Top 10 Stories in HIV Medicine Diane Havlir, MD Professor of - - PDF document

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

Top 10 Stories in HIV Medicine

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Disclosures

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

for NIH funded SEARCH research study

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Story 1: ART Guidelines

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AR1: In 2019, new ART Guidelines recommend which

• f these 2 drug regimens in initial therapy for “most

persons living with HIV?”

• A. Dolutegravir+ lamivudine ( DTG+ 3TC)
• B. Dolutegravir + rilpivirine (DTG+ RPV)
• C. Darunavir(boosted) + DTG
• D. All of the above
• E. None of the above

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Answer: None 2019: What to start in“most patients” CLASS REGIMEN INSTI BIC/TAF/FTC INSTI DTG/ABC/3TC INSTI DTG/TAF/FTC INSTI* RTG/TAF/FTC*

*HHS Guidelines only HHS guidelines, October 2018 IAS-USA Guidelines, JAMA, July, 2018 Some options TDF or TAF recommened

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2019 Updates

n Start ART for HIV-2 upon diagnosis and use INSTI

(integrase strand transfer inhibitor)

n Address substance use disorders when

screening and treating persons for HIV infection

n Provide gender affirmative care for transgender

population

HHS guidelines, July, 2019

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Summary

n This past year, there were some new

recommendations but not “transformative” changes in specific ART regimens

n We anticipate guideline changes in the coming

year upon approval of long-acting injectable cabotegravir/rilpivirine and as more information is forthcoming on combinations and agents

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Story 2: ART imperfections

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Association of Neural Tube Defects (NTD) and Dolutegavir during conception: less, but detectable

0.9 0.3 NTD with DTG at conception 0.1 NTD non-DTG at conception 0.08 NTD HIV-negative Zash, NEJM, 2019 Tsepamo Study, Botswana

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HHS Recommendations for women of childbearing potential

n DTG should not be prescribed for individuals:

• Who are pregnant and within 12 weeks post-conception
• Who are of childbearing potential and planning to become pregnant
• Who are of childbearing potential, sexually active, and not using effective

contraception

n For those who are using effective contraception, a DTG-

based regimen can be considered after weighing the risks and benefits of DTG

n Similar recommendations for bictegravir n Elvitegravir not recommended (pharmacokinetics); little

data on raltegravir

HHS guidelines, July, 2019

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Weight Gain and ART Large Randomized Study: “ADVANCE”

Venter, IAS and NEJM, 2019

• South Africa
• Treatment naïve
• No TB, pregnancy
• Primary endpoint:

viral suppression

• Secondary

endpoints: renal, bone, metabolic

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Large weight gains over time: greatest in DTG/TAF/FTC arm

Venter, IAS and NEJM, 2019

Recipients of DTG/TAF/FTC:

• 10 kg mean

weight increase in women

• 5 kg mean weight

increase in men

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Increasing proportion of obesity: greatest in TAF/FTC+ DTG

Venter, IAS and NEJM, 2019

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Summary

n Integrase strand transfer inhibitors (INSTIs)

remain the cornerstone of HIV therapy but dolutegravir

• was associated with small risk for neural tube defects in

Botswana

• was associated with unplanned weight gain in randomized

studies conducted in Africa

n As providers we must discuss evolving

information with our patients for decision making in optimal ART regimens

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Story 3: To TANGO or not? “2 Drug Regimens”

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Stage Setting

n One of the most dynamic areas in ART

management is “2 drug therapy”

n Why?

• We now have several proven potent “2 drug”

combinations to maintain viral suppression

• Toxicity can potentially be reduced with these

combinations

n Why not?

