Outline
HIV in 2017
March 22, 2017
Advances in Infectious Diseases
Monica Gandhi MD, MPH
Professor of Medicine
Division of HIV, Infectious Diseases, and Global Medicine
Medical director, “Ward 86” HIV Clinic, SFGH
Epidemiology: • Global
• U.S.
HIV testing: • When and how often?
HIV Prevention:
• Where are we in 2017?
HIV Treatment and a glimpse of the Cure
• Where are we in 2017?
When was the first report describing AIDS released?
1.
2.
3.
4.
5.
June 5, 1979
June 5, 1980
June 5, 1981
June 5, 1982
June 5, 1983
GLOBAL EPIDEMIOLOGY
1
First Clinical Descriptions of AIDS
Global HIV prevalence in adults, 1985
MMWR
Where did it come from?
Global HIV prevalence in adults, 1995
UNAIDS/WHO 1995
UNAIDS/WHO 1985
Global HIV prevalence in adults, 2005
UNAIDS/WHO 2005
2
How many people are currently living with HIV worldwide?
1.
2.
3.
4.
5.
15 million
20 million
30 million
37 million
50 million
Adults and children estimated to be living with HIV  2015
Total: 36.7 million [34.0 million – 39.8 million]
People with HIV on antiretroviral therapy 2010-2015
Total: 17 million (46%)
WHY PEOPLE LIVING WITH HIV
ARE BEING LEFT BEHIND
THE TOP 4 REASONS
01 Human rights violations, stigma and discrimination
02 Access to treatment and services
03 Gender-based inequalities
04 Criminalization and exclusion
2014
3
U.S. EPIDEMIOLOGY
>1.2 million HIV‐positive individuals in U.S. (1/8 don’t know status)
Risks in U.S. women cluster with poverty, disempowerment
HIV, especially in women clusters with poverty1,2; interpersonal violence3; incarceration4‐7; self‐esteem, alcohol/drugs8
U.S. Census 2013 estimates:
‐ 13.2% Black/African‐American ‐ 17.1% Hispanic/Latino
‐ 77.7% White
1Amidora. STDs 2006; 2CDC Surveillance 2011; 3Wyatt. Am J Public Health 2002; 4Doherty. JAIDS 2009; 5Doherty. Am J Public Health 2007; 6Adimora. Am J Public Health 2007; 7Khan. J Urban Health 2009; 8Forna. J Natl
Med Assoc. 2006
4
ARS: What percentage of the HIV population in U.S. has achieved the goal of therapy (complete virologic
suppression)?
1.
2.
3.
4.
5.
82%
66%
45%
30%
25%
ARS: How often should a patient be tested for HIV infection?
TESTING
1. Once, then every time the patient reports risk factors
2. Once every 2 years and with reported risk factors
3. Once yearly and with reported risk factors
4. Once every 6 months and with reported risk factors
5. Every admission
5
OraQuick® ADVANCE™ HIV 1/2 Test Oral Fluid Application
U.S. Preventative Services Task Force
Should test after 90 days
Recommendations changed April 2013
• Routine testing once for everyone age 15‐65 Reactive
HIV-1/2
Test Line
Swab upper and lower gums once
each with flat pad of test device
(“grade A” recommendation)
• Paves way for coverage under ACA
• Repeat testing based for Insert device in developer vial. Read result
between 20 and 40 minutes
Those higher risk for HIV infection
Those actively engaged in risky behavior
Those living in high‐prevalence setting
Negative
Positive
Screening for HIV: U.S. Preventive Services Task Force Recommendation Statement. Annals of Internal Medicine, April 30, 2013
ARS: What is the most effective modality of HIV prevention?
PREVENTION
1.
2.
3.
4.
5.
