Beyond the undetectable viral load Graham P Taylor Section of Retrovirology and GU Medicine Division of Infection
How to measure HIV
Patients RNA PCR Symptomatic 100% Asymptomatic 74%
Sensitivity Culture P24 antigen 83% 63% 13% 13%
Van Kerckhoven et al J Clin Microbio 1994;32(7):1669-1673
How much virus in blood if VL undetectable? <1000 copies/ml <400 copies/ml <50 copies/ml <5 copies/L <5,000 copies/L <25,000 copies/ adult blood volume
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 Lung Breast Liver Kidneys Gut Genital tract
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 â&#x2030;&#x2C6; 1 copy/ml 93 plasma samples over median 4 years Low level viraemia detected in 88% (1 â&#x20AC;&#x201C; 50 copies) 96 CVL samples Low 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 â&#x2030;&#x2C6; 1 copy/ml 93 plasma samples over median 4 years Low level viraemia detected in 55% (1 â&#x20AC;&#x201C; 50 copies) Lower levels detected than in elite controllers 93 CVL samples Low 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 enrollment Population – 1,763 couples • 98% heterosexual
DSMB stopped trial April 28, 2011 Number of transmissions
27/1,557 p/yr Delayed
• 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 sites
1/1,585 p/yr Early
Conclusion: 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.
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
>499
3729
8628
Observed Deaths
28
34
Expected Deaths
15.9
34
1.77 (1.17 – 2.55)
1.00 (0.69 – 1.4)
Person-years
SMR (96%CI)
Non-IDU from ESPRIT and SMART Virologically suppressed (<500, <400) CD4 > 350 during preceding 6 months SMR by comparison with Human Mortality Database
Rodger AJ et al AIDS 2013;27:973-979
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. Š 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, Caroline AIDS. 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. Š 2014 Lippincott Williams & Wilkins, Inc. Published by Lippincott Williams & Wilkins, Inc.
2
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 with increases in CD4 decreases in viral load ( 7 - 1 copy) without
â&#x2020;&#x201C;CD4
Reviewed in Okulicz & Lambotte, Curr Opin HIV AIDS 2011;6:163-168
HIV is associated with inflammation 33 – 44 years
45 – 76 years
SMART
CARDIA
% diff SMART
MESA
% diff
hsCRP µg/mL
2.12
1.36
55.2 2.68
2.17
49.6
IL-6 pg/mL
2.09
1.29
62.1 2.63
1.23
151.6
D-dimer µg/mL
0.29
N/A
0.34
0.2
94.3
Cystatin C Mg/dL
0.94
N/A
1.00
0.85
27.2
All differences statistically significant p<0.01
Neuhaus J et al. JID 2010;201:1788-1795
HIV is associated with inflammation despite undetectable Viral loads 33 – 44 years
45 – 76 years
SMART
CARDIA
% diff SMART
MESA
% diff
hsCRP µg/mL
2.12
1.36
55.2 2.68
2.17
49.6
IL-6 pg/mL
2.09
1.29
62.1 2.63
1.23
151.6
D-dimer µg/mL
0.29
N/A
0.34
0.2
94.3
Cystatin C Mg/dL
0.94
N/A
1.00
0.85
27.2
All differences statistically significant p<0.01 Similar pattern seen in subset on HAART with V/L <400 except D-dimers less elevated with HAART Neuhaus J et al. JID 2010;201:1788-1795
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’ 100,000
HIV RNA copies/ml plasma
Viral load
10,000
ART/care discontinued
1,000
100
10
0
5
10
15
20
25
30
Months Persaud D et al. CROI 2013. Abst. 48LB, NEJM 2013 Nov 7;369(19):1828-35
Born with HIV, baby appears to have been cured Early treatment was aggressive By Andrew Pollack and Donald G. McNeil Jr. | New York Times March 04, 2013 Doctors hope for cure in a 2nd baby with HIV Marilynn Marchione, Associated Press 5:30 p.m. EST March 5, 2014 HIV virus returns after cure hope rose 2 Boston patients had transplants of marrow, halted powerful drugs By Kay Lazar | Globe Staff December 06, 2013 HIV appears again in child thought cured Finding dashes hopes of way to treat infants By Yasmeen Abutaleb | Globe Correspondent July 10, 2014
Four years of suppressive therapy in a seronegative HIV-1 infected infant treated from birth
The motherâ&#x20AC;&#x2122;s story â&#x20AC;&#x201C; early intervention Ireland European Caucasian drug use during pregnancy HIV seroconversion between 27 -34 weeks pregnancy. Baseline viral load 2736 HIV RNA copies/ml; CD4 count 940/mL Treated ZDV/3TC/Lop/r Spontaneous labour after 16/7 Px @ 37+6 GA Stat NVP and IV ZDV and Emergency CS
Butler KM et al PIDJ 2014 epub
Four years of suppressive therapy in a seronegative HIV-1 infected infant treated from birth
The daughter’s story – prompt intervention
Commenced cART within 30 MINUTES of delivery 2mg/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 Day Day Day
1 653 HIV RNA copies/ml, subtype B; WT sequence 7 Nevirapine 5mg/kg daily 14 HIV 3500 RNA copies/ml 42 HIV <50
Butler KM et al PIDJ 2014 epub
Four years of suppressive therapy in a seronegative HIV-1 infected infant treated from birth
The daughter’s story – full suppression
20 measures of HIV from 6/52 – 4yrs all <50 Two 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 later HIV Ab detected 29 days from stopping
Butler KM et al PIDJ 2014 epub
Rapid viral rebound after 4 years of suppressive therapy in a seronegative HIV-1 infected infant treated from birth
The daughterâ&#x20AC;&#x2122;s story â&#x20AC;&#x201C; Rapid rebound Treatment discontinued age 4 years HIV RNA detected 7 days after stopping HIV DNA detected 14 days later HIV Ab detected 29 days from stopping
Butler KM et al PIDJ 2014 epub
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 â&#x20AC;&#x2DC;cureâ&#x20AC;&#x2122; is going to take time and not just tests
Thank you