1 Answer: The number of persons living Good News: People are living - - PDF document

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Diane Havlir, MD Professor of Medicine University of California, San Francisco

Top 10 stories in HIV Medicine Disclosures

n Receive funding for research from NIH n Gilead sciences provides antiretroviral therapy

for NIH funded SEARCH research study

n Ate breakfast at Roche Laboratory advisory

meeting

n Serve on advisory board for Gilead/Vatican

collaboration for Tanzania study

Story 1: Global HIV trends and trendiness AR1: The number of persons living with HIV globally is

n Decreasing n Staying about the same n Increasing

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Answer: The number of persons living with HIV is increasing: 36.7 million

Year Total living with HIV ( millions) New HIV infections/year in millions 2001 29.4 3.2 2011 34.0 2.5 2015 36.7 2.1

n Even though new HIV

infections are decreasing

n Persons are living longer

with HIV

n Result-- Net gain in persons

living with HIV and more needs for care!

Good News: People are living longer because of the ART expansion

n 17 million persons are

accessing ART

n WHO calls for

treatment of all persons - 36.7 million

• not restricted by CD4
• Many countries are

adopting these guidelines such as South Africa, Kenya

• Some countries are still

lagging behind such as Nigeria

ART Deaths

Less Good News: Eastern Europe & Central Asia

• 1.5 Million persons with HIV
• 57% increase in new HIV

infections since 2010

• Only 1 in 5 people living

with HIV on ART

• Increasing proportion of

migrants with delayed diagnosis

Source: Pascal Dumont

UNAIDS, 2016; El Bassel et al 2016; Hernando et al, 2015

Source: T. Zafar

Adapted from: Steffanie Strathdee: Opening Plenary Address AIDS 2016, & UNAIDS Report 2016

And also in the Middle East & North Africa– challenges

UNAIDS, 2016

• 230,000 persons with HIV
• Only 17% of PLWHA on ART
• >90% of new HIV infections

among key populations and their sex partners

Adapted from: Steffanie Strathdee: Opening Plenary Address AIDS 2016, & UNAIDS Report 2016

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What about elimination of HIV infection among children globally?

Still falling short: 150,000 children infected with HIV in 2015

And we have a new “Youth Bulge” in Sub-saharan Africa

n Increase in proportion of youth in SSA

• At risk for HIV (population demographics)
• Children with HIV moving into adolescence
• 2.0
• 1.0

0.0 1.0 2.0 0-4 10-14 20-24 30-34 40-44 50-54 60-64 70-74 80-84 90-94 100+ Females Males

• 4.0
• 2.0

0.0 2.0 4.0 0-4 10-14 20-24 30-34 40-44 50-54 60-64 70-74 80-84 90-94 100+ Females Males

1950 2050

Why is this important?

n Adolescents do

worse on ART

n Uninfected youth

bulge (esp. women) may be particularly challenging for PREP

• Young women have

lower PrEP adherence, poorer effectiveness

AGE GROUP 2014 VIRAL SUPPRESSION 5 – 9 year-olds 71% (95 CI; 71 – 72%) 10 – 15 year-olds 65% (95 CI; 65 – 66%) 15 – 19 year-olds 61% (95 CI; 60 – 61%) Adapted from Strathdee, TUPL0101, AIDS 2016 Maskew, TUAB0102, AIDS 2016

AR2: What is the latest trend in HIV care in Africa?

n Drone delivery of HIV medications n 2 drug therapy n Injectable HIV therapy n Treatment “Clubs”

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Answer: Treatment Clubs

n “Treatment Clubs” are part of a larger movement

• f “Differentiated Care”

n What is Differentiated Care?

• A client-centered approach that simplifies and adapts HIV

services across the cascade to reflect the preferences and expectations of various groups of people living with HIV while reducing unnecessary burdens on the health system

What are treatment clubs?