Male and female condoms
Circumcision
HIV vaccine
Pre‐exposure prophylaxis
Treating HIV‐infected individuals 6
Focus on pre‐exposure prophylaxis: PrEP
Clinical trials of TDF/FTC‐based PrEP
Trial
iPrEx1
Preexposure prophylaxis (PrEP) is giving an HIV‐
negative individual a pill (daily, or coitally?) to prevent HIV infection (studied: Tenofovir +/‐
emtricitabine)
We know this works if the person takes it
Recommended by the CDC, approved by FDA, recommended by WHO
Reduction in HIV infections (95% CI)
Men,
transwomen
Cisgender
women
44% ‐
MSM, transwomen
Americas, South Africa, Thailand
(15‐63)
Partners PrEP2
Mutually disclosed serodiscordant
heterosexual couples; Kenya, Uganda
84%
66% (54‐94)
(28‐84)
TDF23
Heterosexual men, women
Botswana
80%
49%
(25‐97)
(‐21‐81)
FEM‐PrEP4
VOICE5
PROUD6
IPERGAY7
Women
Kenya, South Africa, Tanzania
‐
Women Uganda, South Africa, Zimbabwe
‐
6% (‐52‐41)
‐4% (‐49‐27)
MSM (open‐label)
UK
(58‐96)
86%
MSM (intermittent PrEP)
France, Canada
(40‐98)
86%
‐
‐
No. of Adults with PrEP Indication
% of Adults with PrEP Indication
600,000
30
25
Population, Location
24.7
500,000
18.5
20
492,000
468,000
400,000
15
300,000
10
200,000
5
100,000
157,000
115,000
0.2
0.6
Hetero. Men
Hetero.
Women
0
0
MSM
PWID
MSM
PWID
Hetero.
Men
Hetero.
Women
Cohen MS et al. Prevention of HIV‐1 infection with early antiretroviral therapy. NEJM August 2011 (HPTN‐052)
Slide courtesy of Catherine Koss MD
7
HPTN 052 Study Design
HPTN 052: HIV‐1 Transmission
Total HIV-1 Transmission Events: 39
Stable, healthy, serodiscordant couples, sexually active
CD4 count: 350 to 550 cells/mm3 (Africa, Asia, Americas)
Linked
Transmissions:
28
Randomization
Immediate ART
CD4 350‐550
Delayed ART CD4 <250
Primary Transmission Endpoint
Transmission events that were linked to that primary partnership
Primary Clinical Endpoint
WHO stage 4 clinical events, pulmonary tuberculosis, severe bacterial infection and/or death
Occupational exposure PEP
Fluid
Blood
Risks
Unlinked or TBD
Transmissions: 11
People have sex outside of their
partnerships. .
Immediate
Arm: 1
Delayed
Arm: 27
• 23/28 (82%) transmissions in sub‐
Saharan Africa
• 18/28 (64%) transmissions from female to male partners
p < 0.001
96% reduction
• 238 pregnancies
People have unprotected sex .
Occupational PEP – now simplified
Risk
Yes
Semen/vaginal
Yes, not occupational
CSF, synovial, pleural, pericardial, amniotic
Unknown (presumed)
Feces, saliva, nasal, sputum, sweat, tears, urine, vomitus
No, unless bloody
• Percutaneous: 0.3% (95% CI 0.2‐0.5%) rate (deep vs superficial; large bore vs not; blood in tip or not; HIV end‐stage or not but still offer if viral load suppressed)
• Mucous membrane/non‐intact skin: 0.09% (95% CI 0.009‐0.6%) infection rate
CDC guidelines: last updated 9/2013
Kuhar DT. Infection Control and Hospital Epidemiology 2013; 34(9); 875-892
Decide on case‐by‐case basis
Try within 72 hours of exposure (1 week if high‐risk)
28 days
Tenofovir + emtricitabine + raltegravir (no 2 –drug vs 3‐drug PEP)‐ well‐tolerated, minimal interactions and resistance (consult expert if ?)
No nevirapine
Follow up testing at 6 wks, 12 wks and done at 6 months (4 months if 4th generation combination HIV p24 antigen–HIV antibody test available)
Kuhar DT. Infection Control and Hospital Epidemiology 2013; 34(9); 875-892
8
April 18, 2016
TREATMENT
Health care providers should evaluate persons
rapidly for nPEP when care is sought ≤ 72 hours after
a potential nonoccupational exposure that presents a
substantial risk for HIV acquisition
All persons considered for nPEP should have HIV
status checked- rapid combined Ag/Ab, or antibody
blood tests
28 day course of TDF/FTC + raltegravir (alternative
TDF/FTC + darunavir/ritonavir)
ARS: What are the recommendations to start treatment worldwide and in the U.S.?
1. Start HIV treatment when the CD4 count is <500 in U.S. and <350 globally 2. Start HIV treatment when CD4 <500 both sets of recommendations
3. Start HIV treatment regardless of CD4 in U.S. and <500 worldwide
4. Start HIV treatment regardless of CD4 worldwide
When to start treatment for HIV?
