Challenges in Prevention ofMother to Child HIV Transmission

Lynne M Mofenson MDPediatric Adolescent and Maternal AIDS Branch

Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNational Institutes of Health

Department of Health and Human Services

Photo Lora Iannotti

GoalldquoEliminate pediatric HIV infectionrdquo

but also

ldquoMaximize HIV-free survival of infantrdquo

And

ldquoMaximize maternal healthrdquo

Sometimes Means of Achieving theseGoals may be at Odds with Each Other

(eg early weaning and infant survival stopping prolonged maternal HAART and mom health)

Donrsquot ForgetContraception

as the Most Effective Intervention to Prevent MTCT

AndPrevention of HIV

in Women

Four-Phase Strategy for Prevention of Mother to Child HIV Transmission

Wilcher R et al Sex Trans Inf 200884 (Suppl2)ii54-60

Prevention of HIV in Women

(Especially Young

Women)

Prevention of Unintended Pregnancies

in HIV-Infected

Women

Prevention of Transmission

from an HIV-Infected

Woman to Her Infant

Support for HIV-Infected Mother and

Family

Phase I Phase 2 Phase 3 Phase 4

Efficacy of PMTCT Programs is Related to More than Just the PMTCT Regimen Used

To provide PMTCT need to identify HIV-infected women during pregnancy

In 2007 only 18 of pregnant women received HIV testing in RLC

Regardless of what PMTCT intervention must get it to amp accepted by the woman

In 2007 only 33 of HIV-infected pregnant women received ARV for PMTCT in RLC

Program efficacy is as much related to the PMTCT cascade as the specific PMTCT regimen

attend ANC clinic 92

Counseled and tested for HIV

CD4 75

Get ARVs (pre- and perinatal)

50

100 HIV+ mothers

92

68

34

Enter into program

8

32

66

No ARV (25 MTCT) 165 infected

Missed - no PMTCT

PMTCT Cascade Most Critical Thing for PMTCT is Number of Women Completing Cascade

Overall ProgramEffectiveness(early MTCT)

sdNVP 195 tx

AZTsdNVP 175 tx

HAART 171 tx

P Barker WHO Mtg Nov 2008

sdNVP HAART (8 MTCT)AZT+sdNVP HAART (3 MTCT)HAART all (2 MTCT)

CD4 gt200 CD4 lt2003 infected

06 infected1 infected

attend ANC clinic 95

Counseled and tested for HIV

CD4 95

Get ARVs (pre- and perinatal)

95

100 HIV+ mothers

95

90

86

Enter into program

5

10

14

No ARV (25 MTCT) 35 infected

Missed - no PMTCT

PMTCT Cascade Most Critical Thing for PMTCT is Number of Women Completing Cascade

Overall ProgramEffectiveness(early MTCT)

sdNVP 104 tx

AZTsdNVP 61 tx

HAART 52 tx

P Barker WHO Mtg Nov 2008

Change cascadeefficiency

sdNVP HAART (8 MTCT)AZT+sdNVP HAART (3 MTCT)HAART all (2 MTCT)

CD4 gt200 CD4 lt20069 infected26 infected17 infected

To Maximize EffectivenessNeed to Prevent In Utero Transmission

Interventions Need to Start During Pregnancy ndash so Need Early Identification

For Early Intervention

ldquoResidual Transmissionrdquo Even if PreventAll IP and PP Transmission When

Start ARV at 28 Weeks1-2 In Utero Infection

For Maximal Efficacy of Any Regimen Need to Start Early in Pregnancy to Prevent In Utero Transmission

Lallemant M et al N Engl J Med 2000343982-91

0

2

4

6

Tra

nsm

issi

on

LL + LS SS + SLAP 28 wks AP 36 wks

Plt0001

16

51

Even if intervention is 100 effective for IPPP transmission still have ldquoresidual infectionrdquo of 16 starting at 28 weeks

A Key IssueARV Treatment vs ARV Prophylaxis

What Should CD4 Threshold for ARV Treatment be in Pregnancy

(Treatment = HAART Started in Pregnancyand Continued ldquoLife-Longrdquo Even

After No Further MTCT Risk Exists)

Why CD4 Threshold of lt350 for Treatment Includes Most Maternal Deaths and Postnatal Infections

ZEBS Study ndash L Kuhn personal communication 2009

CD4 lt 200 55 of maternal deaths 47 of postnatal infections

0 10 20 30 40 50

lt200

200-350

350-500

gt500

CD

4 C

ount

Percent Transmission

In Utero Intrapartum-Early Postpartum Postpartum

39 45 19

35

76

76 155

73

23

208

133

74

84 of maternal deaths82 of postnatal infections

If assume all pregnant women with CD4 lt350 should be initiated on

antiretroviral treatment for life

then remaining research questions revolve around

what is optimal intervention used solely for PMTCT for women

with CD4 gt350

For Women with CD4 gt350AntepartumIntrapartum PMTCT

AZTsdNVP + ldquotailrdquovs

Maternal HAART

May Have Comparative Efficacyin Women with Higher CD4 Counts

IF ASSUME TREATMENT FOR ALL WITHPREGNANT WOMEN WITH CD4 lt350

Donrsquot ForgetContraception

as the Most Effective Intervention to Prevent MTCT

AndPrevention of HIV

in Women

Four-Phase Strategy for Prevention of Mother to Child HIV Transmission

Wilcher R et al Sex Trans Inf 200884 (Suppl2)ii54-60

Prevention of HIV in Women

(Especially Young

Women)

Prevention of Unintended Pregnancies

in HIV-Infected

Women

Prevention of Transmission

from an HIV-Infected

Woman to Her Infant

Support for HIV-Infected Mother and

Family

Phase I Phase 2 Phase 3 Phase 4

Efficacy of PMTCT Programs is Related to More than Just the PMTCT Regimen Used

To provide PMTCT need to identify HIV-infected women during pregnancy

In 2007 only 18 of pregnant women received HIV testing in RLC

Regardless of what PMTCT intervention must get it to amp accepted by the woman

In 2007 only 33 of HIV-infected pregnant women received ARV for PMTCT in RLC

Program efficacy is as much related to the PMTCT cascade as the specific PMTCT regimen

attend ANC clinic 92

Counseled and tested for HIV

CD4 75

Get ARVs (pre- and perinatal)

50

100 HIV+ mothers

92

68

34

Enter into program

8

32

66

No ARV (25 MTCT) 165 infected

Missed - no PMTCT

PMTCT Cascade Most Critical Thing for PMTCT is Number of Women Completing Cascade

Overall ProgramEffectiveness(early MTCT)

sdNVP 195 tx

AZTsdNVP 175 tx

HAART 171 tx

P Barker WHO Mtg Nov 2008

sdNVP HAART (8 MTCT)AZT+sdNVP HAART (3 MTCT)HAART all (2 MTCT)

CD4 gt200 CD4 lt2003 infected

06 infected1 infected

attend ANC clinic 95

Counseled and tested for HIV

CD4 95

Get ARVs (pre- and perinatal)

95

100 HIV+ mothers

95

90

86

Enter into program

5

10

14

No ARV (25 MTCT) 35 infected

Missed - no PMTCT

PMTCT Cascade Most Critical Thing for PMTCT is Number of Women Completing Cascade

Overall ProgramEffectiveness(early MTCT)

sdNVP 104 tx

AZTsdNVP 61 tx

HAART 52 tx

P Barker WHO Mtg Nov 2008

Change cascadeefficiency

sdNVP HAART (8 MTCT)AZT+sdNVP HAART (3 MTCT)HAART all (2 MTCT)

CD4 gt200 CD4 lt20069 infected26 infected17 infected

To Maximize EffectivenessNeed to Prevent In Utero Transmission

Interventions Need to Start During Pregnancy ndash so Need Early Identification

For Early Intervention

ldquoResidual Transmissionrdquo Even if PreventAll IP and PP Transmission When

Start ARV at 28 Weeks1-2 In Utero Infection

For Maximal Efficacy of Any Regimen Need to Start Early in Pregnancy to Prevent In Utero Transmission

Lallemant M et al N Engl J Med 2000343982-91

0

2

4

6

Tra

nsm

issi

on

LL + LS SS + SLAP 28 wks AP 36 wks

Plt0001

16

51

Even if intervention is 100 effective for IPPP transmission still have ldquoresidual infectionrdquo of 16 starting at 28 weeks

A Key IssueARV Treatment vs ARV Prophylaxis

What Should CD4 Threshold for ARV Treatment be in Pregnancy

(Treatment = HAART Started in Pregnancyand Continued ldquoLife-Longrdquo Even

After No Further MTCT Risk Exists)

Why CD4 Threshold of lt350 for Treatment Includes Most Maternal Deaths and Postnatal Infections

ZEBS Study ndash L Kuhn personal communication 2009

CD4 lt 200 55 of maternal deaths 47 of postnatal infections

0 10 20 30 40 50

lt200

200-350

350-500

gt500

CD

4 C

ount

Percent Transmission

In Utero Intrapartum-Early Postpartum Postpartum

39 45 19

35

76

76 155

73

23

208

133

74

84 of maternal deaths82 of postnatal infections

If assume all pregnant women with CD4 lt350 should be initiated on

antiretroviral treatment for life

then remaining research questions revolve around

what is optimal intervention used solely for PMTCT for women

with CD4 gt350

For Women with CD4 gt350AntepartumIntrapartum PMTCT

AZTsdNVP + ldquotailrdquovs

Maternal HAART

May Have Comparative Efficacyin Women with Higher CD4 Counts

IF ASSUME TREATMENT FOR ALL WITHPREGNANT WOMEN WITH CD4 lt350

Four-Phase Strategy for Prevention of Mother to Child HIV Transmission

Wilcher R et al Sex Trans Inf 200884 (Suppl2)ii54-60

Prevention of HIV in Women

(Especially Young

Women)

Prevention of Unintended Pregnancies

in HIV-Infected

Women

Prevention of Transmission

from an HIV-Infected

Woman to Her Infant

Support for HIV-Infected Mother and

Family

Phase I Phase 2 Phase 3 Phase 4

Efficacy of PMTCT Programs is Related to More than Just the PMTCT Regimen Used

To provide PMTCT need to identify HIV-infected women during pregnancy

In 2007 only 18 of pregnant women received HIV testing in RLC

Regardless of what PMTCT intervention must get it to amp accepted by the woman

In 2007 only 33 of HIV-infected pregnant women received ARV for PMTCT in RLC

Program efficacy is as much related to the PMTCT cascade as the specific PMTCT regimen

attend ANC clinic 92

Counseled and tested for HIV

CD4 75

Get ARVs (pre- and perinatal)

50

100 HIV+ mothers

92

68

34

Enter into program

8

32

66

No ARV (25 MTCT) 165 infected

Missed - no PMTCT

PMTCT Cascade Most Critical Thing for PMTCT is Number of Women Completing Cascade

Overall ProgramEffectiveness(early MTCT)

sdNVP 195 tx

AZTsdNVP 175 tx

HAART 171 tx

P Barker WHO Mtg Nov 2008

sdNVP HAART (8 MTCT)AZT+sdNVP HAART (3 MTCT)HAART all (2 MTCT)

CD4 gt200 CD4 lt2003 infected

06 infected1 infected

attend ANC clinic 95

Counseled and tested for HIV

CD4 95

Get ARVs (pre- and perinatal)

95

100 HIV+ mothers

95

90

86

Enter into program

5

10

14

No ARV (25 MTCT) 35 infected

Missed - no PMTCT

PMTCT Cascade Most Critical Thing for PMTCT is Number of Women Completing Cascade

Overall ProgramEffectiveness(early MTCT)

sdNVP 104 tx

AZTsdNVP 61 tx

HAART 52 tx

P Barker WHO Mtg Nov 2008

Change cascadeefficiency

sdNVP HAART (8 MTCT)AZT+sdNVP HAART (3 MTCT)HAART all (2 MTCT)

CD4 gt200 CD4 lt20069 infected26 infected17 infected

To Maximize EffectivenessNeed to Prevent In Utero Transmission

Interventions Need to Start During Pregnancy ndash so Need Early Identification

For Early Intervention

ldquoResidual Transmissionrdquo Even if PreventAll IP and PP Transmission When

Start ARV at 28 Weeks1-2 In Utero Infection

For Maximal Efficacy of Any Regimen Need to Start Early in Pregnancy to Prevent In Utero Transmission

Lallemant M et al N Engl J Med 2000343982-91

0

2

4

6

Tra

nsm

issi

on

LL + LS SS + SLAP 28 wks AP 36 wks

Plt0001

16

51

Even if intervention is 100 effective for IPPP transmission still have ldquoresidual infectionrdquo of 16 starting at 28 weeks

A Key IssueARV Treatment vs ARV Prophylaxis

What Should CD4 Threshold for ARV Treatment be in Pregnancy

(Treatment = HAART Started in Pregnancyand Continued ldquoLife-Longrdquo Even

After No Further MTCT Risk Exists)

Why CD4 Threshold of lt350 for Treatment Includes Most Maternal Deaths and Postnatal Infections