Health care worker-managed group Client-managed group

n Who? Patients stable on ART

for 6-12 months with viral suppression

n What? Meet every 3 months,

pick up medications, physician visit annually, nurse visits for viral load to group

n Why? Patients like it better,

decongestion in health clinic with universal treatment

Where? Health care worker managed Clubs

Also known as: ART Adherence clubs, family clubs, youth clubs, patient adherence groups

http://www.differentiatedcare.org/Models/ HealthCareWorkerManagedGroup

Location and club “type”

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0% 5% 10% 15% 20% 25% 30% 5,000 10,000 15,000 20,000 25,000 30,000 35,000

Jan Feb Mar Apr May Jun Jul Aug Sept Oct Nov Dec Jan Feb Mar Apr May Jun Jul Aug Sept Oct Nov Dec Jan Feb Mar Apr May Jun Jul Aug Sept Oct Nov Dec Jan Feb Mar Apr May Jun Jul Aug Sept Oct Nov Dec Jan Feb Mar 2011 2012 2013 2014 2015

# RIC in Adherence Clubs % of total ART cohort in an Adherence Club

Outcomes: Adherence Clubs in Cape Town

Wilkinson et al, TMIH, 2016

Data as of June 2016: N=53,523– 36% of the cohort

• Cumulative retention:
• 12 months: 95.2%
• 24 months: 89.3%
• 36 months: 82.1%

97%, 96%, 94% virally supressed

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Story 2: ART options – the new “+2”: TAF/FTC AR3: Which of these is not a first line preferred regimen?

1.

EFV + TAF/FTC

2.

DTG + TAF/FTC

3.

Duranaivr/R/TAF/FTC

4.

Evitegravir/Cobi/TAF/FTC

5.

Raltegravir/+ TAF/FTC

Answer: EFV + TAF/FTC is alternate first line

STARTMRK, GS 102 and 103, SINGLE, FLAMINGO, and ACTG 5257 suggest that integrase inhibitor–based regimens are the preferred starting regimens in the majority of pts

Recommended First Line Regimens INSTI based DTG/ABC/3TC* DTG + TDF/FTC or +TAF/FTC EVG/COBI/TDF/FTC or EVG/COBI/TAF/FTC RAL + TDF/FTC or + TAF/FTC PI based DRV/r + TDF/FTC or + TAF/FTC From 2016 updated DHSS Guidelines: * HLAB5701 negative Cr Clearance >70

Phase 3 Trials Find TAF Non-inferior to TDF

Studies 104 and 111: Week 48 Combined Analysis n

E/C/F/TAF was non-inferior to E/C/F/TDF at Week 48 in each study

• 93% E/C/F/TAF vs. 92% E/C/F/TDF (Study 104)
• 92% E/C/F/TAF vs. 89% E/C/F/TDF (Study 111)
• No differences in outcome when stratified by CD4 and VL

Favors E/C/F/TAF

4.7% ‒0.7% 2.0% HIV-1 RNA <50 c/mL, % Treatment Difference (95% CI) Virologic Outcome ‒12% +12%

Favors E/C/F/TDF Wohl D, et al. 22nd CROI; Seattle, WA; February 23-26, 2015. Abst. 113LB.

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Story 2A: What about 2 drugs only for initial therapy?

777777777 777777777] 7777777777\ 7777777777\\

n Increasing data with 2

drug regimens

• Dolutegravir + 3TC
• Dolutegravir + ripilvirine

n Not ready for prime time–

phase III studies on going

Story 3: Missing persons

Tent encampment in San Francisco

Project Hope Study

n To assess the effect of a 6 month structured patient

navigation intervention with and without conditional financial incentives to improve rates of HIV viral suppression at 1 year among substance users recruited with elevated viral loads

801 HIV-infected adults admitted to 11 hospitals Metsch, JAMA, 2016

Patient Navigation (PN) up to 11 sessions

n Strengths-based approach

incorporates

• Stages of change theory
• Motivational

interviewing (MI)

• Motivates linkage to HIV

primary care, initiation and maintenance of ART

• Emphasizes importance
• f substance use

treatment

PN + Contingency Management

n Escalating scale of

reinforcement:

• 11 PN meetings(up to $220)
• *Completion of paperwork (up to

$80)

• 4 HIV care visits (up to $180)
• Substance use treatment (up to

$90)

• Drug-free specimens (up to

$220)

• 2 blood draws (up to $50)
• HIV medications (up to $170)
• *2-log10 drop in viral load ($50)
• *HIV viral suppression ($100)

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*Reimbursement for these target behaviors was non-escalating.