• Unwise use of these regimens can lead to drug resistance
• f agents we want to preserve
• Requires both drugs are fully active
• Data are mostly from tightly controlled clinical trials

where prior resistance can be identified and adherence may be higher

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Start: ART Naïve: DTG + 3TC vs DTG + 3TC + TDF are comparable

• Gemini Study N=1441
• DTG + 3TC vs DTG +

TDF/FTC

• Inclusion: ART naïve,

no resistance, no hep B or C

• HIV RNA <50 c/mL at

48 weeks similar; 3 drug appears betters CD4 <200

• Adverse events: 24%

(3 drug) vs 18% (2 drug)

HIV RNA <50 c/mL at 48 weeks Cahn, Lancet 2019 92% 2 DR 93% 3 DR

3 drug better when CD4 < 200

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Switch: ART experienced with viral suppression

n Randomized 741 patients on 3 drug ART to switch

to 2 drug ART or stay on 3 drug ART

TANGO study

Van Wyk. IAS 2019.

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Switch to 2 drug regimen was comparable to staying on 3 drug regimen

n HIV viral load

suppression 48 weeks 93.2% vs 93%

n Similar

adverse events in both arms

n No new drug

resistance

Van Wyk. IAS 2019.

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Switching to a 2 drug regimen – Cohort “Experience”

n Spanish Cohort 2016-2019 n Any switch to INSTI regimen

• Switch to 2 DR N= 617
• Switch to 3 DR N= 5047

n Over 2-fold higher virologic failure

with 2 DR vs 3 DR

n Over 2-fold higher virologic failure vs

3 DR among those with viral suppression at time of switch

Teira, EAC, 2019

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Summary

n There are excellent data and options for 2 drug

therapy for persons starting or switching therapy

n However, Use carefully!

• 2 drug therapy should be applied for patients that are similar

to those in the clinical trials

• Do not use in those with resistance to a regimen drug, poor

adherence, low CD4, or starting “same day”

n Depending on your clinical practice, the

proportion of your patients that qualify for 2 drug switches may vary

n This is rapidly evolving field that will change with

anticipated approval of 2 drug injectable therapies

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Story 4: Two New Drugs under study

GS-6207 MK-8591, Islatravir

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GS-6207: Long Acting Capsid Inhibitor

n Novel

mechanism of action

n Active against

ART resistant virus in vitro studies

n Sub-cutaneous

regimen

n Long acting

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GS-6207: Long half life

n Supports 3-6

month SQ dosing interval

n Potent antiviral

activity: 2 log HIV RNA reduction at 10 days

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MK-8591 (Islatravir) + Doravirine dose finding study

n Translocation deficient RTI (TDRTI) n Blocks RT through multiple steps n Oral formulation for treatment

Molina, CROI and IAS, 2019

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MK-8591:Antiviral activity

2 6 Molina LBPED46 Molina, CROI and IAS, 2019

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MK-8591: Two drug continuation phase

ISL 0.25 mg + DOR ISL 0.75 mg +DOR ISL 2.25 mg + DOR DOR+ TDF + 3TC N 29 30 31 31 d/c before week 24 4 3 HIV RNA <50 c/mL week 48 89% 90% 77% 84% Molina, CROI and IAS, 2019

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Summary

n GS-6207 and MK-8591 are promising new agents

in development with unique mechanisms of action

n Current planned studies are pairing these drugs

with other oral drugs for new combination regimens

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Story 5 : HIV “outbreaks”

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AR2 : What country has 160,000 persons living with HIV and a recent outbreak among children?

• A. Swaziland
• B. Ukraine
• C. Honduras
• D. Pakistan

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Answer: Pakistan

n April 2019. Media alerted

government officials about a surge of HIV cases in the Larkana District in Pakistan

n 872/30,192 persons tested

were HIV+; 719 were less than 15 years of age

n Risk Factors: unsafe needle

use, unsafe deliveries, blood banking, hospital infection control

Source: UNAIDS, WHO, photo from NYTimes

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Public Health Response

n Open a new HIV/ART clinic for children n Close down unauthorized labs, blood transfusion

centers, clinics with infection control violations

n Continue testing to identify scope of infected

persons

n Support country efforts to improve overall

prevention and care

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Summary: HIV epidemic in children globally

n 160,000 new HIV infections in children in 2018

• Gaps in ART during pregnancy and increasingly during

breast feeding

• Outbreak in Pakistan is a wake-up call for another important

transmission route often overlooked

n 1.8 million children living with HIV, only 940,000

children accessing ART

n In high burden countries children are 5% of HIV

population but account for 15% of deaths

n Gaps between adults and children are widening

in prevention and treatment and need urgent attention

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Story 6: From youngest to oldest

