge of SIV in Macaques
Protection Against SIV (IV Challenge)
100% (8/8)
88% (7/8)
75% (6/8)
Protected (%)
Controls
0/5
Cabotegravir LA
50 mg/kg (2 doses, 4 weeks apart)
50 mg/kg
25 and 50 mg/kg (4 weeks apart)
Slide: Cabotegravir LA: Prophylactic Efficacy Against IV Challenge of SIV in Macaques
In an IV challenge model, 21 of the 24 cabotegravir LA-treated macaques remained aviremic, resulting in 88% protection. The plasma cabotegravir concentration at the time of challenge is more important for protection than sustaining plasma concentrations with the second cabotegravir LA injection.1
Reference
Andrews CD, St. Bernard L, Poon A. Cabotegravir long-acting injection protects macaques against intravenous challenge. Program and abstracts from the 23rd Conference on Retroviruses and Opportunistic Infection; February 22-25, 2016; Boston, MA. Abstract 105. IV
SIV
Time (weeks)
The plasma cabotegravir concentration at the time of challenge is more important for protection than sustaining
plasma concentrations with the second cabotegravir LA injection.
Andrews CD, et al. 23rd CROI. Boston, Abstract 105.

56. Hepatitis C

57. At your clinic/institution, who is providing the majority of HCV treatment?
PCPs
NPs or PAs
Specialists (hepatology or infectious diseases)
Don’t Treat or Refer Out
Don’t Know

58. ASCEND: HCV Treatment Provided in Primary Care
Open-label, nonrandomized, phase IV longitudinal trial
Primary endpoint: SVR12
600 HCV-infected pts in 3 community centers in Washington, DC
24% coinfected with HIV; 96% black; 18% treatment experienced; 36% F3/F4 fibrosis/cirrhosis
Care provided by: NP (n = 150), PCP (n = 156), or ID or hepatology specialist (n = 294)
All pts treated with LDV/SOF per FDA labelling
Providers completed 3-hr training on AASLD/IDSA HCV guidance
AASLD, American Association for the Study of Liver Diseases; FDA, US Food and Drug Administration; HCV, hepatitis C virus; ID, infectious diseases; IDSA, Infectious Diseases Society of America; LDV, ledipasvir; NP, nurse practitioner; PCP, primary care provider; SOF, sofosbuvir; SVR, sustained virologic response.
ASCEND was a phase IV trial looking at treatment of hepatitis C at 3 community centers in Washington, DC. About one quarter of the patients were coinfected with HIV and HCV, and most patients were black. Treatment was delivered by a nurse practitioner, a primary care provider, or an ID or hepatology specialist. All patients received ledipasvir/sofosbuvir, and all the providers had a 3-hour training course.
Slide credit: clinicaloptions.com
Kattakuzhy SM, et al. CROI Abstract 538LB.

59. ASCEND: Interim per Protocol Efficacy and Adherence
Adherence to clinic visits (Wks 4, 8, 12) significantly higher with PCPs (49%) and NPs (51%) vs specialists (19%) (P = .002) 95 92 97 NP
PCP
Specialist
SVR12 (%)
100 80 60 40 20
Total (n = 304)
HIV/HCV-Coinfected Pts (n = 62) 91 89 93
HCV, hepatitis C virus; NP, nurse practitioner; PCP, primary care provider; SVR, sustained virologic response.
What you can see here is that it didn't matter who did the treatment; SVR rates were consistently high. And then, if you looked at the subset of HIV/HCV-coinfected patients, therapy was successful with no real difference between providers.
Slide credit: clinicaloptions.com
Kattakuzhy SM, et al. CROI Abstract 538LB.

60. Epidemiology
HIV Lifetime Risk

61. Diagnoses of HIV Infection among Men Who Have Sex with Men Aged 13–24 Years, by Race/Ethnicity, 2010–2014 United States and 6 Dependent Areas
This graph displays 2010 through 2014 racial/ethnic trends in the estimated numbers of diagnoses of HIV infection among young (aged 13–24 years at diagnosis) men who have sex with men (MSM) in the United States and 6 dependent areas.
Among young MSM (aged 13–24 years), the racial/ethnic group with the largest number of diagnoses each year during this time period were blacks/African Americans, followed by Hispanics/Latinos, whites, persons of multiple races, Asians, American Indians/Alaska Natives, and Native Hawaiians/other Pacific Islanders. Young Hispanic/Latino MSM experienced the largest increase in numbers of diagnoses of HIV infection of all racial/ethnic groups—from 1,488 diagnoses in 2010 to 1,898 diagnoses in 2014 (representing an increase of 28%).
Data include persons with a diagnosis of HIV infection regardless of stage of disease at diagnosis. All displayed data are estimates. Estimated numbers resulted from statistical adjustment that accounted for reporting delays and missing transmission category, but not for incomplete reporting.
Data on men who have sex with men do not include men with HIV infection attributed to male-to-male sexual contact and injection drug use.
Hispanics/Latinos can be of any race.
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 and missing transmission category, but not for incomplete reporting. Data on men who have sex with men do not include men with HIV infection attributed to male-to-male sexual contact and injection drug use.
a Hispanics/Latinos can be of any race.