6 Month Intervention

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AR4: What do you think happened?

n Patients used funds to buy drugs and no effect n Modest effect at 6 and 12 months n Large effect at 6 months, no effect 12 months n Modest effect at 6 months and no effect at 12

months

Answer: Modest effect at 6 months and no effect at 12 months

26 11.0% 33.6% 34.1% 11.3% 39.1% 35.7% 10.3% 46.2% 38.6% 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Baseline 6-months 12-months TAU PN PN+CM

6-Months χ2(2)=6.54, p=.04 Primary Outcome χ2(2)=0.78, p=.68

What next?

n Continue to study and innovate to find the best

ways to reach this patient population

n Work with community partners and leaders on

housing, mental health services and substance use support

n Provide dignity, empathy and support for our

patients as best we can while we figure this out

Story 4: Long acting agents: Update

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LATTE-2: Cabotegravir IM + Rilpivirine IM for Long-Acting Maintenance ART

n Multicenter, open-label, randomized phase IIb study

• Primary endpoints: HIV-1 RNA < 50 copies/mL at maintenance

Wk 32, PDVF, and safety

Slide credit: clinicaloptions.com Margolis DA, et al. AIDS 2016. Abstract THAB0206LB. CAB 400 mg + RPV 600 mg IM Q4W (n = 115) CAB 600 mg + RPV 900 mg IM Q8W (n = 115) *Pts with HIV-1 RNA < 50 copies/mL from Wk 16-20 continued to maintenance phase.

†Pts eligible for Q4W or Q8W LA extension past Wk 96.

ART-naive HIV- infected pts younger than 18 yrs of age with CD4+ cell count > 200 cells/mm3 (N = 309) CAB 30 mg + ABC/3TC 600/300 mg PO QD (n = 56) CAB 30 mg + ABC/3TC 600/ 300 mg PO QD Wk 32 Wk 20

Induction Phase* Maintenance Phase

Day 1 Wk 96† Wk 16: RPV 25 mg PO QD added Wk 48

LATTE-2: Efficacy and Safety Through Maintenance Wk 48

§

Virologic efficacy of Q4W/Q8W IM therapy similar to oral therapy § 99% of ISRs for pts receiving injectable therapy grade 1 (82%)

• r 2 (17%); none grade 4

– Most frequent ISRs: pain (67%), nodules (7%), swelling (6%) – Reported ISRs decreased over time (86% Day 1, 29% Wk 48) – 2/230 pts (< 1%) withdrew for ISRs (both in Q8W arm)

§

AEs leading to withdrawal

– Pooled Q4W/Q8W IM arms, 4% – Oral arm, 2% Slide credit: clinicaloptions.com Margolis DA, et al. AIDS 2016. Abstract THAB0206LB Outcome, % (n) IM CAB + RPV Q4W (n = 115) IM CAB + RPV Q8W (n = 115) Oral CAB + ABC/3TC (n = 56) Virologic success (HIV-1 RNA < 50 copies/mL) 91 (105) 92 (106) 89 (50) Virologic nonresponse < 1 (1) 7 (8) 2 (1) No virologic data 8 (9) < 1 (1) 9 (5)

LATTE-2: Wk 48 Pt Satisfaction With IM and PO Regimens

Slide credit: clinicaloptions.com Margolis DA, et al. AIDS 2016. Abstract THAB0206LB. Wk 48 Patient-Reported Outcomes, % IM CAB + RPV Q4W (n = 103) IM CAB + RPV Q8W (n = 109) PO CAB + ABC/3TC (n = 49) How satisfied are you with your current treatment? § 6 79 83 67 § 5 20 14 29 § < 5 1 3 4 How satisfied would you be to continue with your present form of treatment? § 6 85 88 55 § 5 13 11 33 § < 5 2 1 12

n

Pt satisfaction assessed using 0 to 6 scoring (0 = very dissatisfied, 6 = very satisfied)

AR5: Approximately how many days is rilpivirine detectable after a single injection?

n 30 days (1 month) n 60 days (2 months) n 90 days (3 months) n >352 days (1 year)

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Answer: Greater than 1 year

n All patients had

detectable RPV levels at a mean 541 days (1.5y) after single dose

Adapted from McGowan et al. IAC

• 2016. Abstract TUAC0103

All Samples 1200mg Samples RPV concentrations decline over time but are detectable long after single dose

