estimating the benefit of an hiv 1 vaccine which reduces viral load set point l.
Download
Skip this Video
Loading SlideShow in 5 Seconds..
Estimating the benefit of an HIV-1 vaccine which reduces viral load set point PowerPoint Presentation
Download Presentation
Estimating the benefit of an HIV-1 vaccine which reduces viral load set point

Loading in 2 Seconds...

play fullscreen
1 / 47

Estimating the benefit of an HIV-1 vaccine which reduces viral load set point - PowerPoint PPT Presentation


  • 239 Views
  • Uploaded on

Estimating the benefit of an HIV-1 vaccine which reduces viral load set point Swati Gupta, DrPH, MPH Merck Research Laboratories Epidemiology Department DIMACS Workshop on Facing the Challenge of Infectious Disease in Africa September 25-27th, 2006

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about 'Estimating the benefit of an HIV-1 vaccine which reduces viral load set point' - andrew


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
estimating the benefit of an hiv 1 vaccine which reduces viral load set point

Estimating the benefit of an HIV-1 vaccine which reduces viral load set point

Swati Gupta, DrPH, MPH

Merck Research Laboratories

Epidemiology Department

DIMACS Workshop on Facing the Challenge of Infectious Disease in Africa

September 25-27th, 2006

slide2

Adults and children estimated to be living with HIV, 2005

Eastern Europe & Central Asia

1.5 million

[1.0 – 2.3 million]

Western &

Central Europe

720 000

[550 000 – 950 000]

North America

1.3 million

[770 000 – 2.1 million]

East Asia

680,000

[420 000 – 1.1 million]

North Africa & Middle East

440 000

[250 000 – 720 000]

Caribbean

330 000

[240 000 – 420 000]

South & South-East Asia

7.6 million

[5.1 – 11.7 million]

Sub-Saharan Africa

24.5 million

[21.6 – 27.4 million]

Latin America

1.6 million

[1.2 – 2.4 million]

Oceania

78 000

[48 000 – 170 000]

Total: 38.6 (33.4 – 46.0) million

slide3

Global estimates for adults and children, 2005

  • People living with HIV
  • New HIV infections in 2005
  • Deaths due to AIDS in 2005

38.6 million

[33.4 – 46.0 million]

4.1 million

[3.4 – 6.2 million]

2.8 million

[2.4 – 3.3 million]

Source: UNAIDS, 2006 Report on the Global AIDS Epidemic

slide4

Over 11,000 new HIV infections a day in 2005

  • More than 95% are in low and middle income countries
  • About 1,500 are in children under 15 years of age
  • About 10,000 are in adults aged 15 years and older of whom:
    • Almost 50% are among women
    • Over 40% are among young people (15-24)

Source: UNAIDS, 2006 Report on the Global AIDS Epidemic

slide5

50

40

30

20

10

0

1985

1990

1995

2000

2005

Year

Estimated number of people living with HIV globally, 1985–2005

Estimated number of people living with HIV, millions

Source: UNAIDS, 2006 Report on the Global AIDS Epidemic

slide6

Estimated number of people living with HIV in sub-Saharan Africa, 1985–2005

30

25

20

15

10

5

0

1985

1990

1995

2000

2005

Year

Source: UNAIDS, 2006 Report on the Global AIDS Epidemic

slide7

Estimated number of adults and children living with HIV by region, 1985–2005

45

40

35

30

25

20

15

10

5

0

1985

1990

1995

2000

2005

Year

Oceania

North Africa & Middle East

Eastern Europe & Central Asia

Latin America and Caribbean

North America and Western Europe

Asia

Sub-Saharan Africa

Estimated number of people living with HIV by region, millions

Source: UNAIDS, 2006 Report on the Global AIDS Epidemic

slide8

A global view of HIV infection

38.6 million people [33.4‒46.0 million] living with HIV, 2005

Source: UNAIDS, 2006 Report on the Global AIDS Epidemic

slide9

HIV prevalence in adults in Asia, 1990−2005

Source: UNAIDS, 2006 Report on the Global AIDS Epidemic

slide10

HIV prevalence in adults in Latin America and the Caribbean, 1990−2005

Source: UNAIDS, 2006 Report on the Global AIDS Epidemic

slide11

HIV prevalence in adults in sub-Saharan Africa, 1990−2005

Source: UNAIDS, 2006 Report on the Global AIDS Epidemic

slide12

Comparison of 2003 and 2005 data

25

25

25

20.0

20

20

20

15

15

15

9.2

9.0

10

10

10

7.6

7.0

5

5

5

3.3

0

0

0

2003

2005

2003

2005

2003

2005

Access to mother-to-child prevention services (all pregnant women)

Coverage of HIV-infected mothers who received antiretroviral prophylaxis

Coverage of antiretroviral therapy

Percent

Percent

Percent

Sources: WHO/UNAIDS (2006). Progress on global access to HIV antiretroviral therapy: a report on “3 by 5” and beyond; USAID et al. (2006). Coverage of selected services for HIV/AIDS prevention, care and support in low and middle income countries in 2003 and 2005.

slide13

Comparison of 2003 and 2005 data (cont.)

60

60

56.0

50

50

40

40

35.0

30

30

25.0

19.7

20

20

12.0

9.3

7.0

10

10

6.3

4.6

3.0

1.0

0.0

0

0

Kenya

Namibia

Uganda

Kenya

Namibia

Uganda

Coverage of HIV-infected mothers

who received antiretroviral prophylaxis

Coverage of antiretroviral therapy

2003

2005

Sources: Individual country reports (2005).

slide14

Benin 2001

Botswana 2001

Burkina Faso 2003

Cameroon 2004

Chad 2004

Ghana 2003

Guinea 2005

Kenya 2003

Lesotho 2004

Madagascar 2003

Malawi 2004

Mali 2001

Mozambique 2003

Nigeria 2003

Rwanda 2004

Senegal 2005

United Republic of Tanzania 2003

Uganda 2004

Zambia 2003

Female

Male

15–24 year olds reporting condom use during sexual intercourse with a non-regular partner, Sub-Saharan Africa, 2001–2005

Countries with date of survey indicated, percent

0

10

20

30

40

50

60

70

80

90

100

Sources: Demographic Health Surveys; HIV/AIDS Indicator Surveys (2001-2005).

slide15

Injecting drug users

Median percentage of most-at-risk populations reached with prevention programs and those who received HIV testing in the last 12 months and who knew their results

50

42% (n=13)

40

38% (n=9)

30

28% (n=10)

%

23% (n=10)

19% (n=10)

20

17% (n=10)

10

0

Percentage who received HIV

testing and who knew their results

Percentage reached with

prevention programs

Sex workers

Men who have sex with men

Source: UNAIDS, 2006 Report on the Global AIDS Epidemic

slide16

25 years of AIDS

12

13

10

7

15

14

1

16

8

6

5

2

4

3

9

People

living

with HIV

1 First cases of unusual immune deficiency are identified among gay men in USA, and a new deadly disease noticed

50

9 In 1991-1993, HIV prevalence in young pregnant women in Uganda and in young men in Thailand begins to decrease, the first major downturns in the epidemic in developing countries

45

2 Acquired Immune Deficiency Syndrome (AIDS) is defined for the first time

40

3 The Human Immune Deficiency Virus (HIV) is identified as the cause of AIDS

10 Highly Active Antiretroviral Treatment launched

35

4 In Africa, a heterosexual AIDS epidemic is revealed

11 Scientists develop the first treatment regimen to reduce mother-to-child transmission of HIV

5 The first HIV antibody test becomes available

30

11

6 Global Network of People living with HIV/AIDS (GNP+) (then International Steering Committee of People Living with HIV/AIDS) founded

Children

orphaned

by AIDS in

sub-Saharan

Africa

12 UNAIDS is created

25

13 Brazil becomes the first developing country to provide antiretroviral therapy through its public health system

Million

20

7 The World Health Organisation launches the Global Programme on AIDS

14 The UN General Assembly Special Session on HIV/AIDS. Global Fund to fight AIDS, Tuberculosis and Malaria launched

15

8 The first therapy for AIDS – zidovudine, or AZT -- is approved for use in the USA

10

15 WHO and UNAIDS launch the "3 x 5" initiative with the goal of reaching 3 million people in developing world with ART by 2005

5

16 Global Coalition on Women and AIDS launched

0

2005

1980

1985

1990

1995

2000

Source: UNAIDS, 2006 Report on the Global AIDS Epidemic

background
Background
  • The continued rapid spread of HIV-1 globally highlights the need for urgent new preventive measures
  • A safe and effective prophylactic vaccine for human immunodeficiency virus (HIV) is now widely thought to be critical in controlling the pandemic, especially in developing countries
  • To understand why there is still no effective HIV vaccine 25 years after the first case of AIDS was diagnosed requires understanding a bit of background about the virus and how our immune systems interact with the virus
background continued
Background (continued)
  • Innate immunity
    • “non-specific” or “non-adaptive” responses
  • Acquired immunity
    • Humoral immunity
      • Coordinated by B cell/antibody responses which have receptors on their surface that allow them to connect with and capture pathogens as they circulate freely in the blood
      • Examples of vaccines which lead to the production of neutralizing antibodies: measles, polio, and hepatitis B vaccines
      • Unfortunately, the induction of neutralizing antibodies against HIV is a difficult task
      • Results of first large scale Phase III efficacy trial
background continued20
Background (continued)
  • Acquired immunity
    • Humoral immunity
    • Cellular immunity
      • Coordinated by CD4+ T cells and CD8+ “killer” T cells that identify and kill pathogen infected cells
      • Vast majority of AIDS vaccines in clinical trials have been designed to induce cellular immune responses
      • Implications of cell mediated immunity (CMI)-based responses to HIV infection in the context of vaccine development
background continued21
Background(continued)
  • Cell mediated immunity (CMI)-based HIV vaccines
    • Current CMI-based vaccines are expected to either prevent infection or contain post-infection viral load set-point in people who become infected despite vaccination
background continued23
Background(continued)
  • Natural history of HIV Infection in the context of CMI-based HIV vaccines

Lyles et al.; JID 2000;181:872-880

background continued24
Background(continued)
  • Natural history of HIV Infection in the context of CMI-based HIV vaccines
    • Current cell mediated immunity (CMI)-based vaccines are expected to either prevent infection or contain post-infection viral load set-point in people who become infected despite vaccination
    • The time to events in the course of HIV disease progression could be extended
    • Magnitude of the potential clinical benefit of a vaccine which reduces viral load setpoint is largely unknown
slide25

Background(continued)

  • Candidate vaccines designed to induce cell-mediated immune responses against human immunodeficiency virus-1 (HIV-1) are currently being developed
  • These vaccines are expected to provide either “complete” or “partial protection” from HIV-1 infection.
    • “Complete protection” refers to preventing establishment of HIV-1 infection
    • “Partial protection” refers to an attenuation of the course of HIV-1 infection due to suppression of viral replication
  • Vaccines which provide “partial protection” are likely to be associated with reduced viral set points after infection
background continued26
Background(continued)
  • Plasma viral load measured up to 18 months after seroconversion strongly predicts the risk of disease progression
  • Therefore, a vaccine capable of reducing viral load set point could provide important clinical benefit such as delaying the onset of AIDS or the need for antiretroviral therapy
  • Using data collected from a cohort study on the natural history of HIV-1 infection, we modeled the potential impact of a vaccine which would reduce viral set point after infection.
methods
Methods
  • Study Population
    • Multicenter AIDS Cohort Study (MACS)
      • On-going (initiated in 1983), prospective cohort study of HIV infection in men who have sex with men
        • 5622 participants enrolled before 2001
        • 4 sites in Baltimore/Washington, Chicago, Los Angeles and Pittsburgh
      • Participants were either HIV-1 seronegative or HIV-1 seropositive but without a clinical AIDS diagnosis at enrollment
      • Participants seen every 6 months
      • Study visits include the following:
        • Behavioral and medical history
        • Physical Exam
        • Blood collection
methods continued
Methods(continued)
  • Role of MACS in describing the epidemiology of

HIV infection

    • Incidence and risk factors of HIV infection
    • Natural history of HIV infection
      • Time to AIDS and death (survival times)
    • Prognostic value viral load characterized
    • Efficacy of combination/HAART therapies on individual and population levels
    • Adverse events / toxicities of therapies
    • Role of genetic markers on infection and disease progression

Source: UNAIDS, 2006 Report on the Global AIDS Epidemic

methods continued29
Methods (continued)
  • Inclusion Criteria for analyses
    • HIV-1 seronegative at enrollment into the MACS and seroconverted during the follow-up period
    • One year or less between their last HIV-1 seronegative (LN) and first HIV-1 seropositive (FP) visits (seroconversion dates were calculated as the midpoint between the LN and FP visits)
    • HIV-1 RNA measurement available at 3, 9 or 15 months post-seroconversion
    • Early HIV-1 RNA measurement was required to precede the initiation of any antiretroviral therapy
methods continued30
Methods (continued)
  • Data Analysis
    • Early HIV-1 RNA measurements were examined to determine if there were in any trends in viral load soon after seroconversion.
    • Lognormal parametric regression models were used to investigate the relationship between viral load set point and time to the following outcome variables:
      • Clinical AIDS (defined as an opportunistic illness)
      • CD4 cell count level (<350 cells/mm3, <200 cells/mm3)
      • Loss of virological control ( HIV-1 RNA >=55,000 copies/mL)
      • Clinical indication for initiation of antiretroviral therapy (HIV-1 RNA >=55,000 copies/mL or CD4+ T-cell count <350 cells/mm3 or diagnosis of an OI)
    • Relative times to events of interest were estimated for those with viral load set points of 30,000 copies/mL (reference group) vs. those with lower viral set points.
slide31

Results

TABLE 1. Viral RNA and CD4+ T-cell count measurements

following seroconversion

HIV-1 RNA (copies/mL)

CD4+ T-cell count (cells/mm3)

Months post seroconversion (PSC)

n

Median (IQR)

Geometric mean (SD)*

n

Median (IQR)

Mean (SD)

~3 months PSC

340

28,832 (7,887, 90,441)

22,387 (6.8)

324

738 (548, 944)

780 (332.6)

~9 months PSC

311

27,986 (7,903, 63,861)

19,815 (5.9)

298

639 (460, 847)

681 (291.1)

~15 months PSC

275

25,495 (9,238, 58,478)

20,797 (4.9)

271

587 (450, 792)

643 (289.4)

* The standard deviation of the geometric mean represents 10 to the x, where x is the standard deviation of the log10 HIV RNA

slide32

Results (continued)

TABLE 2. Demographic statistics for 311 seroconverters

with HIV RNA available at 9 months post- seroconversion

* IQR = Interquartile range

slide33

Event

0.50-log reduction:

HIV-1 RNA = 9,487

0.75-log reduction:

HIV-1 RNA = 5,335

1-log reduction:

HIV-1 RNA = 3,000

1.25-log reduction:

HIV-1 RNA = 1,687

Median time to event (years) Reference group HIV-1 RNA=30,000

Median Time to event (years)

Relative time

(95% CI)

Median Time to event (years)

Relative time

(95% CI)

Median Time to event (years)

Relative time

(95% CI)

Median Time to event (years)

Relative time

(95% CI)

No. free of event at set point, No. of, events

AIDS (defined as diagnosis of an OI)

(310, 93)

8.4

11.9

1.4 (1.3, 1.6)

1.7 (1.5, 2.0)

16.9

2.0 (1.6, 2.5)

20.2

2.4 (1.9, 3.2)

14.2

CD4+ T-cell count

< 200 cells/mm3

(298, 95)

6.1

8.1

1.3 (1.2, 1.5)

9.2

9.2

10.6

1.7 (1.4, 2.1)

12.1

2.0 (1.5, 2.6)

1.5 (1.3, 1.8)

CD4+ T-cell count

< 350 cells/mm3

(263, 133)

3.4

4.5

1.3 (1.2, 1.5)

5.2

1.5 (1.3, 1.8)

5.9

1.7 (1.4, 2.1)

6.8

2.0 (1.6, 2.6)

2.4 (1.6, 3.4)

HIV-1 RNA > 55,000 copies/mL

(149, 59)

2.4

4.3

1.8 (1.4, 2.2)

5.7

7.6

3.1 (1.9, 5.0)

10.1

4.1 (2.3, 7.5)

Clinical indication

for initiation of anti-retroviral therapy**

(137, 76)

1.9

2.7

1.4 (1.2, 1.7)

3.3

1.7 (1.3, 2.2)

3.9

2.0 (1.5, 2.9)

4.7

2.4 (1.6, 3.7)

TABLE 3. Median and relative time (RT)* to clinical events for cohort participants with HIV-1 RNA of 30,000 copies/mL compared with a 0.50, 0.75, 1.00 and 1.25 log reduction in HIV-1 RNA at 9 months post-seroconversion, using Log-Normal Models (n=311)

  • Relative time is a calculated as the ratio of time to each event for the comparison HIV-1 RNA categories (9487, 5335, 3000, 1687 copies/mL) and
  • reference group category of 30,000 copies/mL.
  • ** Clinical indication for initiation of antiretroviral therapy defined as HIV-1 RNA > 55,000 copies/mL or CD4+ T-cell count < 350 cells/mm3 or OI
conclusions
Conclusions
  • The time to key clinical events in the course of HIV-1 disease progression was significantly extended for those with initial HIV-1 RNA 0.5-1.25 log10 copies/mL lower than the reference group
  • For those with an initial viral load measurement of 3,000 vs. 30,000 copies/mL, the relative time to study endpoints was approximately double or higher
    • This applies to those events which occur earlier in HIV disease progression, such as a CD4 cell count below 350 cells/mm3
  • A viral set point of no more than approximately 10,000 copies/mL is still associated with at least a 30% extension in the time to clinical events in HIV disease progression compared to the reference group
conclusions continued
Conclusions(continued)
  • This analysis, based upon natural history data, provides a context for understanding the expected long term clinical value of a reduction in viral set point
  • These findings may be useful in predicting the clinical benefit of HIV-1 vaccines that are currently in clinical trials
limitations
Limitations
  • The MACS does not include women.
    • Additional analyses should be conducted to determine if relative times to events of interest are similar in men and women
  • The MACS participants are predominantly infected with clade B HIV-1.
    • Since the natural history of HIV-1 infection may differ by infecting clade, it will be important to conduct similar analyses in populations infected with non-clade B subtypes.
  • A number of studies have shown the association between specific HLA alleles and disease resistance or progression.
    • Future analyses of the effect of viral load set point on time to events in HIV disease progression could account for individual HLA types.
acknowledgments
Acknowledgments
  • Data in this poster were collected by the Multicenter AIDS Cohort Study (MACS) with centers (Principal Investigators) at The Johns Hopkins University Bloomberg School of Public Health (Joseph B. Margolick, Lisa Jacobson), Howard Brown Health Center and Northwestern University Medical School (John Phair), University of California, Los Angeles (Roger Detels), and University of Pittsburgh (Charles Rinaldo).  
  • The MACS is funded by the National Institute of Allergy and Infectious Diseases, with additional supplemental funding from the National Cancer Institute and the National Heart, Lung and Blood Institute.   UO1-AI-35042, 5-MO1-RR-00722 (GCRC), UO1-AI-35043, UO1-AI-37984, UO1-AI-35039, UO1-AI-35040, UO1-AI-37613, UO1-AI-35041.  
discussion
Discussion
  • HIV-1 RNA measurements were relatively similar at 3, 9, and 15 months after seroconversion (range of geometric means: 19,815-22,387).
  • Compared with a viral set point of 30,000 copies/mL, a viral set point of 3,000 copies/mL was associated with an additional 2.5 years before CD4 count fell to 350 cells/mm3 - a common threshold for initiating antiretroviral therapy.
  • The median time to HIV-1 RNA >= 55,000 copies/mL, commonly defined as the loss of virological control, was three times longer for those with viral load set points of 3,000 compared to those with viral load set points of 30,000 copies/mL.
discussion continued
Discussion (continued)
  • Compared to those with an HIV RNA of 30,000 copies/mL at set point, an HIV RNA of 10,471 (4.02 log10) would be required to significantly reduce the hazard of progressing to a clinical indication to initiate antiretroviral therapy within 3 years by 25%.
slide41

People in sub-Saharan Africa on antiretroviral treatment as percentage of those in need, 2002–2005

2002

2003

2004

2005

Source: WHO/UNAIDS (2005). Progress on global access to HIV antiretroviral therapy: An update on “3 by 5.”

slide42

Impact of AIDS on life expectancy in five African countries, 1970–2010

70

65

60

Botswana

55

South Africa

Life

expectancy

at birth

(years)

50

45

Swaziland

40

35

Zambia

30

Zimbabwe

25

20

1970–1975

1980–1985

1990–1995

2000–2005

1975–1980

1985–1990

1995–2000

2005–2010

Source: United Nations Population Division (2004). World Population Prospects: The 2004 Revision, database.

slide43

Impact of three scenarios on HIV infection in sub-Saharan Africa, 2003–2020

5.0

4.0

Number

of new HIV

infections

(millions)

3.0

2.0

1.0

0.0

2003

2005

2010

2015

2020

Year

Baseline

Treatment-centered

Prevention-centered

Comprehensive response

Source: Salomon JA et al. (2005). Integrating HIV prevention and treatment: from slogans to impact

figure 3 percentage of adenovirus 5 neutralizing antibody titers by country

50

45

40

35

30

25

20

15

10

5

0

Figure 3. Percentage of Adenovirus 5 neutralizing antibody titers by country

Negative

18 - 200

201-1000

> 1000

Brazil

Cameroon

Malawi

S. Africa

Thailand

Dominican

Republic

International

Sites

US

worldwide distribution of hiv 1 clades subtypes
Worldwide Distribution of HIV-1 Clades (Subtypes)*

A, B, AB, Other

B, Other

G

B

A

F

B, Other

B

B, AE

B, BC

B, G, Other

G, Other

B, O

C

C

B, Other

O

A, Other

A

AE, B, Other

B, AE, Other

AG

All

G, Other

A,C,D

B, F, Other

Legend

C

B

B

B dominant + Another

C, Other

C

B, F

O

B, AE

A

B, C

All

Other

Note: *Dominant clades are bolded above; All regions have multiple clades in their populations

figure 4 frequencies of subjects who were responders on elispot assays in 340 hiv positive subjects

100

90

80

70

60

50

40

30

20

10

0

Gag

Nef

Pol1

Pol2

Rev

Tat

Figure 4. Frequencies of subjects who were responders on ELISPOT assays in 340 HIV-positive subjects

US (n=16)

Brazil (n=50)

Thailand (=77)

South Africa (n=48)

Malawi (n=40)

Botswana n=43)

Cameroon (n=51)

Dominican Republic (n=15)