Recommendations NO LONGER differ
by resources
9
When to Begin Treatment for asymptomatic
patients - U.S. guidelines – 3/27/12 & 2/13/13
When to Begin Treatment for asymptomatic
patients – WHO guidelines– September 30, 2015
HIV Infection
HIV Infection
Prior to 3/12, start when CD4 count <500
ART is recommended for all HIV‐positive individuals
Prior to 9/30/15, start when CD4 count <500
ART is recommended for all HIV‐positive individuals
Universal ART policy adopted in San Francisco through HIV Division leadership (Havlir, Hare) and SFDPH January 2010
Prioritize CD4 <350 or stage 3, 4; pregnant and breastfeeding women; all children especially < 1 year DHHS. Guidelines for the use of antiretroviral agents in HIV‐1 infected adults and adolescents; Available at: http://aidsinfo.nih.gov; May 2015
World Health Organization. Guidelines on when to start antiretroviral therapy and on pre‐exposure prophylaxis for HIV. September 30, 2015
25th Annual CCO HIV and Hepatitis C Symposium
START study
clinicaloptions.com
START: Immediate vs Deferred ART

Although rates of serious AIDS‐
related events and serious non‐
AIDS‐related events were both lower, “risk reduction was more pronounced for the AIDS‐related events”
Benefits similar in low, mid and high‐
income countries
START and IPERGAY endorsed by Anthony Fauci, NIAID director, today on WAD
International, randomized phase IV study
– 215 sites in 35 countries
Interim results:
serious AIDS and
non-AIDS events, n
Randomized 1:1
ART-naive adults with
CD4+ cell count
> 500 cells/mm3
(N = 4685)
Immediate ART*
Delayed ART*
(until CD4+ cell count
≤ 350 cells/mm3)
41
86
*Any licensed ART allowed, according to national guidelines.

Study stopped by data and safety monitoring board following results of interim
analysis
– Risk of serious illness or death reduced by 53% with immediate ART
– Rates of serious AIDS-related and non–AIDS-related events lower in immediate
ART arm
START NEJM 2015.
START NEJM 2015.
10
HIV Life Cycle and Antiretroviral Targets
DNA
3) Integration
WHEN TO DELAY
THERAPY
RNA
1) Virus Entry
Hardly EVER (TB meningitis,
other space-occupying
lesions with inflammation,
cryptococcal meningitis)
HIV Life Cycle and Antiretroviral Targets
3) Integration
Integrase
strand transfer
inhibitors
(INSTI):
2) Reverse transcriptase
RT
5) Translation
4) Transcription
CD4 receptor
(CXCR4, CCR5)
9) Re-infection
6) Cleavage
8) Maturation
7) Packaging
The history of ARV approvals- the ascent of the integrase
inhibitor and the descent of EFV/Atazanavir
Dolutegravir
Elvitegravir
DNA
Nucleos(t)ide reverse
2) Reverse transcriptase
RT
transcriptase
inhibitors (NRTIs):
RNA
Non-nucleoside
reverse transcriptase
inhibitors (NNRTIs):
5) Translation
4) Transcription
6) Cleavage
Protease
inhibitors (PIs):
1) Virus Entry
Fusion (entry) inhibitor:
CD4 receptor
e.g. enfuvirtide
(CXCR4, CCR5)
CCR5 receptor
9) Re-infection
antagonist:
e.g. maraviroc
Golconda
8) Maturation
7) Packaging
2012 2013
11
Cumulative problems for EFV (CNS side effects) ‐ EFV as Initial Therapy: Increased Risk for Suicidal Ideation Review of 4 ACTG studies in ART‐naïve patients
Compared 3241 patients starting EFV vs 2091 patients starting non‐EFV‐based ART
Median duration f/u 96 weeks
First suicidal ideation OR attempted OR completed suicide in each group
• 8.08 events per 1000 PY in EFV group vs 3.66 events per 1000 PY in EFV‐free group (HR: 2.28; 95% CI, 1.27‐4.0; P=.006)
Cumulative problems for ATV: ACTG A5257
HIV+ adults, no previous ART (n=1809)
Randomized 1:1:1. Open Label Therapy
ATV/r + FTC/TDF
DRV/r + FTC/TDF
RAL superior to both PI/r regimens for combined
tolerability and virologic efficacy; DRV/r superior to ATV/r;
ATV/r lost due to tolerability issues
Lennox J et al, Ann Int Med, 2014
Mollan KR, et al. Ann Intern Med. 2014;161:1-10.
