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Update From the 2018 Conference on

Retroviruses and Opportunistic

Infections

Jeffrey L. Lennox, MDProfessor of Medicine

Emory University

Atlanta, Georgia

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Learning Objectives

After attending this presentation, learners will be able to

describe the results of studies presented at the 2018

Conference on Retroviruses and Opportunistic Infections

(CROI) including:

▪ Studies on antiretroviral strategies

▪ Information concerning end-organ diseases

▪ Diagnosis and management of opportunistic infections

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Epidemiology Highlights

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Transmission Clusters with Rapid Growth- United States

• 26 States report HIV Sequence data from baseline genotyping to the CDC

• Sequences used to detect clusters where more than 5 transmissions were detected in a 12 month period

• 51,750 sequences analyzed from cases Jan 2013-Dec 2016

Cluster

903 (<2%)

Non-Cluster

50,847

Transmission/100PY 44 4

% Age <30 70 42

% MSM 83 59

Will this knowledge enable a new approach to reduce transmission

in the US? France 40

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Does Pregnancy Increase Risk for HIV Acquisition?

• Analysis of 2751 African women who had HIV-infected partner

• Women participated in 2 HIV prevention trials (Acyclovir or PrEP) and reported sexual behaviors and condom use. Men were tracked for viral load status and transmission risk censored when ART was initiated

• Sequence analysis done to ensure that only HIV linked to known partner was counted as a transmission

• Mean Baseline sex acts per month= 4

• 686 pregnancies studied

• Transmission risk adjusted based on condom use, woman’s age, PrEP use, male viral load

• Early Pregnancy = <14 weeks gestation

Hefron 45

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0

0.2

0.4

0.6

0.8

1

1.2

Non-preg Early Preg Late Preg Post Part

Condomless Sex/mo

Hefron 45

The period from 14 weeks to 6 months post-partum presents an opportunity to encourage condom use, PrEP and male ART

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

Non-preg Early Preg Late Preg Post Part

HIV Relative Risk

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Antiretroviral Therapy

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DTG→BIC, ABC→TAF, 3TC→FTC Switch – Why Bother?

• Suppressed HIV, no active HBV, GFR > 50 mL/min

• Placebo controlled, 4% noninferiority margin

• 90% Male

#22Molina

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DTG → BIC, ABC → TAF, 3TC → FTC Switch – Results

#22

D/A/L

281

B/T/E

282

% HIV RNA > 50 @ 48 wk 0.4 1.1

% Baseline GFR 99 102

Δ Spine BMD + 0.4 + 0.7

Δ Hip BMD + 0.4 + 0.2

# New ART resistance 0 0

# A/E → Drug D/C 2 6

Molina

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ABC → TAF – Effect on Platelets

#677LBMallon

• 61pts on ABC/3TC containing regimen randomized to continue or to switch to TAF/FTC. Platelet aggregation measured by platelet reactivity

• Switch to TAF/FTC resulted in less reactivity of platelets by collagen assay• Does this explain possible CV risk associated with ABC? In the Framingham

study ADP response was much more predictive for CVD than collagen response(MK Puurunen, JAHA 2018)

Trial funded by Gilead Sciences, Inc

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DRV/r +3TC vs DRV/r + TDF/3TC- 48 Week Results

Randomized open label study in treatment naïve patients

145 patients, 24% with baseline HIV RNA >100,000 c/mL

Results of a larger study with DTG/3TC are expected summer 2018

Cahn ANDES #489

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Same Day ART– A Randomized Trial

• Home based testing in rural Lesotho

• Newly HIV +, no other chronic conditions requiring care, randomized

to usual care vs. same day ART

- Usual Care: labs, 2 clinic visits → ART

- Same Day: no labs, 30 days TDF/3TC/EFV

• End Points – 3 month care linkage and % HIV RNA <200 c/mL at 12

months

274 patients Usual Care Same Day

% 3 months linked 43 69

% 12 months suppressed 34 50Labhardt #94

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Expedited ART– Experience in Atlanta

• Grady reduced barriers, with goal to begin ART within 72hrs

• Pre-intervention days to ART = 22, Post-intervention days to ART= 4.

Colasanti #1109

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Hair samples collected sequentially from 599 subjects receiving TDF/FTC + RAL or DRV/r or ATV/r

Hair drug levels measured

Hair levels strongest independent predictor of virologic success

Shown in cohort studies, but never before in randomized clinical trial

Hair Levels to Measure ART Adherence- A5257 Substudy

Gandhi #24

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Do INSTIs Cause IRIS?