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AR3 : How many persons over the age of 55 years are living with HIV in the United States?

• A. 100,000
• B. 200,000
• C. 300,000
• D. 400,000
• E. 500,000

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Answer: 300,000

• 327,000 persons
• ver 55 yrs living

with HIV

• Of these, 60%

have viral suppression

Source: CDC

US HIV epidemic is aging

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Aging and HIV: Equity or Disparity?

n No 2 people age the same n Heterogeneity in prior exposures of HIV +

persons

n Gaps in knowledge on HIV and aging

JIAS, 2019

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Aging: Cancer Risk

n Risk higher HIV+ vs HIV- after 50 years of age for anal,

lung, liver, oral cancers

n Acceleration in risk in general population after 60 years n What will be impact in HIV population?

Mahale, CID, 2018

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Aging: Cancer outcomes

n Retrospective review U.S. Medicare database n 288 HIV+ (colon, lung, prostate, breast cancer)

307,890 HIV-

n Overall mortality was higher among HIV infected

vs uninfected persons

n Cancer specific mortality higher for prostate and

breast cancer

n Relapse rates higher for prostate or breast

cancer in the persons with HIV

Coghill, JAMA Oncology, 2019

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Aging: Long–term care

n Considerations of prior history

including “triggers” living with

• ther ill persons

n Stigma and discrimination

from extended care providers and residents

n Medical treatments that call for

agents that may interact with HIV medications

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Story 7: Yellow Brick Road to an HIV Cure

Saez-Cirion, Trends in Immunology, 2019

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AR4 : How many case reports of HIV cure or prolonged remission in adults are in the medical literature?

• A. One
• B. Two
• C. Three
• D. Four
• E. Five

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Answer: Two “Berlin” and “London” patients

“Berlin Patient”: HIV infected 1995, AML 2007 treated with 2 allogeneic stem cell transplants with CCR5 mutated donor cells, total body radiation and intensive chemotherapy

n No evidence HIV replication more than 10 years

later of antiretroviral therapy

n Questions:

• Which part of his intense regimen was critical for outcome?
• Can his outcome be replicated in other patients?
• Can his outcome be replicated in other patients with a less

intensive regimen?

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The “London” patient

n 2003 HIV+, CD4 290, VL 180,000 n 2012 ART EFV/TDF/3TC n 2012 Stage IVb Hodgkin’s Lymphoma

• Refractory to first and second-line chemotherapy with

treatment using over 9 agents

• HIV therapy switched to RTG/TDF/FTC, treatment

interruption with VL rebound, K65R and S157Q, resuppressed with DTG/RPV/3TC

n 2017 Allogeneic stem cell transplant

(conditioning regimen) with cells with CCR5 mutation

n 2019 No viral replication detected

Gupta, Nature, 2019

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“London Patient” Viral Replication and Chimerism of Donor Cells

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Summary

n Second HIV remission/cure achieved with CCR5

stem cell transplant

n Less “intensive” regimen– no whole-body

radiation

n However, therapy was very intense and not

practical

n Bright spot: Supports cure strategies blocking

CCR5 receptor

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Story 8: Discovering more about PrEP

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Results: 7 infections with F/TAF; 15 infections with F/TDF

Hare, CROI, 2019

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HIV Rate Comparison at Discover sites

n Comparison of

background HIV incidence rates in cities where study conducted suggested high levels of protection with both regimens