ZEBS Study ndash L Kuhn personal communication 2009

CD4 lt 200 55 of maternal deaths 47 of postnatal infections

0 10 20 30 40 50

lt200

200-350

350-500

gt500

CD

4 C

ount

Percent Transmission

In Utero Intrapartum-Early Postpartum Postpartum

39 45 19

35

76

76 155

73

23

208

133

74

84 of maternal deaths82 of postnatal infections

If assume all pregnant women with CD4 lt350 should be initiated on

antiretroviral treatment for life

then remaining research questions revolve around

what is optimal intervention used solely for PMTCT for women

with CD4 gt350

For Women with CD4 gt350AntepartumIntrapartum PMTCT

AZTsdNVP + ldquotailrdquovs

Maternal HAART

May Have Comparative Efficacyin Women with Higher CD4 Counts

IF ASSUME TREATMENT FOR ALL WITHPREGNANT WOMEN WITH CD4 lt350

Efficacy of PMTCT Programs is Related to More than Just the PMTCT Regimen Used

To provide PMTCT need to identify HIV-infected women during pregnancy

In 2007 only 18 of pregnant women received HIV testing in RLC

Regardless of what PMTCT intervention must get it to amp accepted by the woman

In 2007 only 33 of HIV-infected pregnant women received ARV for PMTCT in RLC

Program efficacy is as much related to the PMTCT cascade as the specific PMTCT regimen

attend ANC clinic 92

Counseled and tested for HIV

CD4 75

Get ARVs (pre- and perinatal)

50

100 HIV+ mothers

92

68

34

Enter into program

8

32

66

No ARV (25 MTCT) 165 infected

Missed - no PMTCT

PMTCT Cascade Most Critical Thing for PMTCT is Number of Women Completing Cascade

Overall ProgramEffectiveness(early MTCT)

sdNVP 195 tx

AZTsdNVP 175 tx

HAART 171 tx

P Barker WHO Mtg Nov 2008

sdNVP HAART (8 MTCT)AZT+sdNVP HAART (3 MTCT)HAART all (2 MTCT)

CD4 gt200 CD4 lt2003 infected

06 infected1 infected

attend ANC clinic 95

Counseled and tested for HIV

CD4 95

Get ARVs (pre- and perinatal)

95

100 HIV+ mothers

95

90

86

Enter into program

5

10

14

No ARV (25 MTCT) 35 infected

Missed - no PMTCT

PMTCT Cascade Most Critical Thing for PMTCT is Number of Women Completing Cascade

Overall ProgramEffectiveness(early MTCT)

sdNVP 104 tx

AZTsdNVP 61 tx

HAART 52 tx

P Barker WHO Mtg Nov 2008

Change cascadeefficiency

sdNVP HAART (8 MTCT)AZT+sdNVP HAART (3 MTCT)HAART all (2 MTCT)

CD4 gt200 CD4 lt20069 infected26 infected17 infected

To Maximize EffectivenessNeed to Prevent In Utero Transmission

Interventions Need to Start During Pregnancy ndash so Need Early Identification

For Early Intervention

ldquoResidual Transmissionrdquo Even if PreventAll IP and PP Transmission When

Start ARV at 28 Weeks1-2 In Utero Infection

For Maximal Efficacy of Any Regimen Need to Start Early in Pregnancy to Prevent In Utero Transmission

Lallemant M et al N Engl J Med 2000343982-91

0

2

4

6

Tra

nsm

issi

on

LL + LS SS + SLAP 28 wks AP 36 wks

Plt0001

16

51

Even if intervention is 100 effective for IPPP transmission still have ldquoresidual infectionrdquo of 16 starting at 28 weeks

A Key IssueARV Treatment vs ARV Prophylaxis

What Should CD4 Threshold for ARV Treatment be in Pregnancy

(Treatment = HAART Started in Pregnancyand Continued ldquoLife-Longrdquo Even

After No Further MTCT Risk Exists)

Why CD4 Threshold of lt350 for Treatment Includes Most Maternal Deaths and Postnatal Infections

ZEBS Study ndash L Kuhn personal communication 2009

CD4 lt 200 55 of maternal deaths 47 of postnatal infections

0 10 20 30 40 50

lt200

200-350

350-500

gt500

CD

4 C

ount

Percent Transmission

In Utero Intrapartum-Early Postpartum Postpartum

39 45 19

35

76

76 155

73

23

208

133

74

84 of maternal deaths82 of postnatal infections

If assume all pregnant women with CD4 lt350 should be initiated on

antiretroviral treatment for life

then remaining research questions revolve around

what is optimal intervention used solely for PMTCT for women

with CD4 gt350

For Women with CD4 gt350AntepartumIntrapartum PMTCT

AZTsdNVP + ldquotailrdquovs

Maternal HAART

May Have Comparative Efficacyin Women with Higher CD4 Counts

IF ASSUME TREATMENT FOR ALL WITHPREGNANT WOMEN WITH CD4 lt350

attend ANC clinic 92

Counseled and tested for HIV

CD4 75

Get ARVs (pre- and perinatal)

50

100 HIV+ mothers

92

68

34

Enter into program

8

32

66

No ARV (25 MTCT) 165 infected

Missed - no PMTCT

PMTCT Cascade Most Critical Thing for PMTCT is Number of Women Completing Cascade

Overall ProgramEffectiveness(early MTCT)

sdNVP 195 tx

AZTsdNVP 175 tx

HAART 171 tx

P Barker WHO Mtg Nov 2008

sdNVP HAART (8 MTCT)AZT+sdNVP HAART (3 MTCT)HAART all (2 MTCT)

CD4 gt200 CD4 lt2003 infected

06 infected1 infected

attend ANC clinic 95

Counseled and tested for HIV

CD4 95

Get ARVs (pre- and perinatal)

95

100 HIV+ mothers

95

90

86

Enter into program

5

10

14

No ARV (25 MTCT) 35 infected

Missed - no PMTCT

PMTCT Cascade Most Critical Thing for PMTCT is Number of Women Completing Cascade

Overall ProgramEffectiveness(early MTCT)

sdNVP 104 tx

AZTsdNVP 61 tx

HAART 52 tx

P Barker WHO Mtg Nov 2008

Change cascadeefficiency

sdNVP HAART (8 MTCT)AZT+sdNVP HAART (3 MTCT)HAART all (2 MTCT)

CD4 gt200 CD4 lt20069 infected26 infected17 infected

To Maximize EffectivenessNeed to Prevent In Utero Transmission

Interventions Need to Start During Pregnancy ndash so Need Early Identification

For Early Intervention

ldquoResidual Transmissionrdquo Even if PreventAll IP and PP Transmission When

Start ARV at 28 Weeks1-2 In Utero Infection

For Maximal Efficacy of Any Regimen Need to Start Early in Pregnancy to Prevent In Utero Transmission

Lallemant M et al N Engl J Med 2000343982-91

0

2

4

6

Tra

nsm

issi

on

LL + LS SS + SLAP 28 wks AP 36 wks

Plt0001

16

51

Even if intervention is 100 effective for IPPP transmission still have ldquoresidual infectionrdquo of 16 starting at 28 weeks

A Key IssueARV Treatment vs ARV Prophylaxis

What Should CD4 Threshold for ARV Treatment be in Pregnancy

(Treatment = HAART Started in Pregnancyand Continued ldquoLife-Longrdquo Even

After No Further MTCT Risk Exists)

Why CD4 Threshold of lt350 for Treatment Includes Most Maternal Deaths and Postnatal Infections

ZEBS Study ndash L Kuhn personal communication 2009

CD4 lt 200 55 of maternal deaths 47 of postnatal infections

0 10 20 30 40 50

lt200

200-350

350-500

gt500

CD

4 C

ount

Percent Transmission

In Utero Intrapartum-Early Postpartum Postpartum

39 45 19

35

76

76 155

73

23

208

133

74

84 of maternal deaths82 of postnatal infections

If assume all pregnant women with CD4 lt350 should be initiated on

antiretroviral treatment for life

then remaining research questions revolve around

what is optimal intervention used solely for PMTCT for women

with CD4 gt350

For Women with CD4 gt350AntepartumIntrapartum PMTCT

AZTsdNVP + ldquotailrdquovs

Maternal HAART

May Have Comparative Efficacyin Women with Higher CD4 Counts

IF ASSUME TREATMENT FOR ALL WITHPREGNANT WOMEN WITH CD4 lt350

attend ANC clinic 95

Counseled and tested for HIV

CD4 95

Get ARVs (pre- and perinatal)

95

100 HIV+ mothers

95

90

86

Enter into program

5

10

14

No ARV (25 MTCT) 35 infected

Missed - no PMTCT

PMTCT Cascade Most Critical Thing for PMTCT is Number of Women Completing Cascade

Overall ProgramEffectiveness(early MTCT)

sdNVP 104 tx

AZTsdNVP 61 tx

HAART 52 tx

P Barker WHO Mtg Nov 2008

Change cascadeefficiency

sdNVP HAART (8 MTCT)AZT+sdNVP HAART (3 MTCT)HAART all (2 MTCT)

CD4 gt200 CD4 lt20069 infected26 infected17 infected

To Maximize EffectivenessNeed to Prevent In Utero Transmission

Interventions Need to Start During Pregnancy ndash so Need Early Identification

For Early Intervention

ldquoResidual Transmissionrdquo Even if PreventAll IP and PP Transmission When

Start ARV at 28 Weeks1-2 In Utero Infection

For Maximal Efficacy of Any Regimen Need to Start Early in Pregnancy to Prevent In Utero Transmission

Lallemant M et al N Engl J Med 2000343982-91

0

2

4

6

Tra

nsm

issi

on

LL + LS SS + SLAP 28 wks AP 36 wks

Plt0001

16

51

Even if intervention is 100 effective for IPPP transmission still have ldquoresidual infectionrdquo of 16 starting at 28 weeks

A Key IssueARV Treatment vs ARV Prophylaxis

What Should CD4 Threshold for ARV Treatment be in Pregnancy

(Treatment = HAART Started in Pregnancyand Continued ldquoLife-Longrdquo Even

After No Further MTCT Risk Exists)

Why CD4 Threshold of lt350 for Treatment Includes Most Maternal Deaths and Postnatal Infections

ZEBS Study ndash L Kuhn personal communication 2009

CD4 lt 200 55 of maternal deaths 47 of postnatal infections

0 10 20 30 40 50

lt200

200-350

350-500

gt500

CD

4 C

ount

Percent Transmission

In Utero Intrapartum-Early Postpartum Postpartum

39 45 19

35

76

76 155

73

23

208

133

74

84 of maternal deaths82 of postnatal infections

If assume all pregnant women with CD4 lt350 should be initiated on

antiretroviral treatment for life

then remaining research questions revolve around

what is optimal intervention used solely for PMTCT for women

with CD4 gt350

For Women with CD4 gt350AntepartumIntrapartum PMTCT

AZTsdNVP + ldquotailrdquovs

Maternal HAART

May Have Comparative Efficacyin Women with Higher CD4 Counts

IF ASSUME TREATMENT FOR ALL WITHPREGNANT WOMEN WITH CD4 lt350

To Maximize EffectivenessNeed to Prevent In Utero Transmission

Interventions Need to Start During Pregnancy ndash so Need Early Identification

For Early Intervention

ldquoResidual Transmissionrdquo Even if PreventAll IP and PP Transmission When

Start ARV at 28 Weeks1-2 In Utero Infection

For Maximal Efficacy of Any Regimen Need to Start Early in Pregnancy to Prevent In Utero Transmission

Lallemant M et al N Engl J Med 2000343982-91

0

2

4

6

Tra

nsm

issi

on

LL + LS SS + SLAP 28 wks AP 36 wks

Plt0001

16

51

Even if intervention is 100 effective for IPPP transmission still have ldquoresidual infectionrdquo of 16 starting at 28 weeks

A Key IssueARV Treatment vs ARV Prophylaxis

What Should CD4 Threshold for ARV Treatment be in Pregnancy

(Treatment = HAART Started in Pregnancyand Continued ldquoLife-Longrdquo Even

After No Further MTCT Risk Exists)

Why CD4 Threshold of lt350 for Treatment Includes Most Maternal Deaths and Postnatal Infections

ZEBS Study ndash L Kuhn personal communication 2009

CD4 lt 200 55 of maternal deaths 47 of postnatal infections

0 10 20 30 40 50

lt200

200-350

350-500

gt500

CD

4 C

ount

Percent Transmission

In Utero Intrapartum-Early Postpartum Postpartum

39 45 19

35

76

76 155

73

23

208

133

74

84 of maternal deaths82 of postnatal infections

If assume all pregnant women with CD4 lt350 should be initiated on

antiretroviral treatment for life

then remaining research questions revolve around

what is optimal intervention used solely for PMTCT for women

with CD4 gt350

For Women with CD4 gt350AntepartumIntrapartum PMTCT

AZTsdNVP + ldquotailrdquovs

Maternal HAART

May Have Comparative Efficacyin Women with Higher CD4 Counts

IF ASSUME TREATMENT FOR ALL WITHPREGNANT WOMEN WITH CD4 lt350

For Maximal Efficacy of Any Regimen Need to Start Early in Pregnancy to Prevent In Utero Transmission

Lallemant M et al N Engl J Med 2000343982-91

0

2

4

6

Tra

nsm

issi

on

LL + LS SS + SLAP 28 wks AP 36 wks

Plt0001

16

51

Even if intervention is 100 effective for IPPP transmission still have ldquoresidual infectionrdquo of 16 starting at 28 weeks

A Key IssueARV Treatment vs ARV Prophylaxis

What Should CD4 Threshold for ARV Treatment be in Pregnancy

(Treatment = HAART Started in Pregnancyand Continued ldquoLife-Longrdquo Even

After No Further MTCT Risk Exists)

Why CD4 Threshold of lt350 for Treatment Includes Most Maternal Deaths and Postnatal Infections

ZEBS Study ndash L Kuhn personal communication 2009

CD4 lt 200 55 of maternal deaths 47 of postnatal infections

0 10 20 30 40 50

lt200

200-350

350-500

gt500

CD

4 C

ount

Percent Transmission

In Utero Intrapartum-Early Postpartum Postpartum

39 45 19

35

76

76 155

73

23

208

133

74

84 of maternal deaths82 of postnatal infections

If assume all pregnant women with CD4 lt350 should be initiated on

antiretroviral treatment for life

then remaining research questions revolve around

what is optimal intervention used solely for PMTCT for women

with CD4 gt350

For Women with CD4 gt350AntepartumIntrapartum PMTCT

AZTsdNVP + ldquotailrdquovs

Maternal HAART

May Have Comparative Efficacyin Women with Higher CD4 Counts

IF ASSUME TREATMENT FOR ALL WITHPREGNANT WOMEN WITH CD4 lt350

A Key IssueARV Treatment vs ARV Prophylaxis

What Should CD4 Threshold for ARV Treatment be in Pregnancy

(Treatment = HAART Started in Pregnancyand Continued ldquoLife-Longrdquo Even

After No Further MTCT Risk Exists)

Why CD4 Threshold of lt350 for Treatment Includes Most Maternal Deaths and Postnatal Infections

ZEBS Study ndash L Kuhn personal communication 2009

CD4 lt 200 55 of maternal deaths 47 of postnatal infections

0 10 20 30 40 50

lt200

200-350

350-500

gt500

CD

4 C

ount

Percent Transmission

In Utero Intrapartum-Early Postpartum Postpartum

39 45 19

35

76

76 155

73

23

208

133

74

84 of maternal deaths82 of postnatal infections

If assume all pregnant women with CD4 lt350 should be initiated on

antiretroviral treatment for life

then remaining research questions revolve around

what is optimal intervention used solely for PMTCT for women

with CD4 gt350

For Women with CD4 gt350AntepartumIntrapartum PMTCT

AZTsdNVP + ldquotailrdquovs

Maternal HAART

May Have Comparative Efficacyin Women with Higher CD4 Counts

IF ASSUME TREATMENT FOR ALL WITHPREGNANT WOMEN WITH CD4 lt350

Why CD4 Threshold of lt350 for Treatment Includes Most Maternal Deaths and Postnatal Infections

ZEBS Study ndash L Kuhn personal communication 2009

CD4 lt 200 55 of maternal deaths 47 of postnatal infections

0 10 20 30 40 50

lt200

200-350

350-500

gt500

CD

4 C

ount

Percent Transmission

In Utero Intrapartum-Early Postpartum Postpartum

39 45 19

35

76

76 155

73

23

208

133

74

84 of maternal deaths82 of postnatal infections

If assume all pregnant women with CD4 lt350 should be initiated on

antiretroviral treatment for life

then remaining research questions revolve around

what is optimal intervention used solely for PMTCT for women

with CD4 gt350

For Women with CD4 gt350AntepartumIntrapartum PMTCT

AZTsdNVP + ldquotailrdquovs

Maternal HAART

May Have Comparative Efficacyin Women with Higher CD4 Counts

IF ASSUME TREATMENT FOR ALL WITHPREGNANT WOMEN WITH CD4 lt350

If assume all pregnant women with CD4 lt350 should be initiated on

antiretroviral treatment for life

then remaining research questions revolve around

what is optimal intervention used solely for PMTCT for women

with CD4 gt350

For Women with CD4 gt350AntepartumIntrapartum PMTCT

AZTsdNVP + ldquotailrdquovs

Maternal HAART

May Have Comparative Efficacyin Women with Higher CD4 Counts

IF ASSUME TREATMENT FOR ALL WITHPREGNANT WOMEN WITH CD4 lt350

For Women with CD4 gt350AntepartumIntrapartum PMTCT

AZTsdNVP + ldquotailrdquovs

Maternal HAART

May Have Comparative Efficacyin Women with Higher CD4 Counts

IF ASSUME TREATMENT FOR ALL WITHPREGNANT WOMEN WITH CD4 lt350

AZT + sdNVP results in MTCT Rates of 1 in Women with CD4 gt200 Thailand

Lallemant M et al NEJM 2004351217-28

164

1439

100

5

10

15

20

T

rans

mis

sion

lt=200 gt200

Placebo-Placebo NVP-NVP

CD4 CountComparing Difference in Transmission Rates Between

AZTPlacebo-Placebo and AZTNVP-NVP by CD4

Formula Feeding

MTCT Botswana National Data Oct 2006-Nov 2007 Tlale J et al IAS Mexico City Aug 2008 (Abs ThAC04)

HIV+ pregnant women with CD4gt200 are given AZT from 28 weeks through labor and sdNVP at onset of labor

Women with CD4 lt200 are given HAART

PMTCT uptake stood at 90 in 2007

Most women formula feed

PMTCT program data analyzed from October 2006- November 2007 on records of HIV test results of 10516 children born to HIV-infected women from all health districts

MTCT at Age 6 Weeks by ARV Regimen Botswana National Data Oct 2006-Nov 2007

Tlale J et al IAS Mexico City Aug 2008 (Abs ThAC04)

07 2333 31

4755

70

123

0

5

10

15

HAARTpre-preg

HAARTduringpreg

AZTgt4 wk

+sdNVP

AZTgt4wkalone

AZT lt4 wk

+sdNVP

AZT lt4 wkalone

sdNVP No ART

Most Women Formula Feed Their Infants

MTCT at Age 6 Weeks by ARV Regimen Botswana National Data Oct 2006-Nov 2007

Tlale J et al IAS Mexico City Aug 2008 (Abs ThAC04)

07 2333 31

4755

70

123

0

5

10

15

HAARTpre-preg

HAARTduringpreg

AZTgt4 wk

+sdNVP

AZTgt4wkalone

AZT lt4 wk

+sdNVP

AZT lt4 wkalone

sdNVP No ART

HAART most effective if started prior to pregnancy in women with low CD4

MTCT at Age 6 Weeks by ARV Regimen Botswana National Data Oct 2006-Nov 2007

Tlale J et al IAS Mexico City Aug 2008 (Abs ThAC04)

07 2333 31

4755

70

123

0

5

10

15

HAARTpre-preg

HAARTduringpreg

AZTgt4 wk

+sdNVP

AZTgt4wkalone

AZT lt4 wk

+sdNVP

AZT lt4 wkalone

sdNVP No ART

Starting HAART during pregnancy if CD4 lt200and AZT+sdNVP if CD4 gt200 results insimilar MTCT rates (CI likely overlap)

MTCT at Age 6 Weeks by ARV Regimen Botswana National Data Oct 2006-Nov 2007

Tlale J et al IAS Mexico City Aug 2008 (Abs ThAC04)

07 2333 31

4755

70

123

0

5

10

15

HAARTpre-preg

HAARTduringpreg

AZTgt4 wk

+sdNVP

AZTgt4wkalone

AZT lt4 wk

+sdNVP

AZT lt4 wkalone

sdNVP No ART

Longer AP duration is more effectivethan shorter (lt4 wks) AP drug

MTCT at Age 6 Weeks by ARV Regimen Botswana National Data Oct 2006-Nov 2007

Tlale J et al IAS Mexico City Aug 2008 (Abs ThAC04)

07 2333 31

4755

70

123

0

5

10

15

HAARTpre-preg

HAARTduringpreg

AZTgt4 wk

+sdNVP

AZTgt4wkalone

AZT lt4 wk

+sdNVP

AZT lt4 wkalone

sdNVP No ART

sdNVP reduces MTCT by43 implemented in a

National Program

Mother to Child Transmission 2000-2006 5930 Births to HIV+ Women UKIreland

Townsend CL et al AIDS 200822973-981Prophylaxis MTCT Adjusted Odds Ratio

(for mode delivery sex viral load)

Overall 12

ART gt14 days 08HAART with NNRTI 09

131 (06-28) p=048HAART with PI 11

HAART at conception 01018 (02-13) p=009

HAART during pregnancy 13HAART Elective CS 07

p=015HAART Planned vaginal 07AZT Elective CS (N=464) 0

In Breastfeeding Settings ~40 of All Mother to Child Transmission Can be Attributed to Breastfeeding

10-15 of Infants with Prolonged Breastfeeding Become Infected

Early Antenatal(lt28 wks)

Late Antenatal(28 wks to labor)

Labor and Delivery

Late Postpartum

1-6 mos 6-24 mos0-1 mo

Pregnancy

Early

Breastfeeding ~40

Substantial Proportion of Infections Occur During BF

Prevention of Breast Milk HIV TransmissionHypothesized that ldquosaferrdquo breastfeeding through giving antiretroviral prophylaxis during period when breast milk is most beneficial with early weaning might reduce postnatal transmission

Ongoing studies are evaluating the safety and efficacy of

Infant antiretroviral prophylaxis + early weaning

Maternal HAART during lactation + early weaning

However increasing data indicate early cessation of breastfeeding at 6 months is not safe in some poor countries

Potential Problems with Universal HAART Solely for PMTCT in Developing Countries

ComplexityComplexity ndash implementation issues postnatal adherence issues (= resistance risk)

Limited resources and costLimited resources and cost ndash canrsquot provide ART even to patients who need for own health

Limited regimen choiceLimited regimen choice limited by toxicity with NVP with CD4 gt250 cellsuL EFV teratogenicity PI expense

Pregnancy outcomelongPregnancy outcomelong--term infant outcometerm infant outcome

Maternal healthMaternal health (issues of start-stop HAART)

Differential penetration of ARV drugs into milkDifferential penetration of ARV drugs into milkcould result in resistant virus in milk

If Choose to Use HAARTIn Women with CD4 gt350 for PMTCT

Drug choice problematic

- NVP toxicity

- EFV okay 3rd trimester but PPrepeat pregnancy risk if prolonged

-PI cost

NVP Liver Toxicity More Common in Pregnant than Non-Pregnant Thai Women and Women Receiving

ART for PMTCT than for Treatment Phanuaphak N et al HIV Med 20078357-66

Rate per 100 patient-yearsNon- Preg Preg

P value

ART for RX

ART for PMTCT

P Value

(N=87) (N=244) (N=102) (N=142)Median CD4 152 277 136 414

Sx hepatitis 15 75 002 25 160 00003

Rash+liver 08 43 005 08 102 00003

Gr 12 liver 08 48 004 08 58 002

Gr 34 Rash 55 58 042 - -

First Trimester Efavirenz Use and Central Nervous System Defects

Antiretroviral Pregnancy Registry prospective data do not indicate an increase in overall birth defects (10364 overall 27 95 CI 13-50)However with in utero exposure in primates at doses resulting in drug levels similar to human exposure 320 infant monkeys had severe central nervous system (CNS) defects (eg anencephaly anophthalmia cleft palate)5 retrospective and 1 prospective human cases of CNS defects (eg meningomyelocele) with first trimester efavirenz exposureFDA Class D (+ animal amp potential human risk)

MTCT Botswana National Data Oct 2006-Nov 2007 Tlale J et al IAS Mexico City Aug 2008 (Abs ThAC04)

HIV+ pregnant women with CD4gt200 are given AZT from 28 weeks through labor and sdNVP at onset of labor

Women with CD4 lt200 are given HAART

PMTCT uptake stood at 90 in 2007

Most women formula feed

PMTCT program data analyzed from October 2006- November 2007 on records of HIV test results of 10516 children born to HIV-infected women from all health districts

MTCT at Age 6 Weeks by ARV Regimen Botswana National Data Oct 2006-Nov 2007

Tlale J et al IAS Mexico City Aug 2008 (Abs ThAC04)

07 2333 31

4755

70

123

0

5

10

15

HAARTpre-preg

HAARTduringpreg

AZTgt4 wk

+sdNVP

AZTgt4wkalone

AZT lt4 wk

+sdNVP

AZT lt4 wkalone

sdNVP No ART

Most Women Formula Feed Their Infants

MTCT at Age 6 Weeks by ARV Regimen Botswana National Data Oct 2006-Nov 2007

Tlale J et al IAS Mexico City Aug 2008 (Abs ThAC04)

07 2333 31

4755

70

123

0

5

10

15

HAARTpre-preg

HAARTduringpreg

AZTgt4 wk

+sdNVP

AZTgt4wkalone

AZT lt4 wk

+sdNVP

AZT lt4 wkalone

sdNVP No ART

HAART most effective if started prior to pregnancy in women with low CD4

MTCT at Age 6 Weeks by ARV Regimen Botswana National Data Oct 2006-Nov 2007

Tlale J et al IAS Mexico City Aug 2008 (Abs ThAC04)

07 2333 31

4755

70

123

0

5

10

15

HAARTpre-preg

HAARTduringpreg

AZTgt4 wk

+sdNVP

AZTgt4wkalone

AZT lt4 wk

+sdNVP

AZT lt4 wkalone

sdNVP No ART

Starting HAART during pregnancy if CD4 lt200and AZT+sdNVP if CD4 gt200 results insimilar MTCT rates (CI likely overlap)

MTCT at Age 6 Weeks by ARV Regimen Botswana National Data Oct 2006-Nov 2007

Tlale J et al IAS Mexico City Aug 2008 (Abs ThAC04)

07 2333 31

4755

70

123

0

5

10

15

HAARTpre-preg

HAARTduringpreg

AZTgt4 wk

+sdNVP

AZTgt4wkalone

AZT lt4 wk

+sdNVP

AZT lt4 wkalone

sdNVP No ART

Longer AP duration is more effectivethan shorter (lt4 wks) AP drug

MTCT at Age 6 Weeks by ARV Regimen Botswana National Data Oct 2006-Nov 2007

Tlale J et al IAS Mexico City Aug 2008 (Abs ThAC04)

07 2333 31

4755

70

123

0

5

10

15

HAARTpre-preg

HAARTduringpreg

AZTgt4 wk

+sdNVP

AZTgt4wkalone

AZT lt4 wk

+sdNVP

AZT lt4 wkalone

sdNVP No ART

sdNVP reduces MTCT by43 implemented in a

National Program

Mother to Child Transmission 2000-2006 5930 Births to HIV+ Women UKIreland

Townsend CL et al AIDS 200822973-981Prophylaxis MTCT Adjusted Odds Ratio

(for mode delivery sex viral load)

Overall 12

ART gt14 days 08HAART with NNRTI 09

131 (06-28) p=048HAART with PI 11

HAART at conception 01018 (02-13) p=009

HAART during pregnancy 13HAART Elective CS 07

p=015HAART Planned vaginal 07AZT Elective CS (N=464) 0

In Breastfeeding Settings ~40 of All Mother to Child Transmission Can be Attributed to Breastfeeding

10-15 of Infants with Prolonged Breastfeeding Become Infected

Early Antenatal(lt28 wks)

Late Antenatal(28 wks to labor)

Labor and Delivery

Late Postpartum

1-6 mos 6-24 mos0-1 mo

Pregnancy

Early

Breastfeeding ~40

Substantial Proportion of Infections Occur During BF

Prevention of Breast Milk HIV TransmissionHypothesized that ldquosaferrdquo breastfeeding through giving antiretroviral prophylaxis during period when breast milk is most beneficial with early weaning might reduce postnatal transmission

Ongoing studies are evaluating the safety and efficacy of

Infant antiretroviral prophylaxis + early weaning

Maternal HAART during lactation + early weaning

However increasing data indicate early cessation of breastfeeding at 6 months is not safe in some poor countries

Potential Problems with Universal HAART Solely for PMTCT in Developing Countries

ComplexityComplexity ndash implementation issues postnatal adherence issues (= resistance risk)

Limited resources and costLimited resources and cost ndash canrsquot provide ART even to patients who need for own health

Limited regimen choiceLimited regimen choice limited by toxicity with NVP with CD4 gt250 cellsuL EFV teratogenicity PI expense

Pregnancy outcomelongPregnancy outcomelong--term infant outcometerm infant outcome

Maternal healthMaternal health (issues of start-stop HAART)

Differential penetration of ARV drugs into milkDifferential penetration of ARV drugs into milkcould result in resistant virus in milk

If Choose to Use HAARTIn Women with CD4 gt350 for PMTCT

Drug choice problematic

- NVP toxicity

- EFV okay 3rd trimester but PPrepeat pregnancy risk if prolonged

-PI cost

NVP Liver Toxicity More Common in Pregnant than Non-Pregnant Thai Women and Women Receiving

ART for PMTCT than for Treatment Phanuaphak N et al HIV Med 20078357-66

Rate per 100 patient-yearsNon- Preg Preg

P value

ART for RX

ART for PMTCT

P Value

(N=87) (N=244) (N=102) (N=142)Median CD4 152 277 136 414

Sx hepatitis 15 75 002 25 160 00003

Rash+liver 08 43 005 08 102 00003

Gr 12 liver 08 48 004 08 58 002

Gr 34 Rash 55 58 042 - -

First Trimester Efavirenz Use and Central Nervous System Defects

Antiretroviral Pregnancy Registry prospective data do not indicate an increase in overall birth defects (10364 overall 27 95 CI 13-50)However with in utero exposure in primates at doses resulting in drug levels similar to human exposure 320 infant monkeys had severe central nervous system (CNS) defects (eg anencephaly anophthalmia cleft palate)5 retrospective and 1 prospective human cases of CNS defects (eg meningomyelocele) with first trimester efavirenz exposureFDA Class D (+ animal amp potential human risk)

MTCT at Age 6 Weeks by ARV Regimen Botswana National Data Oct 2006-Nov 2007

Tlale J et al IAS Mexico City Aug 2008 (Abs ThAC04)

07 2333 31

4755

70

123

0

5

10

15

HAARTpre-preg

HAARTduringpreg

AZTgt4 wk

+sdNVP

AZTgt4wkalone

AZT lt4 wk

+sdNVP

AZT lt4 wkalone

sdNVP No ART

Most Women Formula Feed Their Infants

MTCT at Age 6 Weeks by ARV Regimen Botswana National Data Oct 2006-Nov 2007

Tlale J et al IAS Mexico City Aug 2008 (Abs ThAC04)

07 2333 31

4755

70

123

0

5

10

15

HAARTpre-preg

HAARTduringpreg

AZTgt4 wk

+sdNVP

AZTgt4wkalone

AZT lt4 wk

+sdNVP

AZT lt4 wkalone

sdNVP No ART

HAART most effective if started prior to pregnancy in women with low CD4

MTCT at Age 6 Weeks by ARV Regimen Botswana National Data Oct 2006-Nov 2007

Tlale J et al IAS Mexico City Aug 2008 (Abs ThAC04)

07 2333 31

4755

70

123

0

5

10

15

HAARTpre-preg

HAARTduringpreg

AZTgt4 wk

+sdNVP

AZTgt4wkalone

AZT lt4 wk

+sdNVP

AZT lt4 wkalone

sdNVP No ART

Starting HAART during pregnancy if CD4 lt200and AZT+sdNVP if CD4 gt200 results insimilar MTCT rates (CI likely overlap)

MTCT at Age 6 Weeks by ARV Regimen Botswana National Data Oct 2006-Nov 2007

Tlale J et al IAS Mexico City Aug 2008 (Abs ThAC04)

07 2333 31

4755

70

123

0

5

10

15

HAARTpre-preg

HAARTduringpreg

AZTgt4 wk

+sdNVP

AZTgt4wkalone

AZT lt4 wk

+sdNVP

AZT lt4 wkalone

sdNVP No ART

Longer AP duration is more effectivethan shorter (lt4 wks) AP drug

MTCT at Age 6 Weeks by ARV Regimen Botswana National Data Oct 2006-Nov 2007

Tlale J et al IAS Mexico City Aug 2008 (Abs ThAC04)

07 2333 31

4755

70

123

0

5

10

15

HAARTpre-preg

HAARTduringpreg

AZTgt4 wk

+sdNVP

AZTgt4wkalone

AZT lt4 wk

+sdNVP

AZT lt4 wkalone

sdNVP No ART

sdNVP reduces MTCT by43 implemented in a

National Program

Mother to Child Transmission 2000-2006 5930 Births to HIV+ Women UKIreland

Townsend CL et al AIDS 200822973-981Prophylaxis MTCT Adjusted Odds Ratio

(for mode delivery sex viral load)

Overall 12

ART gt14 days 08HAART with NNRTI 09

131 (06-28) p=048HAART with PI 11

HAART at conception 01018 (02-13) p=009

HAART during pregnancy 13HAART Elective CS 07

p=015HAART Planned vaginal 07AZT Elective CS (N=464) 0

In Breastfeeding Settings ~40 of All Mother to Child Transmission Can be Attributed to Breastfeeding

10-15 of Infants with Prolonged Breastfeeding Become Infected

Early Antenatal(lt28 wks)

Late Antenatal(28 wks to labor)

Labor and Delivery

Late Postpartum

1-6 mos 6-24 mos0-1 mo

Pregnancy

Early

Breastfeeding ~40

Substantial Proportion of Infections Occur During BF

Prevention of Breast Milk HIV TransmissionHypothesized that ldquosaferrdquo breastfeeding through giving antiretroviral prophylaxis during period when breast milk is most beneficial with early weaning might reduce postnatal transmission

Ongoing studies are evaluating the safety and efficacy of

Infant antiretroviral prophylaxis + early weaning

Maternal HAART during lactation + early weaning

However increasing data indicate early cessation of breastfeeding at 6 months is not safe in some poor countries

Potential Problems with Universal HAART Solely for PMTCT in Developing Countries

ComplexityComplexity ndash implementation issues postnatal adherence issues (= resistance risk)

Limited resources and costLimited resources and cost ndash canrsquot provide ART even to patients who need for own health

Limited regimen choiceLimited regimen choice limited by toxicity with NVP with CD4 gt250 cellsuL EFV teratogenicity PI expense

Pregnancy outcomelongPregnancy outcomelong--term infant outcometerm infant outcome

Maternal healthMaternal health (issues of start-stop HAART)

Differential penetration of ARV drugs into milkDifferential penetration of ARV drugs into milkcould result in resistant virus in milk

If Choose to Use HAARTIn Women with CD4 gt350 for PMTCT

Drug choice problematic

- NVP toxicity

- EFV okay 3rd trimester but PPrepeat pregnancy risk if prolonged

-PI cost

NVP Liver Toxicity More Common in Pregnant than Non-Pregnant Thai Women and Women Receiving

ART for PMTCT than for Treatment Phanuaphak N et al HIV Med 20078357-66

Rate per 100 patient-yearsNon- Preg Preg

P value

ART for RX

ART for PMTCT

P Value

(N=87) (N=244) (N=102) (N=142)Median CD4 152 277 136 414

Sx hepatitis 15 75 002 25 160 00003

Rash+liver 08 43 005 08 102 00003

Gr 12 liver 08 48 004 08 58 002

Gr 34 Rash 55 58 042 - -

First Trimester Efavirenz Use and Central Nervous System Defects

Antiretroviral Pregnancy Registry prospective data do not indicate an increase in overall birth defects (10364 overall 27 95 CI 13-50)However with in utero exposure in primates at doses resulting in drug levels similar to human exposure 320 infant monkeys had severe central nervous system (CNS) defects (eg anencephaly anophthalmia cleft palate)5 retrospective and 1 prospective human cases of CNS defects (eg meningomyelocele) with first trimester efavirenz exposureFDA Class D (+ animal amp potential human risk)

MTCT at Age 6 Weeks by ARV Regimen Botswana National Data Oct 2006-Nov 2007

Tlale J et al IAS Mexico City Aug 2008 (Abs ThAC04)

07 2333 31

4755

70

123

0

5

10

15

HAARTpre-preg

HAARTduringpreg

AZTgt4 wk

+sdNVP

AZTgt4wkalone

AZT lt4 wk

+sdNVP

AZT lt4 wkalone

sdNVP No ART

HAART most effective if started prior to pregnancy in women with low CD4

MTCT at Age 6 Weeks by ARV Regimen Botswana National Data Oct 2006-Nov 2007

Tlale J et al IAS Mexico City Aug 2008 (Abs ThAC04)

07 2333 31

4755

70

123

0

5

10

15

HAARTpre-preg

HAARTduringpreg

AZTgt4 wk

+sdNVP

AZTgt4wkalone

AZT lt4 wk

+sdNVP

AZT lt4 wkalone

sdNVP No ART

Starting HAART during pregnancy if CD4 lt200and AZT+sdNVP if CD4 gt200 results insimilar MTCT rates (CI likely overlap)

MTCT at Age 6 Weeks by ARV Regimen Botswana National Data Oct 2006-Nov 2007

Tlale J et al IAS Mexico City Aug 2008 (Abs ThAC04)

07 2333 31

4755

70

123

0

5

10

15

HAARTpre-preg

HAARTduringpreg

AZTgt4 wk

+sdNVP

AZTgt4wkalone

AZT lt4 wk

+sdNVP

AZT lt4 wkalone

sdNVP No ART

Longer AP duration is more effectivethan shorter (lt4 wks) AP drug

MTCT at Age 6 Weeks by ARV Regimen Botswana National Data Oct 2006-Nov 2007

Tlale J et al IAS Mexico City Aug 2008 (Abs ThAC04)

07 2333 31

4755

70

123

0

5

10

15

HAARTpre-preg

HAARTduringpreg

AZTgt4 wk

+sdNVP

AZTgt4wkalone

AZT lt4 wk

+sdNVP

AZT lt4 wkalone

sdNVP No ART

sdNVP reduces MTCT by43 implemented in a

National Program

Mother to Child Transmission 2000-2006 5930 Births to HIV+ Women UKIreland

Townsend CL et al AIDS 200822973-981Prophylaxis MTCT Adjusted Odds Ratio

(for mode delivery sex viral load)

Overall 12

ART gt14 days 08HAART with NNRTI 09

131 (06-28) p=048HAART with PI 11

HAART at conception 01018 (02-13) p=009

HAART during pregnancy 13HAART Elective CS 07

p=015HAART Planned vaginal 07AZT Elective CS (N=464) 0

In Breastfeeding Settings ~40 of All Mother to Child Transmission Can be Attributed to Breastfeeding

10-15 of Infants with Prolonged Breastfeeding Become Infected

Early Antenatal(lt28 wks)

Late Antenatal(28 wks to labor)

Labor and Delivery

Late Postpartum

1-6 mos 6-24 mos0-1 mo

Pregnancy

Early

Breastfeeding ~40

Substantial Proportion of Infections Occur During BF

Prevention of Breast Milk HIV TransmissionHypothesized that ldquosaferrdquo breastfeeding through giving antiretroviral prophylaxis during period when breast milk is most beneficial with early weaning might reduce postnatal transmission

Ongoing studies are evaluating the safety and efficacy of

Infant antiretroviral prophylaxis + early weaning

Maternal HAART during lactation + early weaning

However increasing data indicate early cessation of breastfeeding at 6 months is not safe in some poor countries

Potential Problems with Universal HAART Solely for PMTCT in Developing Countries

ComplexityComplexity ndash implementation issues postnatal adherence issues (= resistance risk)

Limited resources and costLimited resources and cost ndash canrsquot provide ART even to patients who need for own health

Limited regimen choiceLimited regimen choice limited by toxicity with NVP with CD4 gt250 cellsuL EFV teratogenicity PI expense

Pregnancy outcomelongPregnancy outcomelong--term infant outcometerm infant outcome

Maternal healthMaternal health (issues of start-stop HAART)

Differential penetration of ARV drugs into milkDifferential penetration of ARV drugs into milkcould result in resistant virus in milk

If Choose to Use HAARTIn Women with CD4 gt350 for PMTCT

Drug choice problematic

- NVP toxicity

- EFV okay 3rd trimester but PPrepeat pregnancy risk if prolonged

-PI cost

NVP Liver Toxicity More Common in Pregnant than Non-Pregnant Thai Women and Women Receiving

ART for PMTCT than for Treatment Phanuaphak N et al HIV Med 20078357-66

Rate per 100 patient-yearsNon- Preg Preg

P value

ART for RX

ART for PMTCT

P Value

(N=87) (N=244) (N=102) (N=142)Median CD4 152 277 136 414

Sx hepatitis 15 75 002 25 160 00003

Rash+liver 08 43 005 08 102 00003

Gr 12 liver 08 48 004 08 58 002

Gr 34 Rash 55 58 042 - -

First Trimester Efavirenz Use and Central Nervous System Defects

Antiretroviral Pregnancy Registry prospective data do not indicate an increase in overall birth defects (10364 overall 27 95 CI 13-50)However with in utero exposure in primates at doses resulting in drug levels similar to human exposure 320 infant monkeys had severe central nervous system (CNS) defects (eg anencephaly anophthalmia cleft palate)5 retrospective and 1 prospective human cases of CNS defects (eg meningomyelocele) with first trimester efavirenz exposureFDA Class D (+ animal amp potential human risk)

MTCT at Age 6 Weeks by ARV Regimen Botswana National Data Oct 2006-Nov 2007

Tlale J et al IAS Mexico City Aug 2008 (Abs ThAC04)

07 2333 31

4755

70

123

0

5

10

15

HAARTpre-preg

HAARTduringpreg

AZTgt4 wk

+sdNVP

AZTgt4wkalone

AZT lt4 wk

+sdNVP

AZT lt4 wkalone

sdNVP No ART

Starting HAART during pregnancy if CD4 lt200and AZT+sdNVP if CD4 gt200 results insimilar MTCT rates (CI likely overlap)

MTCT at Age 6 Weeks by ARV Regimen Botswana National Data Oct 2006-Nov 2007

Tlale J et al IAS Mexico City Aug 2008 (Abs ThAC04)

07 2333 31

4755

70

123

0

5

10

15

HAARTpre-preg

HAARTduringpreg

AZTgt4 wk

+sdNVP

AZTgt4wkalone

AZT lt4 wk

+sdNVP

AZT lt4 wkalone

sdNVP No ART

Longer AP duration is more effectivethan shorter (lt4 wks) AP drug

MTCT at Age 6 Weeks by ARV Regimen Botswana National Data Oct 2006-Nov 2007

Tlale J et al IAS Mexico City Aug 2008 (Abs ThAC04)

07 2333 31

4755

70

123

0

5

10

15

HAARTpre-preg

HAARTduringpreg

AZTgt4 wk

+sdNVP

AZTgt4wkalone

AZT lt4 wk

+sdNVP

AZT lt4 wkalone

sdNVP No ART

sdNVP reduces MTCT by43 implemented in a

National Program

Mother to Child Transmission 2000-2006 5930 Births to HIV+ Women UKIreland

Townsend CL et al AIDS 200822973-981Prophylaxis MTCT Adjusted Odds Ratio

(for mode delivery sex viral load)

Overall 12

ART gt14 days 08HAART with NNRTI 09

131 (06-28) p=048HAART with PI 11

HAART at conception 01018 (02-13) p=009

HAART during pregnancy 13HAART Elective CS 07

p=015HAART Planned vaginal 07AZT Elective CS (N=464) 0

In Breastfeeding Settings ~40 of All Mother to Child Transmission Can be Attributed to Breastfeeding

10-15 of Infants with Prolonged Breastfeeding Become Infected

Early Antenatal(lt28 wks)

Late Antenatal(28 wks to labor)

Labor and Delivery

Late Postpartum

1-6 mos 6-24 mos0-1 mo

Pregnancy

Early

Breastfeeding ~40

Substantial Proportion of Infections Occur During BF

Prevention of Breast Milk HIV TransmissionHypothesized that ldquosaferrdquo breastfeeding through giving antiretroviral prophylaxis during period when breast milk is most beneficial with early weaning might reduce postnatal transmission

Ongoing studies are evaluating the safety and efficacy of

Infant antiretroviral prophylaxis + early weaning

Maternal HAART during lactation + early weaning

However increasing data indicate early cessation of breastfeeding at 6 months is not safe in some poor countries

Potential Problems with Universal HAART Solely for PMTCT in Developing Countries

ComplexityComplexity ndash implementation issues postnatal adherence issues (= resistance risk)

Limited resources and costLimited resources and cost ndash canrsquot provide ART even to patients who need for own health

Limited regimen choiceLimited regimen choice limited by toxicity with NVP with CD4 gt250 cellsuL EFV teratogenicity PI expense

Pregnancy outcomelongPregnancy outcomelong--term infant outcometerm infant outcome

Maternal healthMaternal health (issues of start-stop HAART)

Differential penetration of ARV drugs into milkDifferential penetration of ARV drugs into milkcould result in resistant virus in milk

If Choose to Use HAARTIn Women with CD4 gt350 for PMTCT

Drug choice problematic

- NVP toxicity

- EFV okay 3rd trimester but PPrepeat pregnancy risk if prolonged

-PI cost

NVP Liver Toxicity More Common in Pregnant than Non-Pregnant Thai Women and Women Receiving

ART for PMTCT than for Treatment Phanuaphak N et al HIV Med 20078357-66

Rate per 100 patient-yearsNon- Preg Preg

P value

ART for RX

ART for PMTCT

P Value

(N=87) (N=244) (N=102) (N=142)Median CD4 152 277 136 414

Sx hepatitis 15 75 002 25 160 00003

Rash+liver 08 43 005 08 102 00003

Gr 12 liver 08 48 004 08 58 002

Gr 34 Rash 55 58 042 - -

First Trimester Efavirenz Use and Central Nervous System Defects

Antiretroviral Pregnancy Registry prospective data do not indicate an increase in overall birth defects (10364 overall 27 95 CI 13-50)However with in utero exposure in primates at doses resulting in drug levels similar to human exposure 320 infant monkeys had severe central nervous system (CNS) defects (eg anencephaly anophthalmia cleft palate)5 retrospective and 1 prospective human cases of CNS defects (eg meningomyelocele) with first trimester efavirenz exposureFDA Class D (+ animal amp potential human risk)

MTCT at Age 6 Weeks by ARV Regimen Botswana National Data Oct 2006-Nov 2007

Tlale J et al IAS Mexico City Aug 2008 (Abs ThAC04)

07 2333 31

4755

70

123

0

5

10

15

HAARTpre-preg

HAARTduringpreg

AZTgt4 wk

+sdNVP

AZTgt4wkalone

AZT lt4 wk

+sdNVP

AZT lt4 wkalone

sdNVP No ART

Longer AP duration is more effectivethan shorter (lt4 wks) AP drug

MTCT at Age 6 Weeks by ARV Regimen Botswana National Data Oct 2006-Nov 2007

Tlale J et al IAS Mexico City Aug 2008 (Abs ThAC04)

07 2333 31

4755

70

123

0

5

10

15

HAARTpre-preg

HAARTduringpreg

AZTgt4 wk

+sdNVP

AZTgt4wkalone

AZT lt4 wk

+sdNVP

AZT lt4 wkalone

sdNVP No ART

sdNVP reduces MTCT by43 implemented in a

National Program

Mother to Child Transmission 2000-2006 5930 Births to HIV+ Women UKIreland

Townsend CL et al AIDS 200822973-981Prophylaxis MTCT Adjusted Odds Ratio

(for mode delivery sex viral load)

Overall 12

ART gt14 days 08HAART with NNRTI 09

131 (06-28) p=048HAART with PI 11

HAART at conception 01018 (02-13) p=009

HAART during pregnancy 13HAART Elective CS 07

p=015HAART Planned vaginal 07AZT Elective CS (N=464) 0

In Breastfeeding Settings ~40 of All Mother to Child Transmission Can be Attributed to Breastfeeding

10-15 of Infants with Prolonged Breastfeeding Become Infected

Early Antenatal(lt28 wks)

Late Antenatal(28 wks to labor)

Labor and Delivery

Late Postpartum

1-6 mos 6-24 mos0-1 mo

Pregnancy

Early

Breastfeeding ~40

Substantial Proportion of Infections Occur During BF

Prevention of Breast Milk HIV TransmissionHypothesized that ldquosaferrdquo breastfeeding through giving antiretroviral prophylaxis during period when breast milk is most beneficial with early weaning might reduce postnatal transmission

Ongoing studies are evaluating the safety and efficacy of

Infant antiretroviral prophylaxis + early weaning

Maternal HAART during lactation + early weaning

However increasing data indicate early cessation of breastfeeding at 6 months is not safe in some poor countries

Potential Problems with Universal HAART Solely for PMTCT in Developing Countries

ComplexityComplexity ndash implementation issues postnatal adherence issues (= resistance risk)

Limited resources and costLimited resources and cost ndash canrsquot provide ART even to patients who need for own health

Limited regimen choiceLimited regimen choice limited by toxicity with NVP with CD4 gt250 cellsuL EFV teratogenicity PI expense

Pregnancy outcomelongPregnancy outcomelong--term infant outcometerm infant outcome

Maternal healthMaternal health (issues of start-stop HAART)

Differential penetration of ARV drugs into milkDifferential penetration of ARV drugs into milkcould result in resistant virus in milk

If Choose to Use HAARTIn Women with CD4 gt350 for PMTCT

Drug choice problematic

- NVP toxicity

- EFV okay 3rd trimester but PPrepeat pregnancy risk if prolonged

-PI cost

NVP Liver Toxicity More Common in Pregnant than Non-Pregnant Thai Women and Women Receiving

ART for PMTCT than for Treatment Phanuaphak N et al HIV Med 20078357-66

Rate per 100 patient-yearsNon- Preg Preg

P value

ART for RX

ART for PMTCT

P Value

(N=87) (N=244) (N=102) (N=142)Median CD4 152 277 136 414

Sx hepatitis 15 75 002 25 160 00003

Rash+liver 08 43 005 08 102 00003

Gr 12 liver 08 48 004 08 58 002

Gr 34 Rash 55 58 042 - -

First Trimester Efavirenz Use and Central Nervous System Defects

Antiretroviral Pregnancy Registry prospective data do not indicate an increase in overall birth defects (10364 overall 27 95 CI 13-50)However with in utero exposure in primates at doses resulting in drug levels similar to human exposure 320 infant monkeys had severe central nervous system (CNS) defects (eg anencephaly anophthalmia cleft palate)5 retrospective and 1 prospective human cases of CNS defects (eg meningomyelocele) with first trimester efavirenz exposureFDA Class D (+ animal amp potential human risk)

MTCT at Age 6 Weeks by ARV Regimen Botswana National Data Oct 2006-Nov 2007

Tlale J et al IAS Mexico City Aug 2008 (Abs ThAC04)

07 2333 31

4755

70

123

0

5

10

15

HAARTpre-preg

HAARTduringpreg

AZTgt4 wk

+sdNVP

AZTgt4wkalone

AZT lt4 wk

+sdNVP

AZT lt4 wkalone

sdNVP No ART

sdNVP reduces MTCT by43 implemented in a

National Program

Mother to Child Transmission 2000-2006 5930 Births to HIV+ Women UKIreland

Townsend CL et al AIDS 200822973-981Prophylaxis MTCT Adjusted Odds Ratio

(for mode delivery sex viral load)

Overall 12

ART gt14 days 08HAART with NNRTI 09

131 (06-28) p=048HAART with PI 11

HAART at conception 01018 (02-13) p=009

HAART during pregnancy 13HAART Elective CS 07

p=015HAART Planned vaginal 07AZT Elective CS (N=464) 0

In Breastfeeding Settings ~40 of All Mother to Child Transmission Can be Attributed to Breastfeeding

10-15 of Infants with Prolonged Breastfeeding Become Infected

Early Antenatal(lt28 wks)

Late Antenatal(28 wks to labor)

Labor and Delivery

Late Postpartum

1-6 mos 6-24 mos0-1 mo

Pregnancy

Early

Breastfeeding ~40

Substantial Proportion of Infections Occur During BF

Prevention of Breast Milk HIV TransmissionHypothesized that ldquosaferrdquo breastfeeding through giving antiretroviral prophylaxis during period when breast milk is most beneficial with early weaning might reduce postnatal transmission

Ongoing studies are evaluating the safety and efficacy of

Infant antiretroviral prophylaxis + early weaning

Maternal HAART during lactation + early weaning

However increasing data indicate early cessation of breastfeeding at 6 months is not safe in some poor countries

Potential Problems with Universal HAART Solely for PMTCT in Developing Countries

ComplexityComplexity ndash implementation issues postnatal adherence issues (= resistance risk)

Limited resources and costLimited resources and cost ndash canrsquot provide ART even to patients who need for own health

Limited regimen choiceLimited regimen choice limited by toxicity with NVP with CD4 gt250 cellsuL EFV teratogenicity PI expense

Pregnancy outcomelongPregnancy outcomelong--term infant outcometerm infant outcome

Maternal healthMaternal health (issues of start-stop HAART)

Differential penetration of ARV drugs into milkDifferential penetration of ARV drugs into milkcould result in resistant virus in milk

If Choose to Use HAARTIn Women with CD4 gt350 for PMTCT

Drug choice problematic

- NVP toxicity

- EFV okay 3rd trimester but PPrepeat pregnancy risk if prolonged

-PI cost

NVP Liver Toxicity More Common in Pregnant than Non-Pregnant Thai Women and Women Receiving