Recap: Long acting ART given by injection

n Cabotegravir and rilpivirine combination given by

injection works for maintenance for HIV treatment

n Patients reported high satisfaction scores n A 4 week dosing interval was chosen to go

forward in the Phase 3 studies

n The long “tail” of ripilvirine requires patients do

not discontinue therapy without protection of another drug for a year in the clinical studies

Story 5: Confidence

n How confident are we that there will be no HIV

transmission from a person who is HIV infected with viral suppression to an HIV uninfected person in the absence of condoms?

PARTNERS Study

Rodger, JAMA 2016; 316(2):171-181

n Serodifferent couples recruited from 14 European

countries

• HIV positive partner on ART, VL < 200
• Having condomless sex (and remained serodifferent)
• Intend to have sex in upcoming months

n 888 couples contributed data

• Median 5-11 years on ART before study (MSM, hetero)

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There were zero new HIV infections

Rodger, JAMA 2016; 316(2):171-181

Undetectable viral load does not prevent against other STDs including Hepatitis C

Rising syphlis rates in San Francisco

Story 6: PREP is taking off… in some places

n How many in US n Who? where? n And what do we hope PREP expansion will do in

reducing new HIV cases?

From the Fenway Institute

Men and Women Starting FTC/TDF for PrEP in US, 2012 to 2015

4-YearTotal: 79,684 6,210 Women: 18,812 Men: 60,872 9,023 21,906 42,545 McCallister, TUAX0105LB, AIDS 2016

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AR6: What state is not in the top 5 for PREP uptake?

n California n New Jersey n New York n Texas n Florida South Northeast Midwest West TX 6.8% NY 15.9% IL 5.4% CA 16.7% FL 5.7% MA 5.1% MN 2.5% WA 3.5% GA 3.7% PA 4.7% OH 2.1% AZ 1.8% DC 3.3% NJ 2.5% MO 1.2% CO 1.5% NC 1.7% CT 0.8% MI 1.2% OR 1.2% MD 1.5% RI 0.5% IN 1.0% NV 0.6% VA 1.2% NH 0.2% WI 0.6% UT 0.5% TN 1.0% ME 0.2% KS 0.5% NM 0.4% LA 0.9% VT 0.1% IA 0.3% HI 0.2% AL 0.5% NE 0.2% ID 0.2% SC 0.4% ND 0.1% MT 0.1% KY 0.4% SD 0.0% WY 0.1% OK 0.4% AK 0.0% MS 0.3% DE 0.3% AR 0.2% WV 0.1% McCallister, TUAX0105LB, AIS2016

Answer: New Jersey. CA, NY, TX, FL, & IL account for 50.5% of unique individuals starting PREP

What might we gain with PrEP?

n 40% coverage among MSM over the next 10

years would avert

• 1162 infections/100,000 persons
• 33% of all new expected HIV infections

n The predicted Number Needed to Treat (NNT)

would be 25

n Reducing NNT requires better adherence

Jenness, JID, 2016

A modeling study of varying PREP coverage and adherence

Story 7: Hepatitis C cure is taking

• ff… in many places

n And not a moment too late!! n >3.5 million persons living

with hepatitis C in US alone,

• nly half aware

n New cases increasing –

30,000/year

n Deaths estimated as

20,000/year

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Hepatitis C cures for treatment naïve: 12 weeks covering all genotypes!!

GT 1 GT 2 GT 3 GT 4,

Sofosbuvir- ledispavir X X Sofosbuvir- velpatasvir X X X X Sofosbuvir- daclatasvir X X X X Elbasvir- grazoprevir X X

Adapted from Up to Date

A few key points

n New curative hepatitis C treatments are

compatible with many ART regimens and most do not require ribavirin and none require interferon

n They are well tolerated n Treatment regimens do differ for cirrhotics and

previously treated patients who were not cured… stay tuned

n Cure does not provide immunity, and patients

can get re-infected with hepatitis C

Story 8: Cryptococcal meningitis

• n Steroids

n Cryptococcal meningitis: 600,000

deaths worldwide annually

n Even with amphotericin + 5 FC,

mortality approaches 30%

n Gluco-corticosteroids reduce mortality

in some CNS infections

• TB
• Bacterial meningitis

n What about cryptococcal meningitis?