62. Diagnoses of HIV Infection among Men Who Have Sex with Men Aged 13–24 Years, by Race/Ethnicity, 2014—United States and 6 Dependent Areas
N = 8,018
This pie chart displays the percentage distribution by race/ethnicity of young (aged 13–24 years at diagnosis) men who have sex with men (MSM) who were diagnosed with HIV infection during 2014 in the United States and 6 dependent areas. Of all MSM aged 13–24 years diagnosed with HIV infection in 2014, an estimated 54% were black/African American, followed by Hispanics/Latinos (24%) and whites (16%). This breakdown differs from the percentage breakdown in which all ages were considered: blacks/African Americans accounted for 38% of diagnoses among all adult and adolescent MSM, whites accounted for 30%, and Hispanics/Latinos accounted for 27% (see slide 6 in series). 
Data include persons with a diagnosis of HIV infection regardless of stage of disease at diagnosis. All displayed data are estimates. Estimated numbers resulted from statistical adjustment that accounted for reporting delays and missing transmission category, but not for incomplete reporting.   
Data on men who have sex with men do not include men with HIV infection attributed to male-to-male sexual contact and injection drug use.
Hispanics/Latinos can be of any race.
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 and missing transmission category, but not for incomplete reporting. Data on men who have sex with men do not include men with HIV infection attributed to male-to-male sexual contact and injection drug use.
a Hispanics/Latinos can be of any race.

63. CDC: Estimated Lifetime Risk of a Diagnosis of HIV Infection in the US
Overall lifetime risk has decreased
From 1 in 78 ( ) to 1 in 99 ( )
Large disparities by sex, race/ethnicity, and risk group for lifetime risk
All males (1.6%)
Black 7 times white (5% versus 0.8%)
MSM 79 times heterosexual (17% versus 0.2%)
PWID 13 times heterosexual (2.8% versus 0.2%)
All females (0.4%)
Black 18 times white (2.1% versus 0.1%)
Lifetime Risk of an
HIV Diagnosis Among MSM
50%
(1 in 2)
Slide: CDC: Estimated Lifetime Risk of a Diagnosis of HIV Infection in the US
Hess and colleagues estimated the lifetime risk of an HIV diagnosis for sex, age, and racial/ethnic subgroups as well as by state. They used HIV diagnosis, mortality, and census population data to derive lifetime and age-conditional risk estimates of being diagnosed with HIV. Data on HIV diagnoses (adjusted for reporting delays) were obtained from the National HIV Surveillance System (NHSS). The numbers of HIV diagnoses (NHSS) and non-HIV deaths (mortality data) between 2009 and 2013 were used to calculate probabilities of a diagnosis of HIV at a given age, conditional on never having developed HIV prior to that age using a competing risks method. The lifetime risk estimate is the cumulative probability of being diagnosed with HIV from birth. Age-conditional risk measures were the probabilities of an individual of a specified age being diagnosed with HIV within 10 years.1
Overall, the estimated lifetime risk of being diagnosed with HIV has decreased from 1 in 78 ( ) to 1 in 99 ( ). There were large disparities by sex, race/ethnicity, and risk group for lifetime risk.1
All males (1.6%).
Black 7 times white (5% versus 0.8%).
MSM 79 times heterosexual (17% versus 0.2%).
PWID 13 times heterosexual (2.8% versus 0.2%).
All females (0.4%), with black females 18 times white females (2.1% versus 0.1%).
Reference
Hess K, Hu X, Lansky A, et al. Estimating the lifetime risk of a diagnosis of HIV infection in the United States. Program and abstracts from the 23rd Conference on Retroviruses and Opportunistic Infection; February 22-25, 2016; Boston, MA. Abstract 52.
Risk (%)
25%
(1 in 4)
17%
(1 in 6) 9%
(1 in 11)
Overall
Black
Hispanic
White
PWID: persons who inject drugs.
Data sources: National HIV Surveillance System, National Center for Health Statistics (mortality), census data.
Hess K, et al. 23rd CROI. Boston, Abstract 52.

64. Lifetime Risk of HIV Diagnosis by State
Source: Centers for Disease Control (CDC)

65. Mental Health and HIV

66. Mental Disorders and Substance Abuse

67. Childhood Sexual Trauma

69. Persons Living with Diagnosed or Undiagnosed HIV Infection HIV Care Continuum Outcomes, 2012 — United States and Puerto Rico
This slide presents data on four HIV care continuum outcomes: HIV diagnosis (based on data from the National HIV Surveillance System) and receipt of HIV medical care, antiretroviral prescription, and viral suppression (based on data from the Medical Monitoring Project). The denominator is the estimated number of persons aged ≥13 years with diagnosed or undiagnosed HIV infection (prevalence, based on data from NHSS) in the United States.
Of an estimated 1,218,400 persons living with (diagnosed or undiagnosed) HIV infection in the United States at the end of 2012, 87.2% had been diagnosed, 39.1% received medical care, 36.2% were prescribed antiretroviral therapy, and 30.2% achieved viral suppression.
National HIV Surveillance System: Estimated number of persons aged ≥13 years with diagnosed or undiagnosed HIV infection (denominator) who were alive at the end of the specified year. Estimated number of persons aged ≥13 years with diagnosed HIV infection (numerator) who were alive at the end of the specified year; calculated as part of the overall prevalence estimate.
Medical Monitoring Project: Estimated number of persons aged ≥18 years who received HIV medical care January to April of 2012, whose medical record contained documentation of antiretroviral therapy prescription, or whose most recent VL in the previous 12 months was undetectable or <200 copies/mL—United States and Puerto Rico.
National HIV Surveillance System,: Estimated number of persons aged ≥13 years living with diagnosed or undiagnosed HIV infection (prevalence) in the United States at the end of The estimated number of persons with diagnosed HIV infection was calculated as part of the overall prevalence estimate.
Medical Monitoring Project: Estimated number of persons aged ≥18 years who received HIV medical care during January to April of 2012, were prescribed ART, or whose most recent VL in the previous year was undetectable or <200 copies/mL—United States and Puerto Rico.

70. THANK YOU
Questions /Discussion