Beyond the undetectable viral load

Graham P TaylorSection of Retrovirology and GU MedicineDivision of Infection

How to measure HIV

SensitivityPatients RNA PCR Culture P24 antigen

Symptomatic 100% 83% 63%Asymptomatic 74% 13% 13%

Van Kerckhoven et al J Clin Microbio 1994;32(7):1669-1673

How much virus in blood if VL undetectable?

<5,000 copies/L

<25,000 copies/ adult blood volume

<1000 copies/ml

<400 copies/ml

<50 copies/ml

<5 copies/L

Where to measure HIV viral load

Peripheral Blood ~1% Lymphocytes

Lymph Node ~5% Lymphocytes

Plasma <1 - >2,000,000 copies viral RNA/ml

680 x 106 new virions per day

Compartmentalisation of HIV

Brain

Breast

Genital tract

Lung

LiverKidneysGut

What does an undetectable HIV viral load mean?

Prevention of HIV transmission through sexual intercourse?Prevention of HIV mother-to-child transmission?Longevity?Low morbidity?Cure?

HIV RNA in plasma & cervico-vaginal lavage in elite controllers

33 elite controllers from WIHS ( <80 HIV RNA copies/ml plasma x 2 years)Aptima qualitative assay using 0.5 ml plasma in quadruplicate.Sensitivity ≈ 1 copy/ml

93 plasma samples over median 4 yearsLow level viraemia detected in 88% (1 – 50 copies)

96 CVL samplesLow level viral load detected in 13%

Landay A et al. AIDS 2014;28:739-743

HIV RNA in plasma & cervico-vaginal lavage in patients on fully suppressive cART

31 patients on fully suppressive cART from WIHS ( <80 HIV RNA copies/ml plasma x 2 years)Aptima qualitative assay using 0.5 ml plasma in quadruplicate.Sensitivity ≈ 1 copy/ml

93 plasma samples over median 4 yearsLow level viraemia detected in 55% (1 – 50 copies)Lower levels detected than in elite controllers

93 CVL samplesLow level viral load detected in 4%

Landay A et al. AIDS 2014;28:739-743

Early or Late Initiation of ARVs to Prevent Transmission: HPTN 052

Design: Early vs. delayed ART (start when CD4 count <250 cells/mm3) to infected partner in discordant couple with CD4+ count of 350-550 cells/mm3

at enrollmentPopulation – 1,763 couples

• 98% heterosexualDSMB stopped trial April 28, 2011Number of transmissions

• Total - 39» 4 early therapy (0.3/100 py)» 35 delayed therapy (2.2/100 py)

• Linked - 28» Transmissions linked by pol

sequences» 23/28 linked transmissions in African

sitesConclusion: Treatment is prevention

Cohen M, et al. 6th IAS; Rome, Italy; July 17-20, 2011. Abst. MOAX0102; Cohen MS, et al. N Engl J Med. July 18, 2011.

Delayed

Early

1/1,585 p/yr

27/1,557 p/yr

What does an undetectable HIV viral load mean?

Prevention of HIV transmission through sexual intercourse?Prevention of HIV mother-to-child transmission?Longevity?Low morbidity?Cure?

Very low risk of MTCT with interventions: UK & Ireland

Data 2000 – 2006 n = 5136 infants

Transmission •0.1% if HAART and VL <50 (3/2202)

Townsend C et al, AIDS 2008

What does an undetectable HIV viral load mean?

Prevention of HIV transmission through sexual intercourse?Prevention of HIV mother-to-child transmission?Longevity?Low morbidity?Cure?

UK HIV & AIDS Diagnoses 1984 -1999

Standardised Mortality Rates with treated HIV

CD4 350 – 499 >499Person-years 3729 8628Observed Deaths 28 34Expected Deaths 15.9 34SMR (96%CI) 1.77 (1.17 – 2.55) 1.00 (0.69 – 1.4)

Rodger AJ et al AIDS 2013;27:973-979

Non-IDU from ESPRIT and SMARTVirologically suppressed (<500, <400)CD4 > 350 during preceding 6 monthsSMR by comparison with Human Mortality Database

© 2014 Lippincott Williams & Wilkins, Inc. Published by Lippincott Williams & Wilkins, Inc. 2

Life Expectancy of Men with HIV (UK)

Impact on life expectancy of HIV-1 positive individuals of CD4+ cell count and viral load response to antiretroviral therapy.

May, Margaret; Gompels, Mark; Delpech, Valerie; Porter, Kholoud; Orkin, Chloe; Kegg, Stephen; Hay, Phillip; Johnson, Margaret; Palfreeman, Adrian; Gilson, Richard; Chadwick, David; Martin, Fabiola; Hill, Teresa; Walsh, John; Post, Frank; Fisher, Martin; Ainsworth, Jonathan; Jose, Sophie; Leen, Clifford; Nelson, Mark; Anderson, Jane; Sabin, Caroline

AIDS. 28(8):1193-1202, May 15, 2014.DOI: 10.1097/QAD.0000000000000243

Fig. 1 . Expected age at death of men aged 35 years at different durations of antiretroviral therapy according to current CD4+ cell count and viral suppression compared with the general population.

© 2014 Lippincott Williams & Wilkins, Inc. Published by Lippincott Williams & Wilkins, Inc. 2

Life expectancy of Women with HIV

Impact on life expectancy of HIV-1 positive individuals of CD4+ cell count and viral load response to antiretroviral therapy.May, Margaret; Gompels, Mark; Delpech, Valerie; Porter, Kholoud; Orkin, Chloe; Kegg, Stephen; Hay, Phillip; Johnson, Margaret; Palfreeman, Adrian; Gilson, Richard; Chadwick, David; Martin, Fabiola; Hill, Teresa; Walsh, John; Post, Frank; Fisher, Martin; Ainsworth, Jonathan; Jose, Sophie; Leen, Clifford; Nelson, Mark; Anderson, Jane; Sabin, CarolineAIDS. 28(8):1193-1202, May 15, 2014.DOI: 10.1097/QAD.0000000000000243

Fig. 2. Expected age at death of women aged 35 years at different durations of antiretroviral therapy according to current CD4+ cell count and viral suppression compared with the general population.

What does an undetectable HIV viral load mean?

Prevention of HIV transmission through sexual intercourse?Prevention of HIV mother-to-child transmission?Longevity?Low morbidity?Cure?

Undetectable HIV in plasma

HIV infection

LTNP

EC

Elite controllers - definitions

HIV VL <50 on three occasions spanning > 12 months and the absence of ART for >1 year prior to (and during) the control period. International HIV Controller Consortium

HIV <50 for > 2years (Sajadi et al, JAIDS 2009)

HIV <50 on 90% of tests during >10 years (French HIV Controller Group)

Elite controllers - outcomes

CD4 counts may increase (small group)remain stable (small group)decline (larger group)

CD4 count decline associated with v/l 1<50 v <1

Elite control may be for a limited period

Treatment with cART may be associated withincreases in CD4

decreases in viral load ( 7 - 1 copy) without ↓CD4

Reviewed in Okulicz & Lambotte, Curr Opin HIV AIDS 2011;6:163-168

HIV is associated with inflammation

33 – 44 years 45 – 76 yearsSMART CARDIA % diff SMART MESA % diff

hsCRPµg/mL

2.12 1.36 55.2 2.68 2.17 49.6

IL-6pg/mL

2.09 1.29 62.1 2.63 1.23 151.6

D-dimerµg/mL

0.29 N/A 0.34 0.2 94.3

Cystatin CMg/dL

0.94 N/A 1.00 0.85 27.2

Neuhaus J et al. JID 2010;201:1788-1795

All differences statistically significant p<0.01

HIV is associated with inflammation despite undetectable Viral loads

33 – 44 years 45 – 76 yearsSMART CARDIA % diff SMART MESA % diff

hsCRPµg/mL

2.12 1.36 55.2 2.68 2.17 49.6

IL-6pg/mL

2.09 1.29 62.1 2.63 1.23 151.6

D-dimerµg/mL

0.29 N/A 0.34 0.2 94.3

Cystatin CMg/dL

0.94 N/A 1.00 0.85 27.2

Neuhaus J et al. JID 2010;201:1788-1795

All differences statistically significant p<0.01Similar pattern seen in subset on HAART with V/L <400 except D-dimers less elevated with HAART

T-cell activation is more common in HIV even when undetectable

Hunt PW et al JID 2008;197:126-133

T-cell activation is associated with low CD4 counts in Elite Controllers

Hunt PW et al JID 2008;197:126-133

T-cell activation is associated with LPS concn

Hunt PW et al JID 2008;197:126-133

High LPS persists despite fully suppressive cART

Hunt PW et al JID 2008;197:126-133

A model of inflammation and coagulation

Nicholas T Funderburg. Curr. Opin. HIV AIDS 2014;9:80-86

What does an undetectable HIV viral load mean?

Prevention of HIV transmission through sexual intercourse?Prevention of HIV mother-to-child transmission?Longevity?Low morbidity?Cure?

‘Functional cure in the Mississippi Baby’

10

100

1,000

10,000

100,000

0 5 10 15 20 25 30

Viral load

ART/carediscontinued

Months

HIV

RN

A c

opie

s/m

l p

lasm

a

Persaud D et al. CROI 2013. Abst. 48LB, NEJM 2013 Nov 7;369(19):1828-35

HIV virus returns after cure hope rose2 Boston patients had transplants of marrow, halted powerful drugsBy Kay Lazar| Globe Staff December 06, 2013

HIV appears again in child thought curedFinding dashes hopes of way to treat infantsBy Yasmeen Abutaleb| Globe Correspondent July 10, 2014

Doctors hope for cure in a 2nd baby with HIVMarilynn Marchione, Associated Press 5:30 p.m. EST March 5, 2014

Born with HIV, baby appears to have been curedEarly treatment was aggressiveBy Andrew Pollack and Donald G. McNeil Jr.| New York Times March 04, 2013

Four years of suppressive therapy in a seronegative

HIV-1 infected infant treated from birth

IrelandEuropean Caucasian drug use during pregnancyHIV seroconversion between 27 -34 weeks pregnancy.Baseline viral load 2736 HIV RNA copies/ml; CD4 count 940/mLTreated ZDV/3TC/Lop/rSpontaneous labour after 16/7 Px @ 37+6 GAStat NVP and IV ZDV and Emergency CS

Butler KM et al PIDJ 2014 epub

The mother’s story – early intervention

Four years of suppressive therapy in a seronegative

HIV-1 infected infant treated from birth

Commenced cART within 30 MINUTES of delivery2mg/kg Lamivudine; 2mg/kg nevirapine; 4mg/kg zidovudine

2mg/kg Lamivudine; 4mg/kg zidovudine bd + stat nevirapine 2mg/kg @ 48 hours

Exclusive Formula-Feeding

Day 1 653 HIV RNA copies/ml, subtype B; WT sequenceDay 7 Nevirapine 5mg/kg dailyDay 14 HIV 3500 RNA copies/ml Day 42 HIV <50

Butler KM et al PIDJ 2014 epub

The daughter’s story – prompt intervention

Four years of suppressive therapy in a seronegative

HIV-1 infected infant treated from birth

20 measures of HIV from 6/52 – 4yrs all <50Two RNA assays (Roche then Abbott)

31/12 & 35/12 HIV Ab/Ag NEGATIVE (2 assays 2 labs)

31, 38 and 49/12 HIV DNA PCR –ve LTR and pol primers

Treatment discontinued age 4 years

HIV RNA detected 7 days after stopping HIV DNA detected 14 days laterHIV Ab detected 29 days from stopping

Butler KM et al PIDJ 2014 epub

The daughter’s story – full suppression

Rapid viral rebound after 4 years of suppressive therapy in a seronegative

HIV-1 infected infant treated from birth

Treatment discontinued age 4 years

HIV RNA detected 7 days after stopping HIV DNA detected 14 days laterHIV Ab detected 29 days from stopping

Butler KM et al PIDJ 2014 epub

The daughter’s story – Rapid rebound

Conclusions

Undetectable HIV is good for health and survival

Elite control may not be sustained

Inflammation in HIV associated with CD4 decay

Inflammation (and associated risks especially cardiovascular) persists

Proving ‘cure’ is going to take time and not just tests

Thank you