AR7: Cryptococcal meningitis in HIV disease – How much do adjunctive steroids reduce mortality?

n 10% n 20% n 30% n 40% n Not at all

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Answer: Not at all, in fact it was harmful

n Double blind

randomized placebo controlled trial

n HIV+ adults with

cryptococcal meningitis in Southeast Asia and Uganda

n All patients received

amphotericin and 5 FC

n Intervention :

Dexamethasone vs placebo x 6 weeks

Mortality 41% P, 47% I Beardsley, NEJM, 2016

Story 9: The HIV provider pool

n Who are we? n Will there be enough providers to meet future

demand?

HIV Providers in the United States

Characteristic Proportion Age <40 years 17.5% 40-49 years 24.0% 50-59 years 38.4% > 60 years 20.1% Female 43.5% White 62.9% Black/AA 10.8% Hispanic 10.7% Degree: MD 80% NP 15% PA 5% Years caring for HIV: 0-10 35.3% 11- 20 36.1% 21-30 28.6

• Weiser. CID. 2016

Key Challenges

n Shortage of manpower of HIV providers

• About 10% providers expected to leave practice over the

next 5 years

• Influx of new providers is >10%, but insufficient to meet

projected care needs of growing HIV population

n Dissatisfaction in several domains

• Effort required to keep up with clinical advances
• Time spent on documentation/administration
• Salary equity to other specialties

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Story 10: Treating our way out of the epidemic - Myth or Madness?

How close are we with test, treat and prevent approach ? San Francisco East Africa (SEARCH)

• 15,995 living

with HIV

• 255 new

diagnosis (17% decline)

• 197 deaths

Universal ART PrEP GTZ*

San Francisco: New HIV case decline

*GTZ:Getting to Zero San Francisco– Zero infections, Zero deaths, Zero stigma

www.gettingtozerosf.org

But… Great Disparities and Health Inequities: Viral Suppression

SEARCH Key Questions

Can a population-based ART strategy “shut down” new HIV infections?* What are the additional gains? (maternal child health, TB, education, household earning power?) What is the best way to do it? What would it cost? Can efficient HIV chronic care models be adapted to establish care for other chronic diseases (hypertension and diabetes)?

*

SEARCH Partners

PEPFAR NIH WHO World Bank UNAIDS Gilead Sciences Uganda MOH Kenya MOH

UGANDA KENYA

Mbarara Tororo Homa Bay//Migori

320,000 person study in 32 communities in rural East Africa

SEARCH: Sustainable East Africa Research for Community Health

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HIV Testing and Treatment Community based and Client Centered

n GOAL: 90/90/90 n APPROACH:

• Community based, out of facility
• Multi-disease: HIV, DM, HT, malaria
• “Collapse the Cascade”-- immediate

link to public health services

1.Two week multi- disease Health Fairs 2.Home testing for non-participants 3.Patient centered ART care

UN AIDS 90-90-90 Target Exceeded after 2 years SEARCH intervention

70% 80% 86% 96% 91% 89% 97% 94% 90% 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% % HIV+ w/ Prior Dx % Prior Dx ever on ART % Ever on ART w/ Supp

Cascade coverage among prevalent HIV+

Baseline Follow Up Year 1 Follow Up Year 2 Petersen, IAC, 2016

90% target 82% population level viral suppression

Conclusion

n We still have a growing population of persons

living with HIV, half of whom are still not in care,

• r on treatment

n There continues to be great strides in HIV

treatment uptake, new options, roll-out of PREP and research for a HIV cure

n Disparities remain a major challenge – for HIV

and co-infections like hepatitis C with some, but suboptimal progress

n HIV workforce issues need to be addressed

Acknowledgments

Begin, be bold and venture to be wise Horace Persons living with HIV Monica Gandhi Annie Luetkemeyer Susan Scheer + team Susan Buchbinder Vivek Jain Moses Kamya Maya Petersen Gabe Chamie Meg Newman Colleagues at WHO UNAIDS and the Global Fund SF Getting to zero consortium

Special thanks to: