hiv history and future - kathleen squires md
DESCRIPTION
Eastern Pennsylvania Branch-American Society for Microbiology, 41st Annual Symposium, Nov 17 2011TRANSCRIPT
HIV at 30:
History and Future Kathleen E. Squires, M.D.
Professor of Medicine
Director, Division of Infectious Diseases
Thomas Jefferson University and Hospital
Presented at the 41st Annual Symposium
“Global Movement of Infectious Pathogens and Improved Laboratory Detection”
Eastern PA Branch-American Society for Microbiology
November 17, 2011
Thomas Jefferson University, Philadelphia
HIV/AIDS: The Beginning
Initial Cases
• Young previously healthy males
• Presenting with rarely encountered conditions
– Pneumocystis carinii pneumonia
– Kaposi‟s sarcoma
• Rapidly progressive disease and death
• Common risk factor-MSM
Global Summary:
People Living With HIV
North America 1,400,000
Caribbean 240,000
Latin America 2,000,000
North Africa & Middle East
310,000
Sub-Saharan Africa
22,400,000
Western Europe 850,000
East Asia & Pacific 850,000
South & South East Asia 3,800,000
Australia & New Zealand
59,000
Eastern Europe & Central Asia
1,500,000
47% of Cases are Women
6% of Cases are Children Most via Mother-to-Child Transmission
UNAIDS 2010.
CDC Revises Estimation of
New Cases of HIV Infection
Methodology
New non-AIDS HIV cases from 22 states
Use of BED assay to identify recent infections
Stratified extrapolation approach confirmed with back calculation
Revised estimate 2006
56,300 (95% CI: 48,200 - 64,500)
Black
45%
White
35%
Hispanic
17%
Racial
Distribution
Hall HI, et al. JAMA 2008;300:520-529.
Risk Groups 80000
70000
60000
50000
40000
30000
20000
10000
0
Infe
cti
on
s
1977-
1979
1980-
1981
1982-
1983
1984-
1985
1986-
1987
1988-
1990
1991-
1993
1994-
1996
1997-
1999
2000-
2002
2003-
2006
Period
MSM IDU MSM/IDU Heterosexual
A simplified lineage scheme of retroviruses. This phylogenetic tree is not intended to quantitatively
represent evolutionary distances between viruses but to illustrate the relative relatedness between these infectious
agents. As can be seen, there is a greater sequence homology between HIV-1 and SIVcpz, and between HIV-2 and
SIVsm/mac, than there is between the two human pathogens HIV-1 and HIV-2. Also of note in this phylogenetic tree
is the obvious parallel between infection of human and non-human primates. For each class of human pathogen
represented, there is a closely related simian retrovirus.
Tebit, DN, Arts, EJ et al. The Lancet 2011:11;46-48
Origin of HIV: Lentivirus Family
Tebit, DN, Arts, EJ et al. The Lancet 2011:11;46-48
Worldwide Spread of HIV-1
Kahn JO, Walker BD. N Engl J
Med. 1998;339:33-39.
Exposure to HIV at
mucosal surface (sex)
Virus collected by
dendritic cells, carried
to lymph node
HIV replicates in
CD4 cells, released
into blood
Virus spreads to
other organs
Day 0
Day 0-2
Day 4-11
Day 11 on
The Pathogenesis of HIV-1 Infection: Compartments
Colon, Duodenum and
Rectum Chromaffin Cells
Lymphocytes in Blood,
Semen and Vaginal Fluid
Skin Langerhans‟ Cells
Bone Marrow
Brain Macrophages
and Glial Cells
Lymph Nodes
Thymus Gland
Lung Alveolar
Macrophages
Gut is area of massive T cell loss
CD4 Cell Count
Natural History of Untreated HIV-1 Infection
Time in Years Infection
CD4
Cells
1000
800
600
400
200
0
Early Opportunistic Infections
Late Opportunistic Infections
+
1 2 3 4 5 6 7 8 9 10 11 12 13 14
HIV Replication Cycle and Sites of Drug Activity
Capsid
proteins
and viral
RNA
CD4
Receptor
Viral RNA
New HIV
particles Protease Reverse
Transcriptase
Unintegrated
double stranded
Viral DNA
Integrated
viral DNA
Viral
mRNA
Integrase
gag-pol
polyprotein
Attachment
and Fusion Uncoating Reverse
Transcription
Integration Transcription Translation
1 2 3 4 5 6 Assembly
And Release
Protease Inhibitors
NRTIs
NNRTIs
Cellular DNA
CCR5 or
CXCR4 co-receptor
HIV Virions
Fusion Inhibitors
Adapted:Levy JA. HIV and the Pathogenesis of AIDS. 2nd ed. Washington, DC: American Society for Microbiology; 1998:9-11
.
