HIV: Treatment as Prevention

Christopher KC Lee Infectious Diseases Unit Hospital Sungai Buloh

ARV therapy in the developing world

Note: at the end of 2011 1110 paediatrics cases on ART

Access is Improving but not good enough

Viral Load as a predictor of Heterosexual HIV transmission

Quinn et al, N Engl J Med. 2000;342:921-929

HAART stops HIV replication HIV load falls to undetectable levels in plasma as well as in sexual fluids

Sharp reduction in HIV transmission

Impact of ART Sero-discordant

Heterosexual Couples

92% reduction in HIV Transmission Risk from 5.64 to 0.46 transmissions per 100 person-years
S Attia, M Egger, M Muller, M Zwahlen and N Lowa. AIDS. 2009 Jul 17;23(11):1397-404

Cohen et al. N Engl J Med 365;6 August 11, 2011

Antiviral Treatment as Prevention

Extensive biological plausibility
The concentration of HIV-1 in blood and genital tract correlates with sexual transmission Antiretroviral agents that concentrate in the genital tract reduce HIV-1 viral load

Most observational reports indicate ART reduces transmission of HIV-1 in couples

Cohen et al. N Engl J Med 365;6 August 11, 2011

A Randomized Controlled Trial

To determine if ART reduces HIV-1
transmission magnitude? durability of benefit?

To determine if ART is used earlier to

reduce HIV-1 transmission personal health benefit(s)?

Cohen et al. N Engl J Med 365;6 August 11, 2011

HPTN 052 Enrollment

10,838 Individuals Screened
Major reasons for exclusion: 3058 HIV+ but CD4 count out of range 2565 HIV- but HIV+ partner ineligible 308 Seroconcordant couples 155 Ineligible due to sexual history

1763 Couples (3526 Individuals) Randomized

Immediate Arm 886 Couples

Delayed Arm 877 Couples

Cohen et al. N Engl J Med 365;6 August 11, 2011

HPTN 052 Enrollment

(Total Enrollment: 1763 couples)

U.S.

Thailand
Americas 278

Kenya Brazil Botswana South Africa Malawi Zimbabwe

India
Asia 531

Africa 954

Cohen et al. N Engl J Med 365;6 August 11, 2011

HPTN 052 Enrollment

Region
Americas (278)

Site
Porto Alegre, Brazil Rio de Janeiro, Brazil Boston, United States Chennai, India

Couples
90 186 2 250

Asia (531)

Pune, India
Chiang Mai, Thailand

175
106

Gaborone, Botswana
Kisumu, Kenya

77
60

Blantyre, Malawi
Africa (954) Lilongwe, Malawi Johannesburg, South Africa Soweto, South Africa Harare, Zimbabwe

230
251 46 50 240

Total
Cohen et al. N Engl J Med 365;6 August 11, 2011

1763

HPTN 052: Baseline Characteristics

Index
Immediate N = 886 Female Age (median) Married Any unprotected sex CD4 (median [IQR]) HIV RNA log10 (median [IQR]) 49% 33 94% 6% Delayed N = 877 50% 32 95% 8%

Partner
Immediate N = 893 49% 32 93% 8% ----Delayed N = 882 47% 32 94% 8% -----

442
[373-522] 4.4 [3.8-4.9]

428
[357-522] 4.4 [3.9-4.9]

HPTN 052: Baseline Characteristics

Index
Immediate N = 886 Female Age (median) Married Any unprotected sex CD4 (median [IQR]) HIV RNA log10 (median [IQR]) 49% 33 94% 6% Delayed N = 877 50% 32 95% 8%

Partner
Immediate N = 893 49% 32 93% 8% ----Delayed N = 882 47% 32 94% 8% -----

442
[373-522] 4.4 [3.8-4.9]

428
[357-522] 4.4 [3.9-4.9]

HPTN 052: HIV-1 Transmission

Total HIV-1 Transmission Events: 39

Immediate Arm 4

Delayed Arm 35

p < 0.0001
Cohen et al. N Engl J Med 365;6 August 11, 2011

HPTN 052: HIV-1 Transmission

Total HIV-1 Transmission Events: 39

Linked Transmissions: 28

Unlinked or TBD Transmissions: 11

18/28 (64%) transmissions from infected

participants with CD4 >350 cells/mm3

Immediate Arm: 1

Delayed Arm: 27

23/28 (82%) transmissions in sub-Saharan

Africa

18/28 (64%) transmissions from female to

p < 0.001

male partners

HPTN 052: HIV-1 Transmission

Study Arm

Follow-up (PY)*

Incidence/100PY [95% CI]

Linked Overall 0.3
[0.1 0.6]

Immediate Delayed

1585 1567

0.1
[0.0 0.4]

1.7
[1.1 2.5]

2.2
[1.6 3.1]

*Person-years specific for transmission events

Median follow-up: 1.7 years

HPTN052: HIV-1 Transmissions

HPTN 052: Effect of ART

Proportion of participants with VL<400 at each visit 1 0 0 8 0 6 0 4 0 2 0 0
0 3 6 9 12 15 18 21 24 27 30 33 Months 36 39 42 45

Immediate Arm Delayed Arm (not on ART) Delayed Arm (on ART)

HIV Transmission: CD4 Count and HIV-1 RNA

28 Linked Transmissions
C D 4 + ( c el ls / m m 3)

Immediate (1)

Delayed (27)

HI V R N A (lo g10 co pie s/ m m3 )

Immediate (1)

Delayed (27)

Median proximal CD4 (range): 400 (229-858) Immediate arm: 584 (584-584) Delayed arm: 391 (229-858)

Median proximal log10 VL (range): 4.9 (2.6-5.8) Immediate arm: 2.6 (2.6-2.6) Delayed arm: 4.9 (2.6-5.8)

HIV-1 RNA and CD4 Over Time (ITT)

CD4 (cells/mm3)
Immediate

Proportion <400 copies/ml

Delayed

Immediate Delayed

Time to ART Initiation (Delayed Arm)

21% initiated therapy
Mostly (75%) triggered by a decline in CD4 count

Median time to initiation was 3.5 years

Median CD4 at initiation was 225 cells/mm3
Q1Q3: 199 247

ART Regimens
Immediate Arm N initiating ART (AZT/3TC)/EFV (AZT/3TC)/ATV (FTC/TDF)/EFV (AZT/3TC)/(LPV/RTV) Other 886 72% 10% 9% 7% 2% Delayed Arm 184 70% 7% 11% 2% 10%

CD4 Trends Post ART Initiation

CD4 (cells/mm3)
Immediate

Delayed

Immediate Delayed

Brief Summary
ART response in Immediate arm was rapid and
robust

In Delayed arm ART was initiated in a minority of

participants and was significantly associated with baseline CD4 and viral load

Virologic failure was uncommon in either arm The magnitude of CD4 responses were similar
but the absolute CD4 levels achieved were lower in the delayed arm
Cohen et al. N Engl J Med 365;6 August 11, 2011

Adherence According to Region

Africa
N on ART N with evaluable adherence Adherence>75% Adherence>95% Mean (SD) adherence (%) Median adherence (%) 615 582 95% 74% 95 (12) 99

Non-Africa
533 517 96% 82% 95 (15) 99

Treatment for Prevention

Can it work? Will it work?

Can we afford it?

TasP in the "Real World"?

? Whether substantial population-level reductions in new HIV infections could be achieved in "real-world" sub-Saharan African settings where stable, cohabiting couples are often not the norm and where considerable operational challenges exist to the successful & sustainable delivery of treatment to large no. of patients. One of Africa's largest population-based prospective cohort studies (in rural KwaZulu-Natal, SA) followed up a total of 16,667 individuals who were HIV-uninfected at baseline, observing individual HIV seroconversions over 2004 - 2011. Holding other key HIV risk factors constant, individual HIV acquisition risk declined significantly with increasing ART coverage in the local community. Conclusion: An HIV-uninfected individual living in a community with high ART coverage (30-40% of all HIV-infected individuals on ART) was 38% less likely to acquire HIV than someone living in a community where ART coverage was low (<10% of all HIV-infected individuals on ART).

Tanser F et al. Science. 2013 Feb 22;339(6122):966-71.

New infections, behaviour change and treatment coverage in Botswana UNAIDS Report 2011