Hare, CROI, 2019

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Other observations

n Resistance: Unlikely different- 4 persons with

FTC resistance in TDF/FTC (suspected baseline infection)

n Safety: Both regimens were very well tolerated;

less bone mineral density loss in spine with F/TAF

n Pharmacokinetic analysis showed faster onset of

action and sustained duration of protection with F/TAF

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Summary

n FTC/TAF adds a new option for PrEP for MSM n May be better for those with renal/bone disease n Suggestion of faster onset and durability n Challenges/Issues for F/TAF

• Access for F/TAF
• Access for women
• Weight gain, lipids, Use for 2-1-1 regimen
• “Persistence” in the real world for all PrEP regimens

F/TAF approved by FDA for adults >35 kg at risk for HIV infection. Not approved for use by women who have vaginal receptive intercourse

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Story 9: HIV+ organ transplants

H I V + HIV+

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AR5 : What is the HOPE act?

• A. Allows HIV- donors for HIV+ transplant recipient
• B. Allows HIV+ donors for HIV+ transplant recipient
• C. Places HIV+ persons at top of transplant waiting lists
• D. Reduces the number of “clicks” needed to write an

EPIC note

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n HIV- to HIV + recipient: In hospital outcomes and

survival for kidney transplants are = between HIV+ recipients and HIV- recipients

n Number of HIV+ persons in need of a transplant

is increasing, but for kidneys, they spend more time on dialysis while waiting

n HIV+ to HIV+ transplant: South Africa, 51 done

2008-2018, 5-year survival ~ 80%

n Hope Act opens the door for the US in 2013,

implemented in 2015

Answer: The Hope Act allows HIV+ to HIV+ transplants

Selhort, NEJM, 2019; Wilk, Am J Transplant, 2019

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Transplants to HIV+ persons is increasing

HOPE Act Wilk, Am J Transplant, 2019

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Location of Organ Donors and Recipients

Wilk, Am J Transplant, 2019

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Summary

n The HOPE act increased the eligibility pool for

donors for HIV+ persons

n However, it appears to be underutilized to date

• 50 donors transplanted 102 organs
• 212 HIV+ on the waiting list
• Estimated 600 HIV+ potential donors annually
• Most programs accepting HIV+ organs on east or west

coast

n No concerning safety signals, but need more

follow-up

Wilk, Am J Transplant, 2019

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Story 10: Living in the USA

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United States “End the HIV Epidemic” in Ten Years

n February 5, 2019: President announces the

“End the HIV Epidemic” in the State of the Union Address

n Goal: Reduce new HIV infections by 90% over 10

years

Fauci, JAMA, 2019

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HIV Epidemic in the United States

n US has the most new HIV infections

annually ~ 40,000-- of any high-income nation in the world

n Decrease in new HIV infections has

stalled

n Highest % of new cases in the South

among blacks

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HIV Epidemic Snapshot

• 1.1 persons

million persons living with HIV

• 86% aware of

their HIV diagnosis

• 51% have viral

suppression

CDC, 2019

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El-Sadr, NEJM, 2019

US lagging in overall viral suppression

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Some of the highest rates of population level viral suppression with universal test and treat in Sub-Saharan Africa

Country level Universal Test and Treat

Makhema, NEJM, 2019; Hayes, NEJM, 2019; Havlir, NEJM,2019

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What can we do?

n Support HIV testing, expansion of PrEP and other

evidence based prevention measures

n Optimally treat our patients with a multi-disease

approach

n Participate in municipal or regional activities that

respond to epidemics

n Be a resource to colleagues and education

advocate for society

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Acknowledgments

Meg Newman Monica Gandhi Annie Luetkemeyer Susan Buchbinder Gabe Chamie Vivek Jain Moses Kamya Maya Petersen Colleagues at WHO UNAIDS and the Global Fund SF Getting to zero consortium

Special thanks to:

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