Nucleus
Integrase Inhibitors
FDA-Approved Drugs for HIV Therapy:
2011
NNRTIs
Delavirdine (DLV)
Efavirenz (EFV)
Nevirapine (NVP)
Rilpivirine (RLP)
PIs
Amprenavir (APV)
Atazanavir (ATV)
Darunavir (DRV)
Fosamprenavir (FPV)
Indinavir (IDV)
Lopinavir/ritonavir (LPV/RTV)
Nelfinavir (NFV)
Ritonavir (RTV)
Saquinavir (SQV hgc)
Tipranavir (TPV)
Abacavir (ABC)
Didanosine (ddI)
Emtricitabine (FTC)
Lamivudine (3TC)
Stavudine (d4T)
Tenofovir (TDF)
Zalcitabine (ddC)
Zidovudine (ZDV)
3TC/ABC
3TC/ABC/ZDV
3TC/ZDV
FTC/TDF
NRTIs
Fusion Inhibitors (FIs)
Enfuvirtide (ENF)
FDA-Approved Drugs for HIV Therapy:
2011
Multiple Class
EFV/FTC/TDF
RLP/FTC/TDF
Integrase Inhibitors
Maraviroc (MRV)
CCR5 Inhibitors
Raltegravir (RAL)
When to Begin HIV Treatment
DHHS Guidelines < 12/1/2009
HIV Infection
Asymptomatic
Treat
Treat
CD4+ T cells/mm3
Consider
Treatment
DHHS. Guidelines for the use of antiretroviral agents in HIV-1 infected adults and adolescents; Available
at: http://aidsinfo.nih.gov.
History of AIDS-
defining illness or
severe symptoms
RISKS BENEFITS
<350 >350 Nov 2008
When to Begin Treatment
DHHS Guidelines >12/1/09
HIV Infection
Asymptomatic
Treat
Treat
CD4+ T cells/mm3
Consider
Treatment
DHHS. Guidelines for the use of antiretroviral agents in HIV-1 infected adults and adolescents; Available
at: http://aidsinfo.nih.gov.
h/o AIDS-defining
illness , severe sx,
pregnancy, HepB,
HIVAN
50% of
panel say
treat
50% of panel
say optional
<500 >500 Dec 1, 2009
Acute OIs
What Antiretroviral Agents To Start
DHHS guidelines 2011
Preferred regimens
Efavirenz + tenofovir + emtricitabine (Atripla®)
Raltegravir + tenofovir + emtricitabine
Ritonavir-atazanavir + tenofovir + emtricitabine
Ritonavir-darunavir + tenofovir + emtricitabine
Alternative regimens: NNRTIs (NVP or EFV) or other PIs (FPV/r, LPV/r, SQV/r) PLUS
ABC/3TC* or AZT/3TC or TFV/FTC
Acceptable or may be acceptable regimens: EFV+ ddI + (3TC or FTC); Unboosted
ATV with (ABC or AZT)/3TC; Maraviroc + AZT/3TC or Raltegravir + (ABC or AZT)/3TC or
(DRV/r or SQV/r) + (ABC or AZT)/3TC
*Other major combination NRTI agent of ABC/3TC demoted to alternative Dec „09
100
0
85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 00 02 04 06 08 10 12
400
300
200
Monotherapy
Dual-NRTI combinations
HAART
0
– 1
– 2
– 3
Slide courtesy of C. J. Cohen, MD. Years
Ch
an
ge
in
CD
4+
Ce
ll C
ou
nt
Fro
m B
as
eli
ne
(ce
lls
/mm
3)
Ch
an
ge
in H
IV-1
RN
A F
rom
Ba
se
line
(log
10 c
op
ies
/mL
)
Improving Outcomes With Evolving
Antiretroviral Regimens
CD4+ RNA Monotherapy
Dual-NRTI combinations
HAART
CD4+ RNA
100
0
85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 06
400
300
200
Monotherapy
Dual-NRTI combinations
HAART
0
– 1
– 2
– 3
Slide courtesy of C. J. Cohen, MD. Years
Ch
an
ge
in
CD
4+
Ce
ll C
ou
nt
Fro
m B
as
eli
ne
(ce
lls
/mm
3)
Ch
an
ge
in H
IV-1
RN
A F
rom
Ba
se
line
(log
10 c
op
ies
/mL
)
Improving Outcomes With Evolving
Antiretroviral Regimens
CD4+ RNA Monotherapy
CD4+ RNA
100
0
85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 06