• ART naïve adults/children in Africa, CD4 <100

• Randomized to ART vs. ART + 12 weeks RAL

• IRIS judged by blinded committee based on clinical description and timing with regard to ART

Gibb # 23

ART + RAL ART

Number Subjects 902 933

Mean Baseline CD4 38 36

% Baseline VL > 100k 77 74

Δ VL @ wk 4 - 3.4 L - 2.7 L

% Mortality @ wk 24 10.9 10.2

# Fatal IRIS 36 31

# All IRIS 89 86

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Resistance to INSTIs Without Integrase Mutation

• In vitro selected a DTG resistant virus that had WT integrase gene

• A mutation in the nef region caused a replicating, nonintegrated 1LTR DNA

• A patient has been reported with a similar mutation during DTG failure2

Delelis #244, 2.Witjing JID 2018

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End Organ Disease

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HIV and Arterial Disease

• Study of 908 HIV+ vs 11,106 HIV- Danes showed that an

abnormal Ankle-Brachial Index was twice as likely (12%)

among HIV+, controlling for risk factors1

• Presence of carotid artery plaque was associated with a

doubling of the risk of all cause mortality among men in the

MACS2

• In a separate MACS study men had sequential coronary

CT angiographies performed. HIV+ white males, but not

black males, were more likely than uninfected males to

have plaque progression31. Knudsen #76, 2. Hanna #78, 3. Post #77

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Impact of Low Dose Methotrexate on Endothelial Function

• In persons with rheumatoid arthritis the anti-inflammatory

Methotrexate has been associated with reduced CVD

• Elevated inflammatory blood measures have been observed in

persons with controlled HIV, and correlate with CVD events

• Will low dose Methotrexate be safe, reduce inflammatory

markers, and improve endothelial function in those with HIV?

• Escalating doses of MTX or placebo were given to subjects

with suppressed HIV and with known CVD or > 1 CVD risk

factor

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Low Dose MTX in Treated HIV-ACTG 5314

Hsue #79

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Frequency of Serious Clinical Events After Developing CKD

• Analyzed HIV + subjects with (2467) or without (1872) CKD as defined by a eGFR <60 mL/min or a 25% decline if Baseline <60

• Improved ART adherence, better diabetes treatment and smoking cessation would have improved mortality

• Treating dyslipidemia would prevent most CVD Ryom #75

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Opportunistic Infections

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Latent T.B. Treatment – A New Hope?

• For HIV+ patients current guidelines recommend either INH for 6 months, RIF/PZA for 2 months, or RIF for 4 months

• Will Rifapentine (RFP) enable a 4 week regimen?

• 2986 HIV+ in high TB setting randomized to daily INH for 9 months or daily INH + Rifapentine for 1 month

# 37

INH 9 INH + RFP 1 p

# Confirmed TB 14 18 NS

# INH Resistant 1 2

# RIF Resistant 1 1Chaisson A5279

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TB- Test and Treat or Treat All?

• 1050 ART naive, CD4<100

Blanc 29LB

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TB- Test and Treat or Treat All?

Blanc 29LB

• No survival advantage for treatment in the absence of a TB diagnosis

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INH Preventive Rx- Start During Pregnancy or Delay?

Randomized, placebo controlled, double blind trial

HIV-infected pregnant woman in high TB burden areas randomized

A- INH 300 mg Daily for 28 weeks

B- Placebo Daily through 12 weeks post-partum

Excluded those with suspected or known TB, recent TB treatment,

acute hepatitis or >grade 1 peripheral neuropathy

All women were on ART

Endpoints were AE>grade 3 or DC of protocol med due to toxicity

956 enrolled, 81% with HIV RNA <200 c/mL, median CD4 493

Gupta I1078 142LB

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INH Preventive Rx During Pregnancy- Results

No difference in the primary outcomes by treatment arms

Pregnancy complications more common with INH

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Cryptococcal Meningitis – Test of Higher Dose Fluconazole

• In areas where AmpB and 5-FC are not available WHO

recommends 14 Days of Fluconazole 1200 mg for CM

• ACTG 5225 compared 1200 mg Flu to AmpB and to 1600 mg

and 2000 mg Flu.

Characteristic 1200 mg 1600 mg 2000 mg Amp B

# Subjects 22 50 48 48

CD4 20 24 28 26

# on ART 0 8 12 11

CSF Pressure 200 200 210 260

Crypt CFU log10 5.2 5.0 4.4 4.7

Sameneka #35

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Cryptococcal Meningitis – Test of Higher Dose Fluconazole

Sameneka #35

Survival improved with higher dose Fluconazole

QTc prolonged with Flu, but not dose related. Vomiting 31% in 2000mg, 14% 600mg, 9% 1200mg

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Cryptococcal Meningitis – Does Sertraline Help?

• In a 2016 Sertraline dose ranging, open label study there

was indication of increased fungal clearance

• This double-blind, placebo controlled study compared

Amp B + Fluconazole 800mg ± Sertraline

• LP’s day 1, 3, 7, 10, 14

• 460 1st episode CM

The DSMB stopped the study when no impact of sertraline

found on mortality or fungal clearance#36Astro-CM

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Treatment as Prevention for Hep C

• Screened 3722 MSM

in the Swiss Cohort

with HCV PCR and

treated 90% of 177

positives

• 31 were incident cases

• Repeated screening of

all 3722 a year later

and discovered 16

incident cases

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Other Highlights

INSTI may not preserve telomere length as well as TDF/TFC (#758)

A combination of a broadly neutralizing antibody plus a TLR7 agonist

prevented viral rebound in monkeys with suppressed SHIV when ART

was withdrawn (#73LB)

Single dose, potent HDAC inhibitor Romidepsin did not induce HIV

expression in patients with suppressed HIV (#72)

Treating acute HIV very early may lead to more latently infected cells

since it interferes with cytotoxic T-cell responses (#66,#67)