Ascent of the integrase inhibitor
RAL + FTC/TDF
Current Guidelines:
What to Start – 2016
Three and one in phase III trials
Recommended Regimens (n=6)
INSTI (n=5)
Dolutegravir/ABC/3TC
Dolutegravir + TDF/FTC
Elvitegravir/cobi/TDF/FTC§
Elvitegravir/cobi/TAF/FTC – added 11/15
Raltegravir +TDF/FTC
PI (n=1)
Darunavir/ritonavir +TDF/FTC
Dolutegravir
Elvitegravir
Raltegravir
§
Only if CrCl >70
http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf
David Lazar‐ The Ascent
12
Alternative Regimens
NNRTI (n=2)
Efavirenz/TDF/FTC
Rilpivirine/TDF/FTC*
PI (n=5)
ATV/r or cobi§ + TDF/FTC
DRV/cobi§ + TDF/FTC
DRV/r or cobi + ABC/3TC
ARS: How many single pill combinations for the treatment of HIV are there now?
*Only if VL <100K and CD4 >200. §Only if Cr Cl >70
Effective and tolerable but have potential disadvantages, have limitations for use in certain patient populations, or have less supporting data than Recommended Regimens
1.
2.
3.
4.
5.
2
3
4
5
6
An alternative regimen may be the preferred regimen for some patients
Currently available SPCs
Picture of SPC
Drugs in SPC
Approval Food effects
date
TDF/FTC/efavirenz (Atripla®)
TDF/FTC/rilpivirine (Complera®)
2006
Food  levels
2011
Take with solid
meal (390kcal)
TDF/FTC/elvitegravir/ cobicistat (Stribild®)
ABC/3TC/dolutegravir (Triumeq®)
TAF/FTC/elvitegravir/ cobicistat (Genvoya®)
TAF/FTC/rilpivirine (Odefsey®)
2012
Take with food (373kcal)
2014
Food  levels
2015
Take with food (373kcal)
Take with solid
meal (390kcal)
2016
Examining questions of dual therapy
NRTI intolerance (HLA‐B5701 and renal failure) or NRTI mutations
Minimize pill burden
Minimize toxicities
Minimize cost
Preserve treatment options for future
INSTIs (e.g. dolutegravir, cabotegravir) potent and medium‐high genetic barrier to resistance– will this allow the possibility?
Allow for long‐acting therapy (just 2 available right now; in phase III trials)
13
SWORD‐1 and ‐2: Switch to Dolutegravir Plus Rilpivirine Noninferior to Remaining on Baseline ART at Week 48 in Virologically Suppressed Patients
CROI 2017 #44LB
2 true virologic “failures” in SWORD arm – one developed K103K/E (NNRTI mutation), no INSTI mutations
14
The Mississippi Baby
28 month old child (now 37 mo) born at 35 weeks gestation (2.5kg) via NSVD
Rapid HIV test positive in mother during labor (CD4 644; viral load 2423 copies/ml)
No antiretrovirals in labor (precipitous delivery)
HIV viral load (~20,000 copies/mL) at 30 hours of age
AZT/3TC/NVP (usually 1 drug) started as “prophylaxis” by 31 hours of age (31 hrs‐7d), therapeutic dose of NVP used; latter switched to LPV/r (protease inhibitor) (7d‐18 months) after 1 week
Persaud. NEJM 2013
“Typical biphasic decay”
What happened to baby?
Mother and baby lost to follow‐up when baby 18 months old
Baby off treatment
Re‐appeared ~24 months Plasma HIV RNA remained undetectable (off therapy)
Super low HIV DNA in PBMC, no infectious virus (“graveyard” sequences)
No Western blot reactivity for child (remains reactive for mother)
•Baby (~42 months) still negative (CROI March, 2014)
•Baby (nearly 4 yrs) on 7/10/14 announced to have HIV viremia (16,750 copies/mL)
Persaud. NEJM 2013
15
Cure research initiative
(Steve Deeks and team)
Strategies being pursued
• Early ART may be curative
• Stem cell transplants to reduce reservoir
• Drugs to flush out HIV from latent reservoirs
• Vaccines to enhance host clearance
Barriers anticipated
• Current ART not fully suppressive
• No high through‐put reliable assays to examine reservoir
• Flush out drugs may not work as monotherapy
16