400
300
200
Monotherapy
Dual-NRTI combinations
HAART
0
– 1
– 2
– 3
Slide courtesy of C. J. Cohen, MD. Years
Ch
an
ge
in
CD
4+
Ce
ll C
ou
nt
Fro
m B
as
eli
ne
(ce
lls
/mm
3)
Ch
an
ge
in H
IV-1
RN
A F
rom
Ba
se
line
(log
10 c
op
ies
/mL
)
Improving Outcomes With Evolving
Antiretroviral Regimens
CD4+ RNA Monotherapy
Dual-NRTI combinations
CD4+ RNA
100
0
85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 00 02 04 06 08 10 12
400
300
200
Monotherapy
Dual-NRTI combinations
HAART
0
– 1
– 2
– 3
Slide courtesy of C. J. Cohen, MD. Years
Ch
an
ge
in
CD
4+
Ce
ll C
ou
nt
Fro
m B
as
eli
ne
(ce
lls
/mm
3)
Ch
an
ge
in H
IV-1
RN
A F
rom
Ba
se
line
(log
10 c
op
ies
/mL
)
Improving Outcomes With Evolving
Antiretroviral Regimens
CD4+ RNA Monotherapy
Dual-NRTI combinations
HAART
CD4+ RNA
Role of Assays in HIV Management
• HIV resistance assays
– Genotype
– Phenotype
– Virtual Phenotype
• Tropism assays
– Trophile
– Genotype
HIV: The Future
• Chronic Infection
– High rates of virologic suppression in patients on therapy
– ? Nearly normal life span
• Persistent elevated levels of inflammatory markers
• Higher risk of specific co-morbidities
– Cardiac disease, hepatitis B &C/cirrhosis/hepatocellular carcinoma,
non-AIDS associated neoplasm
• Is there a cure?
– NIAID RFA
• 5 funded program project grants
~42-59% chronically
~1,100,000
~21%
People Living
with HIV/AIDS
People with HIV/AIDS
Not In Care
People with HIV Who Don't Know
They Are Infected
~56,000
New Infections, 2006
US HIV Epidemic—For Context
NOTE: Data are estimates. SOURCE: Hall HI, et al., "Estimation of HIV Incidence in the United States". JAMA, Vol. 300, No. 5, August 2008; CDC, MMWR, Vol. 57, No. 39, 2008; Fleming P, et al., "HIV Prevalence in the United States 2000", 9th Conference on Retroviruses and Opportunistic Infections, 2002.
Slide 26
National HIV/AIDS Strategy
http://www.whitehouse.gov/sites/default/files/microsites/ONAP_rpt.pdf
Slide 27
HIV Prevention
• Vaccine-the Holy Grail
• Circumcision
• Pre-exposure prophylaxis
• Treatment as prevention
• Bio-medical prevention
• Can we treat our way out of this epidemic?
• Community viral load
Efficacy of HIV Prevention Strategies
From Randomized Clinical Trials
Abdool Karim SS, et al. Lancet. 2011;[Epub ahead of print].
100 0 20 40 60 80
Efficacy (%)
Study Effect Size, % (95% CI)
ART for prevention; HPTN 052, Africa, Asia, Americas
PrEP for discordant couples; Partners PrEP, Uganda, Kenya
PrEP for heterosexual men and women; TDF2, Botswana
Medical male circumcision; Orange Farm, Rakai, Kisumu
PrEP for MSMs; iPrEX, Americas, Thailand, South Africa
Sexually transmitted diseases treatment; Mwanza, Tanzania
Microbicide; CAPRISA 004, South Africa
HIV vaccine; RV144, Thailand
96 (73-99)
73 (49-85)
63 (21-84)
54 (38-66)
44 (15-63)
42 (21-58)
39 (6-60)
31 (1-51)
Current CDC Guidance on PrEP
http://www.cdc.gov/nchhstp/newsroom/PrEPMSMGuidanceGraphic.html
HPTN 052: Immediate vs Delayed ART in
Serodiscordant Couples
Cohen MS, et al. IAS 2011. Abstract MOAX0102.
Cohen MS, et al. N Engl J Med. 2011;[Epub ahead of print].
Immediate ART
Initiate ART at CD4+ cell count 350-550 cells/mm3
(n = 886 couples)
Delayed ART
Initiate ART at CD4+ cell count ≤ 250 cells/mm3*
(n = 877 couples)
HIV-infected, sexually active
serodiscordant
couples; CD4+ cell count
of the infected partner:
350-550 cells/mm3
(N = 1763 couples)
*Based on 2 consecutive values ≤ 250 cells/mm3.
• Primary efficacy endpoint: virologically linked HIV transmission
• Primary clinical endpoints: WHO stage 4 events, pulmonary TB, severe bacterial
infection and/or death
• Couples received intensive counseling on risk reduction and use of condoms
DSMB recommended release of results as soon as possible following April 28, 2011, review; follow-up
continues but all HIV-infected partners offered ART after release of results
HPTN 052: HIV Transmission Reduced by
96% in Serodiscordant Couples
Single transmission in patient in
immediate ART arm believed
to have occurred close to time therapy
began and prior to HIV-1 RNA
suppression
Total HIV-1 Transmission Events: 39
(4 in immediate arm and
35 in delayed arm; P < .0001)
Linked Transmissions:
28
Unlinked or TBD
Transmissions: 11
P < .001
Immediate
Arm: 1
Delayed Arm:
27
Cohen MS, et al. IAS 2011. Abstract MOAX0102.
Cohen MS, et al. N Engl J Med. 2011;[Epub ahead of print].
HPTN 052: Multivariate Analysis of
Factors Associated With Linked
Transmissions Variable HR 95% CI
Treatment, immediate vs delayed 0.04 0.01-0.28
Baseline CD4+ count, per 100 cells/mm3 decrease 1.24 1.00-1.54
Baseline HIV-1 RNA, per 1 log10 copies/mL increase 2.85 1.51-5.41
Baseline condom use, 100% vs < 100% 0.33 0.12-0.91
Sex of infected partner, male vs female 0.73 0.33-1.65
Cohen MS, et al. IAS 2011. Abstract MOAX0102.
Cohen MS, et al. N Engl J Med. 2011;[Epub ahead of print].
61% of transmissions occurred from infected patient with CD4+ cell count > 350 cells/mm3
All transmissions occurred prior to starting ART
82% of transmissions occurred in African patients
HPTN 052: Primary Clinical Events During
Follow-up • 41% reduction in HIV-related clinical events in HIV-infected patients
randomized to immediate vs delayed therapy
– Excess events in delayed arm driven mainly by TB (33 vs 17 cases),
particularly extrapulmonary TB (17 vs 3 cases)
Fa
ilu
re P
rob
ab
ilit
y
0
0.10
0.15
0.20
0.25
Yrs Since Randomization
0 1 2 3 4 5
0.05
HR: 0.6 (95% CI: 0.4-0.9; P = .01)
Delayed (n = 65)
Immediate (n = 40)
877 886
701 700
317 333
86 85
32 36
25 29
Number at risk
Grinsztejn B, et al. IAS 2011. Abstract MOAX0105.
Cohen MS, et al. N Engl J Med. 2011;[Epub ahead of print].
HIV: The Future
• Can incidence be decreased?
– Routine HIV testing
• CDC 2006 guidance-every person 13-64 should be tested at least
once and undergo repeat testing based on ongoing risk factors
• Emphasis on point-of-care testing
– Aligned with National AIDS Strategy to identify HIV-positive
individuals and facilitate entry to care
– Rapid HIV testing, STI test and treat, ? CD4 cell counts and HIV viral
load
• Use of 4th generation Ag/Ab tests to identify individuals with acute
infection
HIV: The Future
• Can incidence be decreased?
– Access to and retention in care
• Treatment for personal health
• Treatment as prevention (HPTN 052)
• Tension between “mainstreaming” HIV care
and evidence that HIV expert care improves
outcomes
HIV at 50
• Point of care HIV testing
– as routine as RPR
• ART for all diagnosed patients
• Point of care CD4 and HIV VL
– Primary care venues
• ??? Functional cure
• ??? Preventive vaccine