ART for PMTCT than for Treatment Phanuaphak N et al HIV Med 20078357-66

Rate per 100 patient-yearsNon- Preg Preg

P value

ART for RX

ART for PMTCT

P Value

(N=87) (N=244) (N=102) (N=142)Median CD4 152 277 136 414

Sx hepatitis 15 75 002 25 160 00003

Rash+liver 08 43 005 08 102 00003

Gr 12 liver 08 48 004 08 58 002

Gr 34 Rash 55 58 042 - -

First Trimester Efavirenz Use and Central Nervous System Defects

Antiretroviral Pregnancy Registry prospective data do not indicate an increase in overall birth defects (10364 overall 27 95 CI 13-50)However with in utero exposure in primates at doses resulting in drug levels similar to human exposure 320 infant monkeys had severe central nervous system (CNS) defects (eg anencephaly anophthalmia cleft palate)5 retrospective and 1 prospective human cases of CNS defects (eg meningomyelocele) with first trimester efavirenz exposureFDA Class D (+ animal amp potential human risk)

Mother to Child Transmission 2000-2006 5930 Births to HIV+ Women UKIreland

Townsend CL et al AIDS 200822973-981Prophylaxis MTCT Adjusted Odds Ratio

(for mode delivery sex viral load)

Overall 12

ART gt14 days 08HAART with NNRTI 09

131 (06-28) p=048HAART with PI 11

HAART at conception 01018 (02-13) p=009

HAART during pregnancy 13HAART Elective CS 07

p=015HAART Planned vaginal 07AZT Elective CS (N=464) 0

In Breastfeeding Settings ~40 of All Mother to Child Transmission Can be Attributed to Breastfeeding

10-15 of Infants with Prolonged Breastfeeding Become Infected

Early Antenatal(lt28 wks)

Late Antenatal(28 wks to labor)

Labor and Delivery

Late Postpartum

1-6 mos 6-24 mos0-1 mo

Pregnancy

Early

Breastfeeding ~40

Substantial Proportion of Infections Occur During BF

Prevention of Breast Milk HIV TransmissionHypothesized that ldquosaferrdquo breastfeeding through giving antiretroviral prophylaxis during period when breast milk is most beneficial with early weaning might reduce postnatal transmission

Ongoing studies are evaluating the safety and efficacy of

Infant antiretroviral prophylaxis + early weaning

Maternal HAART during lactation + early weaning

However increasing data indicate early cessation of breastfeeding at 6 months is not safe in some poor countries

Potential Problems with Universal HAART Solely for PMTCT in Developing Countries

ComplexityComplexity ndash implementation issues postnatal adherence issues (= resistance risk)

Limited resources and costLimited resources and cost ndash canrsquot provide ART even to patients who need for own health

Limited regimen choiceLimited regimen choice limited by toxicity with NVP with CD4 gt250 cellsuL EFV teratogenicity PI expense

Pregnancy outcomelongPregnancy outcomelong--term infant outcometerm infant outcome

Maternal healthMaternal health (issues of start-stop HAART)

Differential penetration of ARV drugs into milkDifferential penetration of ARV drugs into milkcould result in resistant virus in milk

If Choose to Use HAARTIn Women with CD4 gt350 for PMTCT

Drug choice problematic

- NVP toxicity

- EFV okay 3rd trimester but PPrepeat pregnancy risk if prolonged

-PI cost

NVP Liver Toxicity More Common in Pregnant than Non-Pregnant Thai Women and Women Receiving

ART for PMTCT than for Treatment Phanuaphak N et al HIV Med 20078357-66

Rate per 100 patient-yearsNon- Preg Preg

P value

ART for RX

ART for PMTCT

P Value

(N=87) (N=244) (N=102) (N=142)Median CD4 152 277 136 414

Sx hepatitis 15 75 002 25 160 00003

Rash+liver 08 43 005 08 102 00003

Gr 12 liver 08 48 004 08 58 002

Gr 34 Rash 55 58 042 - -

First Trimester Efavirenz Use and Central Nervous System Defects

Antiretroviral Pregnancy Registry prospective data do not indicate an increase in overall birth defects (10364 overall 27 95 CI 13-50)However with in utero exposure in primates at doses resulting in drug levels similar to human exposure 320 infant monkeys had severe central nervous system (CNS) defects (eg anencephaly anophthalmia cleft palate)5 retrospective and 1 prospective human cases of CNS defects (eg meningomyelocele) with first trimester efavirenz exposureFDA Class D (+ animal amp potential human risk)

In Breastfeeding Settings ~40 of All Mother to Child Transmission Can be Attributed to Breastfeeding

10-15 of Infants with Prolonged Breastfeeding Become Infected

Early Antenatal(lt28 wks)

Late Antenatal(28 wks to labor)

Labor and Delivery

Late Postpartum

1-6 mos 6-24 mos0-1 mo

Pregnancy

Early

Breastfeeding ~40

Substantial Proportion of Infections Occur During BF

Prevention of Breast Milk HIV TransmissionHypothesized that ldquosaferrdquo breastfeeding through giving antiretroviral prophylaxis during period when breast milk is most beneficial with early weaning might reduce postnatal transmission

Ongoing studies are evaluating the safety and efficacy of

Infant antiretroviral prophylaxis + early weaning

Maternal HAART during lactation + early weaning

However increasing data indicate early cessation of breastfeeding at 6 months is not safe in some poor countries

Potential Problems with Universal HAART Solely for PMTCT in Developing Countries

ComplexityComplexity ndash implementation issues postnatal adherence issues (= resistance risk)

Limited resources and costLimited resources and cost ndash canrsquot provide ART even to patients who need for own health

Limited regimen choiceLimited regimen choice limited by toxicity with NVP with CD4 gt250 cellsuL EFV teratogenicity PI expense

Pregnancy outcomelongPregnancy outcomelong--term infant outcometerm infant outcome

Maternal healthMaternal health (issues of start-stop HAART)

Differential penetration of ARV drugs into milkDifferential penetration of ARV drugs into milkcould result in resistant virus in milk

If Choose to Use HAARTIn Women with CD4 gt350 for PMTCT

Drug choice problematic

- NVP toxicity

- EFV okay 3rd trimester but PPrepeat pregnancy risk if prolonged

-PI cost

NVP Liver Toxicity More Common in Pregnant than Non-Pregnant Thai Women and Women Receiving

ART for PMTCT than for Treatment Phanuaphak N et al HIV Med 20078357-66

Rate per 100 patient-yearsNon- Preg Preg

P value

ART for RX

ART for PMTCT

P Value

(N=87) (N=244) (N=102) (N=142)Median CD4 152 277 136 414

Sx hepatitis 15 75 002 25 160 00003

Rash+liver 08 43 005 08 102 00003

Gr 12 liver 08 48 004 08 58 002

Gr 34 Rash 55 58 042 - -

First Trimester Efavirenz Use and Central Nervous System Defects

Antiretroviral Pregnancy Registry prospective data do not indicate an increase in overall birth defects (10364 overall 27 95 CI 13-50)However with in utero exposure in primates at doses resulting in drug levels similar to human exposure 320 infant monkeys had severe central nervous system (CNS) defects (eg anencephaly anophthalmia cleft palate)5 retrospective and 1 prospective human cases of CNS defects (eg meningomyelocele) with first trimester efavirenz exposureFDA Class D (+ animal amp potential human risk)

Prevention of Breast Milk HIV TransmissionHypothesized that ldquosaferrdquo breastfeeding through giving antiretroviral prophylaxis during period when breast milk is most beneficial with early weaning might reduce postnatal transmission

Ongoing studies are evaluating the safety and efficacy of

Infant antiretroviral prophylaxis + early weaning

Maternal HAART during lactation + early weaning

However increasing data indicate early cessation of breastfeeding at 6 months is not safe in some poor countries

Potential Problems with Universal HAART Solely for PMTCT in Developing Countries

ComplexityComplexity ndash implementation issues postnatal adherence issues (= resistance risk)

Limited resources and costLimited resources and cost ndash canrsquot provide ART even to patients who need for own health

Limited regimen choiceLimited regimen choice limited by toxicity with NVP with CD4 gt250 cellsuL EFV teratogenicity PI expense

Pregnancy outcomelongPregnancy outcomelong--term infant outcometerm infant outcome

Maternal healthMaternal health (issues of start-stop HAART)

Differential penetration of ARV drugs into milkDifferential penetration of ARV drugs into milkcould result in resistant virus in milk

If Choose to Use HAARTIn Women with CD4 gt350 for PMTCT

Drug choice problematic

- NVP toxicity

- EFV okay 3rd trimester but PPrepeat pregnancy risk if prolonged

-PI cost

NVP Liver Toxicity More Common in Pregnant than Non-Pregnant Thai Women and Women Receiving

ART for PMTCT than for Treatment Phanuaphak N et al HIV Med 20078357-66

Rate per 100 patient-yearsNon- Preg Preg

P value

ART for RX

ART for PMTCT

P Value

(N=87) (N=244) (N=102) (N=142)Median CD4 152 277 136 414

Sx hepatitis 15 75 002 25 160 00003

Rash+liver 08 43 005 08 102 00003

Gr 12 liver 08 48 004 08 58 002

Gr 34 Rash 55 58 042 - -

First Trimester Efavirenz Use and Central Nervous System Defects

Antiretroviral Pregnancy Registry prospective data do not indicate an increase in overall birth defects (10364 overall 27 95 CI 13-50)However with in utero exposure in primates at doses resulting in drug levels similar to human exposure 320 infant monkeys had severe central nervous system (CNS) defects (eg anencephaly anophthalmia cleft palate)5 retrospective and 1 prospective human cases of CNS defects (eg meningomyelocele) with first trimester efavirenz exposureFDA Class D (+ animal amp potential human risk)

Potential Problems with Universal HAART Solely for PMTCT in Developing Countries

ComplexityComplexity ndash implementation issues postnatal adherence issues (= resistance risk)

Limited resources and costLimited resources and cost ndash canrsquot provide ART even to patients who need for own health

Limited regimen choiceLimited regimen choice limited by toxicity with NVP with CD4 gt250 cellsuL EFV teratogenicity PI expense

Pregnancy outcomelongPregnancy outcomelong--term infant outcometerm infant outcome

Maternal healthMaternal health (issues of start-stop HAART)

Differential penetration of ARV drugs into milkDifferential penetration of ARV drugs into milkcould result in resistant virus in milk

If Choose to Use HAARTIn Women with CD4 gt350 for PMTCT

Drug choice problematic

- NVP toxicity

- EFV okay 3rd trimester but PPrepeat pregnancy risk if prolonged

-PI cost

NVP Liver Toxicity More Common in Pregnant than Non-Pregnant Thai Women and Women Receiving

ART for PMTCT than for Treatment Phanuaphak N et al HIV Med 20078357-66

Rate per 100 patient-yearsNon- Preg Preg

P value

ART for RX

ART for PMTCT

P Value

(N=87) (N=244) (N=102) (N=142)Median CD4 152 277 136 414

Sx hepatitis 15 75 002 25 160 00003

Rash+liver 08 43 005 08 102 00003

Gr 12 liver 08 48 004 08 58 002

Gr 34 Rash 55 58 042 - -

First Trimester Efavirenz Use and Central Nervous System Defects

Antiretroviral Pregnancy Registry prospective data do not indicate an increase in overall birth defects (10364 overall 27 95 CI 13-50)However with in utero exposure in primates at doses resulting in drug levels similar to human exposure 320 infant monkeys had severe central nervous system (CNS) defects (eg anencephaly anophthalmia cleft palate)5 retrospective and 1 prospective human cases of CNS defects (eg meningomyelocele) with first trimester efavirenz exposureFDA Class D (+ animal amp potential human risk)

If Choose to Use HAARTIn Women with CD4 gt350 for PMTCT

Drug choice problematic

- NVP toxicity

- EFV okay 3rd trimester but PPrepeat pregnancy risk if prolonged

-PI cost

NVP Liver Toxicity More Common in Pregnant than Non-Pregnant Thai Women and Women Receiving

ART for PMTCT than for Treatment Phanuaphak N et al HIV Med 20078357-66

Rate per 100 patient-yearsNon- Preg Preg

P value

ART for RX

ART for PMTCT

P Value

(N=87) (N=244) (N=102) (N=142)Median CD4 152 277 136 414

Sx hepatitis 15 75 002 25 160 00003

Rash+liver 08 43 005 08 102 00003

Gr 12 liver 08 48 004 08 58 002

Gr 34 Rash 55 58 042 - -

First Trimester Efavirenz Use and Central Nervous System Defects

Antiretroviral Pregnancy Registry prospective data do not indicate an increase in overall birth defects (10364 overall 27 95 CI 13-50)However with in utero exposure in primates at doses resulting in drug levels similar to human exposure 320 infant monkeys had severe central nervous system (CNS) defects (eg anencephaly anophthalmia cleft palate)5 retrospective and 1 prospective human cases of CNS defects (eg meningomyelocele) with first trimester efavirenz exposureFDA Class D (+ animal amp potential human risk)

NVP Liver Toxicity More Common in Pregnant than Non-Pregnant Thai Women and Women Receiving

ART for PMTCT than for Treatment Phanuaphak N et al HIV Med 20078357-66

Rate per 100 patient-yearsNon- Preg Preg

P value

ART for RX

ART for PMTCT

P Value

(N=87) (N=244) (N=102) (N=142)Median CD4 152 277 136 414

Sx hepatitis 15 75 002 25 160 00003

Rash+liver 08 43 005 08 102 00003

Gr 12 liver 08 48 004 08 58 002

Gr 34 Rash 55 58 042 - -

First Trimester Efavirenz Use and Central Nervous System Defects

Antiretroviral Pregnancy Registry prospective data do not indicate an increase in overall birth defects (10364 overall 27 95 CI 13-50)However with in utero exposure in primates at doses resulting in drug levels similar to human exposure 320 infant monkeys had severe central nervous system (CNS) defects (eg anencephaly anophthalmia cleft palate)5 retrospective and 1 prospective human cases of CNS defects (eg meningomyelocele) with first trimester efavirenz exposureFDA Class D (+ animal amp potential human risk)

First Trimester Efavirenz Use and Central Nervous System Defects

Antiretroviral Pregnancy Registry prospective data do not indicate an increase in overall birth defects (10364 overall 27 95 CI 13-50)However with in utero exposure in primates at doses resulting in drug levels similar to human exposure 320 infant monkeys had severe central nervous system (CNS) defects (eg anencephaly anophthalmia cleft palate)5 retrospective and 1 prospective human cases of CNS defects (eg meningomyelocele) with first trimester efavirenz exposureFDA Class D (+ animal amp potential human risk)

Maternal Antenatal HAART and Pregnancy Outcome

Published data Low Birth Weight

HAART pre-conception

HAART start during Pregnancy

Machado Sex Tx Dis 2008 (Brazil) N=696

333 165

ShortAZT+-3TC+sdNVP HAART

Ekouevi AIDS 2008(Cote drsquoIvoire) N=326

124 223p=002

Mitochondrial Dysfunction in Infants and In Utero ARV Exposure

bull In utero ARV exposure has been reported to be associated with

Mostly aSx transient neonatal lactic acid elevations in 50-95 (some transient neurosx)Mild clinically aSx but persistent hematologic abnormalitiesRarely with clinically Sx of mitochondrial dysfunction ndash primarily neurologic Sx

Combination ARV exposure may be associated with greater risk than single drug exposure

Antiretroviral Drug Penetration into Human Breast MilkMaternal PlasmaBreast Milk Ratio

NRTIAZT 044-1863TC 18-557TDF Low levels (non-bioavailable form - TFV not TDF)NNRTIEFV 054NVP 060-075PIATV 004-011LPVr 011NFV 006-024Shapiro R JID 2005192720 (3TC NVP)Giuliano M JAIDS 200744286 (AZT 3TC NVP)Mirochnick M AAC 2009531170 (AZT 3TC NVP)Colebunders R AIDS 2005191912 (NVP NFV IDV)

Schneider S JAIDS 200848450 (EFV)Mirochnick M CROI 2009 Abs 940 (TDF)Spenser L CROI 2009 Abs 942 (AZT 3TC ATV)Corbett A CROI 2009 Abs 947 (AZT 3TC LPVr)

Behind Every Healthy Child is a Healthy Mother

Maternal Health Are There Long-Term

Consequences in Healthy Women of Receiving

HAART During Pregnancy for Prophylaxis of MTCT

and then Stopping HAART

SubgroupInterrupted ART

pt (rate 100pt-yr)Continuous ART

pt (rate 100pt-yr)HazardRatio

Baseline CD4350-449 24 (32) 18 (22) 15450-549 27 (37) 7 (09) 41550-649 19 (35) 7 (13) 28gt650 50 (32) 15 (20) 32Duration ART0-lt3 yrs 23 (28) 7 (08) 163-5 yrs 30 (27) 8 (11) 155-lt7 yrs 27 (33) 15 (17) 18gt7 yrs 40 (36) 17 (15) 25Hx ART baselineNo 4 (27) 1 (05) 52Yes 22 (44) 9 (17) 26

Hazard Ratio for OIDeath Interrupted vs Continuous ART by Subgroup SMART

Lack of Long-Term Adverse Effects of AZT Prophylaxis in Women in PACTG 076

Bardeguez A et al JAIDS 200332170-81

7 915

18

3 2

1925

0

10

20

30

o

f Wom

en

Category Cdisease

CD4 lt200 Death OVERALLProgression

or death

AZT PL

No significant differences between AZT and Placebo Groups (overall progressiondeath p=028)

WITS Progression after Stopping ARV Prophylaxis Watts DH et al 12th CROI 2005 Los Angeles CA Abs S109

Among ART-naiumlve women entering pregnancy with a CD4 gt 350 and initiating ARV for PMTCT change in CD4 and HIV RNA were similar over the 1st year postpartum among women stopping or continuing therapy PP

No women in either group progressed to AIDS or death during the 1st year postpartum

However a non-significant trend to increased risk CDC Class B events (RR 29 06-134) andsignificant increase in activated CD8 cells (CD38+ DR+) was observed among women stopping compared to continuing ART PP

For Women with CD4 gt350Postnatal PMTCT via Breastfeeding

Infant ARV ProphylaxisVs

Maternal HAART

May Have Comparative Efficacyin Women with Higher CD4 Counts

IF ASSUME TREATMENT FOR ALL WITHPREGNANT WOMEN WITH CD4 lt350

In fan t Ag e

Prob

abili

ty o

f HIV

-1 In

fect

ion

1wk 9wk 6m o 9m o 12m o 15m o 18m o 24m o

000

005

010

015

020

025

030

C ontro lE xtended NV PE xtended NV P +ZD V

Age1

wk6

wks9

wks14

wks6

mos9

mos12

mos15

mos18

mos24

mosEstimates ()

Control 03 51 74 84 101 106 115 124 139 145

Extended NVP 01 17 26 28 40 52 70 78 101 112

Extended NVP+ZDV 02 16 24 28 52 64 81 87 102 123

14 Week Extended ARV Prophylaxis Significantly Reduces Postnatal HIV Infection PEPI Malawi

Kumwenda N et al NEJM 2008359119-29

Maternal Antiretroviral Prophylaxis of Breast Milk HIV Transmission

Observational suggest maternal HAART during lactation may reduce transmission

For women who require therapy for their own health the benefit of HAART for maternal health outweighs potential risks

These women are at highest risk for postnatal transmission and HAART may reduce this risk

NVP toxicity not a concern in women with low CD4

Research needed for women with high CD4

Overall Transmission

MITRA MITRA (Infant ART N=398)

MITRAMITRA--PlusPlus(Maternal ART N=440)

6 Weeks 38(20-56)

41(21-60)

6 Months 49(27-71)

50(32-70)

Increment MTCT6 weeks-6 months 11 09

No significant difference in terms of postnataltransmission between maternal or infant

prophylaxis strategies

MITRA (Infant ARV) vs MITRA-PLUS (Maternal HAART) to Prevent Postnatal MTCT Tanzania

Kilewo et al 4th IAS Sydney Australia 2007 Abs TuAX101

Kisumu Breastfeeding Study (KIBS) Maternal HAART for PMTCT in 500 Breastfeeding Mothers in Kenya Thomas T et al 15th CROI 2008 Boston MA Abs 45aLB

0-7 Days 6 Wks 3 Mos 6 Mos

Overall MTCT 24 39 41 50

Postnatal Tx +15 +17 +26

By CD4 count

CD4 lt250 34 43 52 52

CD4 gt250 21 38 38 49

For Women with CD4 gt350No Significant Difference in Postnatal MTCTKiBS (Maternal HAART) vs PEPI (Infant ARV)

(infants uninfected at birth)

KiBS PEPI

KiBSKiBS

interventionintervention

PEPI interventionPEPI intervention

Thomas T Fowler M and KiBS

study

team unpublished

Taha T Kumwenda N Hoover D and PEPI

study team unpublished

Postpartum Prophylaxis of Breast Milk MTCT

Issue of ARV Drug Resistancein Infants

Problem with Infant NVP Prophylaxis but also with Maternal HAART

NVP Resistance More Frequent in Infants Infected While Receiving Extended NVP but Not in Infants

Infected After Extended NVP was Stopped India SWEN Study Moorthy A et al PLosONE 20094e4096

92

38

15 15

0

20

40

60

80

100 SWEN sdNVP

Infants Diagnosed with HIV AfterAge 6 Weeks (Late BF MTCT)

Infants Diagnosed with HIVWithin the First 6 Weeks of Life

P=0002

P=10

Standard assay

Resistance in BF Infected Infants in KIBS (Maternal HAART Prophylaxis)

Zeh C et al 15th CROI 2008 Boston MA Abs 45aLB

First Positive Viral (PCR) Test

Wk 14 + 24 Specimen

Week PostpartumN

Not amplified

N resist N tested

N resistN tested

Delivery 12 3 09 11122 Wks 2 1 01 126 Wks 6 0 16 1614 Wks 2 0 22 2224 Wks 2 0 12 1236 - 72 Wks 5 1 04 NATotal 29 10 319 (16) 1624 (67)

Resistance not seen on first viral test but rather appears to haveemerged during breastfeeding period

Summary Breastfeeding and HIV Transmissionbull ARV prophylaxis of infant or the mother during

breastfeeding will likely both reduce postnatal MTCT possibly to a similar extent

bull Infants who become infected in both scenarios are likely to have resistant virus

bull Women who require treatment should receive HAART which will likely decrease PP MTCT

bull However the risks and benefits of infant vs maternal prophylaxis need to be compared for women with higher CD4

bull Longer interventions to permit safe prolonged breastfeeding need to be assessed

PROMISEPromoting Maternal Infant

Survival Everywhere

Mitochondrial Dysfunction in Infants and In Utero ARV Exposure

bull In utero ARV exposure has been reported to be associated with

Mostly aSx transient neonatal lactic acid elevations in 50-95 (some transient neurosx)Mild clinically aSx but persistent hematologic abnormalitiesRarely with clinically Sx of mitochondrial dysfunction ndash primarily neurologic Sx

Combination ARV exposure may be associated with greater risk than single drug exposure

Antiretroviral Drug Penetration into Human Breast MilkMaternal PlasmaBreast Milk Ratio

NRTIAZT 044-1863TC 18-557TDF Low levels (non-bioavailable form - TFV not TDF)NNRTIEFV 054NVP 060-075PIATV 004-011LPVr 011NFV 006-024Shapiro R JID 2005192720 (3TC NVP)Giuliano M JAIDS 200744286 (AZT 3TC NVP)Mirochnick M AAC 2009531170 (AZT 3TC NVP)Colebunders R AIDS 2005191912 (NVP NFV IDV)

Schneider S JAIDS 200848450 (EFV)Mirochnick M CROI 2009 Abs 940 (TDF)Spenser L CROI 2009 Abs 942 (AZT 3TC ATV)Corbett A CROI 2009 Abs 947 (AZT 3TC LPVr)

Behind Every Healthy Child is a Healthy Mother

Maternal Health Are There Long-Term

Consequences in Healthy Women of Receiving

HAART During Pregnancy for Prophylaxis of MTCT

and then Stopping HAART

SubgroupInterrupted ART

pt (rate 100pt-yr)Continuous ART

pt (rate 100pt-yr)HazardRatio

Baseline CD4350-449 24 (32) 18 (22) 15450-549 27 (37) 7 (09) 41550-649 19 (35) 7 (13) 28gt650 50 (32) 15 (20) 32Duration ART0-lt3 yrs 23 (28) 7 (08) 163-5 yrs 30 (27) 8 (11) 155-lt7 yrs 27 (33) 15 (17) 18gt7 yrs 40 (36) 17 (15) 25Hx ART baselineNo 4 (27) 1 (05) 52Yes 22 (44) 9 (17) 26

Hazard Ratio for OIDeath Interrupted vs Continuous ART by Subgroup SMART

Lack of Long-Term Adverse Effects of AZT Prophylaxis in Women in PACTG 076

Bardeguez A et al JAIDS 200332170-81

7 915

18

3 2

1925

0

10

20

30

o

f Wom

en

Category Cdisease

CD4 lt200 Death OVERALLProgression

or death

AZT PL

No significant differences between AZT and Placebo Groups (overall progressiondeath p=028)

WITS Progression after Stopping ARV Prophylaxis Watts DH et al 12th CROI 2005 Los Angeles CA Abs S109

Among ART-naiumlve women entering pregnancy with a CD4 gt 350 and initiating ARV for PMTCT change in CD4 and HIV RNA were similar over the 1st year postpartum among women stopping or continuing therapy PP

No women in either group progressed to AIDS or death during the 1st year postpartum

However a non-significant trend to increased risk CDC Class B events (RR 29 06-134) andsignificant increase in activated CD8 cells (CD38+ DR+) was observed among women stopping compared to continuing ART PP

For Women with CD4 gt350Postnatal PMTCT via Breastfeeding

Infant ARV ProphylaxisVs

Maternal HAART

May Have Comparative Efficacyin Women with Higher CD4 Counts

IF ASSUME TREATMENT FOR ALL WITHPREGNANT WOMEN WITH CD4 lt350

In fan t Ag e

Prob

abili

ty o

f HIV

-1 In

fect

ion

1wk 9wk 6m o 9m o 12m o 15m o 18m o 24m o

000

005

010

015

020

025

030

C ontro lE xtended NV PE xtended NV P +ZD V

Age1

wk6

wks9

wks14

wks6

mos9

mos12

mos15

mos18

mos24

mosEstimates ()

Control 03 51 74 84 101 106 115 124 139 145

Extended NVP 01 17 26 28 40 52 70 78 101 112

Extended NVP+ZDV 02 16 24 28 52 64 81 87 102 123

14 Week Extended ARV Prophylaxis Significantly Reduces Postnatal HIV Infection PEPI Malawi

Kumwenda N et al NEJM 2008359119-29

Maternal Antiretroviral Prophylaxis of Breast Milk HIV Transmission

Observational suggest maternal HAART during lactation may reduce transmission

For women who require therapy for their own health the benefit of HAART for maternal health outweighs potential risks

These women are at highest risk for postnatal transmission and HAART may reduce this risk

NVP toxicity not a concern in women with low CD4

Research needed for women with high CD4

Overall Transmission

MITRA MITRA (Infant ART N=398)

MITRAMITRA--PlusPlus(Maternal ART N=440)

6 Weeks 38(20-56)

41(21-60)

6 Months 49(27-71)

50(32-70)

Increment MTCT6 weeks-6 months 11 09

No significant difference in terms of postnataltransmission between maternal or infant

prophylaxis strategies

MITRA (Infant ARV) vs MITRA-PLUS (Maternal HAART) to Prevent Postnatal MTCT Tanzania

Kilewo et al 4th IAS Sydney Australia 2007 Abs TuAX101

Kisumu Breastfeeding Study (KIBS) Maternal HAART for PMTCT in 500 Breastfeeding Mothers in Kenya Thomas T et al 15th CROI 2008 Boston MA Abs 45aLB

0-7 Days 6 Wks 3 Mos 6 Mos

Overall MTCT 24 39 41 50

Postnatal Tx +15 +17 +26

By CD4 count

CD4 lt250 34 43 52 52

CD4 gt250 21 38 38 49

For Women with CD4 gt350No Significant Difference in Postnatal MTCTKiBS (Maternal HAART) vs PEPI (Infant ARV)

(infants uninfected at birth)

KiBS PEPI

KiBSKiBS

interventionintervention

PEPI interventionPEPI intervention

Thomas T Fowler M and KiBS

study

team unpublished

Taha T Kumwenda N Hoover D and PEPI

study team unpublished

Postpartum Prophylaxis of Breast Milk MTCT

Issue of ARV Drug Resistancein Infants

Problem with Infant NVP Prophylaxis but also with Maternal HAART

NVP Resistance More Frequent in Infants Infected While Receiving Extended NVP but Not in Infants

Infected After Extended NVP was Stopped India SWEN Study Moorthy A et al PLosONE 20094e4096

92

38

15 15

0

20

40

60

80

100 SWEN sdNVP

Infants Diagnosed with HIV AfterAge 6 Weeks (Late BF MTCT)

Infants Diagnosed with HIVWithin the First 6 Weeks of Life

P=0002

P=10

Standard assay

Resistance in BF Infected Infants in KIBS (Maternal HAART Prophylaxis)

Zeh C et al 15th CROI 2008 Boston MA Abs 45aLB

First Positive Viral (PCR) Test

Wk 14 + 24 Specimen

Week PostpartumN

Not amplified

N resist N tested

N resistN tested

Delivery 12 3 09 11122 Wks 2 1 01 126 Wks 6 0 16 1614 Wks 2 0 22 2224 Wks 2 0 12 1236 - 72 Wks 5 1 04 NATotal 29 10 319 (16) 1624 (67)

Resistance not seen on first viral test but rather appears to haveemerged during breastfeeding period

Summary Breastfeeding and HIV Transmissionbull ARV prophylaxis of infant or the mother during

breastfeeding will likely both reduce postnatal MTCT possibly to a similar extent

bull Infants who become infected in both scenarios are likely to have resistant virus

bull Women who require treatment should receive HAART which will likely decrease PP MTCT

bull However the risks and benefits of infant vs maternal prophylaxis need to be compared for women with higher CD4

bull Longer interventions to permit safe prolonged breastfeeding need to be assessed

PROMISEPromoting Maternal Infant

Survival Everywhere

Antiretroviral Drug Penetration into Human Breast MilkMaternal PlasmaBreast Milk Ratio

NRTIAZT 044-1863TC 18-557TDF Low levels (non-bioavailable form - TFV not TDF)NNRTIEFV 054NVP 060-075PIATV 004-011LPVr 011NFV 006-024Shapiro R JID 2005192720 (3TC NVP)Giuliano M JAIDS 200744286 (AZT 3TC NVP)Mirochnick M AAC 2009531170 (AZT 3TC NVP)Colebunders R AIDS 2005191912 (NVP NFV IDV)

Schneider S JAIDS 200848450 (EFV)Mirochnick M CROI 2009 Abs 940 (TDF)Spenser L CROI 2009 Abs 942 (AZT 3TC ATV)Corbett A CROI 2009 Abs 947 (AZT 3TC LPVr)

Behind Every Healthy Child is a Healthy Mother

Maternal Health Are There Long-Term

Consequences in Healthy Women of Receiving

HAART During Pregnancy for Prophylaxis of MTCT

and then Stopping HAART

SubgroupInterrupted ART

pt (rate 100pt-yr)Continuous ART

pt (rate 100pt-yr)HazardRatio

Baseline CD4350-449 24 (32) 18 (22) 15450-549 27 (37) 7 (09) 41550-649 19 (35) 7 (13) 28gt650 50 (32) 15 (20) 32Duration ART0-lt3 yrs 23 (28) 7 (08) 163-5 yrs 30 (27) 8 (11) 155-lt7 yrs 27 (33) 15 (17) 18gt7 yrs 40 (36) 17 (15) 25Hx ART baselineNo 4 (27) 1 (05) 52Yes 22 (44) 9 (17) 26

Hazard Ratio for OIDeath Interrupted vs Continuous ART by Subgroup SMART

Lack of Long-Term Adverse Effects of AZT Prophylaxis in Women in PACTG 076

Bardeguez A et al JAIDS 200332170-81

7 915

18

3 2

1925

0

10

20

30

o

f Wom

en

Category Cdisease

CD4 lt200 Death OVERALLProgression

or death

AZT PL

No significant differences between AZT and Placebo Groups (overall progressiondeath p=028)

WITS Progression after Stopping ARV Prophylaxis Watts DH et al 12th CROI 2005 Los Angeles CA Abs S109

Among ART-naiumlve women entering pregnancy with a CD4 gt 350 and initiating ARV for PMTCT change in CD4 and HIV RNA were similar over the 1st year postpartum among women stopping or continuing therapy PP

No women in either group progressed to AIDS or death during the 1st year postpartum

However a non-significant trend to increased risk CDC Class B events (RR 29 06-134) andsignificant increase in activated CD8 cells (CD38+ DR+) was observed among women stopping compared to continuing ART PP

For Women with CD4 gt350Postnatal PMTCT via Breastfeeding

Infant ARV ProphylaxisVs

Maternal HAART

May Have Comparative Efficacyin Women with Higher CD4 Counts

IF ASSUME TREATMENT FOR ALL WITHPREGNANT WOMEN WITH CD4 lt350

In fan t Ag e

Prob

abili

ty o

f HIV

-1 In

fect

ion

1wk 9wk 6m o 9m o 12m o 15m o 18m o 24m o

000

005

010

015

020

025

030

C ontro lE xtended NV PE xtended NV P +ZD V

Age1

wk6

wks9

wks14

wks6

mos9

mos12

mos15

mos18

mos24

mosEstimates ()

Control 03 51 74 84 101 106 115 124 139 145

Extended NVP 01 17 26 28 40 52 70 78 101 112

Extended NVP+ZDV 02 16 24 28 52 64 81 87 102 123

14 Week Extended ARV Prophylaxis Significantly Reduces Postnatal HIV Infection PEPI Malawi

Kumwenda N et al NEJM 2008359119-29

Maternal Antiretroviral Prophylaxis of Breast Milk HIV Transmission

Observational suggest maternal HAART during lactation may reduce transmission

For women who require therapy for their own health the benefit of HAART for maternal health outweighs potential risks

These women are at highest risk for postnatal transmission and HAART may reduce this risk

NVP toxicity not a concern in women with low CD4

Research needed for women with high CD4

Overall Transmission

MITRA MITRA (Infant ART N=398)

MITRAMITRA--PlusPlus(Maternal ART N=440)

6 Weeks 38(20-56)

41(21-60)

6 Months 49(27-71)

50(32-70)

Increment MTCT6 weeks-6 months 11 09

No significant difference in terms of postnataltransmission between maternal or infant

prophylaxis strategies

MITRA (Infant ARV) vs MITRA-PLUS (Maternal HAART) to Prevent Postnatal MTCT Tanzania

Kilewo et al 4th IAS Sydney Australia 2007 Abs TuAX101

Kisumu Breastfeeding Study (KIBS) Maternal HAART for PMTCT in 500 Breastfeeding Mothers in Kenya Thomas T et al 15th CROI 2008 Boston MA Abs 45aLB

0-7 Days 6 Wks 3 Mos 6 Mos

Overall MTCT 24 39 41 50

Postnatal Tx +15 +17 +26

By CD4 count

CD4 lt250 34 43 52 52

CD4 gt250 21 38 38 49

For Women with CD4 gt350No Significant Difference in Postnatal MTCTKiBS (Maternal HAART) vs PEPI (Infant ARV)

(infants uninfected at birth)

KiBS PEPI

KiBSKiBS

interventionintervention

PEPI interventionPEPI intervention

Thomas T Fowler M and KiBS

study

team unpublished

Taha T Kumwenda N Hoover D and PEPI

study team unpublished

Postpartum Prophylaxis of Breast Milk MTCT

Issue of ARV Drug Resistancein Infants

Problem with Infant NVP Prophylaxis but also with Maternal HAART

NVP Resistance More Frequent in Infants Infected While Receiving Extended NVP but Not in Infants

Infected After Extended NVP was Stopped India SWEN Study Moorthy A et al PLosONE 20094e4096

92

38

15 15

0

20

40

60

80

100 SWEN sdNVP

Infants Diagnosed with HIV AfterAge 6 Weeks (Late BF MTCT)

Infants Diagnosed with HIVWithin the First 6 Weeks of Life

P=0002

P=10

Standard assay

Resistance in BF Infected Infants in KIBS (Maternal HAART Prophylaxis)

Zeh C et al 15th CROI 2008 Boston MA Abs 45aLB

First Positive Viral (PCR) Test

Wk 14 + 24 Specimen

Week PostpartumN

Not amplified

N resist N tested

N resistN tested

Delivery 12 3 09 11122 Wks 2 1 01 126 Wks 6 0 16 1614 Wks 2 0 22 2224 Wks 2 0 12 1236 - 72 Wks 5 1 04 NATotal 29 10 319 (16) 1624 (67)

Resistance not seen on first viral test but rather appears to haveemerged during breastfeeding period

Summary Breastfeeding and HIV Transmissionbull ARV prophylaxis of infant or the mother during

breastfeeding will likely both reduce postnatal MTCT possibly to a similar extent

bull Infants who become infected in both scenarios are likely to have resistant virus

bull Women who require treatment should receive HAART which will likely decrease PP MTCT

bull However the risks and benefits of infant vs maternal prophylaxis need to be compared for women with higher CD4

bull Longer interventions to permit safe prolonged breastfeeding need to be assessed

PROMISEPromoting Maternal Infant

Survival Everywhere

Behind Every Healthy Child is a Healthy Mother

Maternal Health Are There Long-Term

Consequences in Healthy Women of Receiving

HAART During Pregnancy for Prophylaxis of MTCT

and then Stopping HAART

SubgroupInterrupted ART

pt (rate 100pt-yr)Continuous ART

pt (rate 100pt-yr)HazardRatio

Baseline CD4350-449 24 (32) 18 (22) 15450-549 27 (37) 7 (09) 41550-649 19 (35) 7 (13) 28gt650 50 (32) 15 (20) 32Duration ART0-lt3 yrs 23 (28) 7 (08) 163-5 yrs 30 (27) 8 (11) 155-lt7 yrs 27 (33) 15 (17) 18gt7 yrs 40 (36) 17 (15) 25Hx ART baselineNo 4 (27) 1 (05) 52Yes 22 (44) 9 (17) 26

Hazard Ratio for OIDeath Interrupted vs Continuous ART by Subgroup SMART

Lack of Long-Term Adverse Effects of AZT Prophylaxis in Women in PACTG 076

Bardeguez A et al JAIDS 200332170-81

7 915

18

3 2

1925

0

10

20

30

o

f Wom

en

Category Cdisease

CD4 lt200 Death OVERALLProgression

or death

AZT PL

No significant differences between AZT and Placebo Groups (overall progressiondeath p=028)

WITS Progression after Stopping ARV Prophylaxis Watts DH et al 12th CROI 2005 Los Angeles CA Abs S109

Among ART-naiumlve women entering pregnancy with a CD4 gt 350 and initiating ARV for PMTCT change in CD4 and HIV RNA were similar over the 1st year postpartum among women stopping or continuing therapy PP

No women in either group progressed to AIDS or death during the 1st year postpartum

However a non-significant trend to increased risk CDC Class B events (RR 29 06-134) andsignificant increase in activated CD8 cells (CD38+ DR+) was observed among women stopping compared to continuing ART PP

For Women with CD4 gt350Postnatal PMTCT via Breastfeeding

Infant ARV ProphylaxisVs

Maternal HAART

May Have Comparative Efficacyin Women with Higher CD4 Counts

IF ASSUME TREATMENT FOR ALL WITHPREGNANT WOMEN WITH CD4 lt350

In fan t Ag e

Prob

abili

ty o

f HIV

-1 In

fect

ion

1wk 9wk 6m o 9m o 12m o 15m o 18m o 24m o

000

005

010

015

020

025

030

C ontro lE xtended NV PE xtended NV P +ZD V

Age1

wk6

wks9

wks14

wks6

mos9

mos12

mos15

mos18

mos24

mosEstimates ()

Control 03 51 74 84 101 106 115 124 139 145

Extended NVP 01 17 26 28 40 52 70 78 101 112

Extended NVP+ZDV 02 16 24 28 52 64 81 87 102 123

14 Week Extended ARV Prophylaxis Significantly Reduces Postnatal HIV Infection PEPI Malawi

Kumwenda N et al NEJM 2008359119-29

Maternal Antiretroviral Prophylaxis of Breast Milk HIV Transmission

Observational suggest maternal HAART during lactation may reduce transmission

For women who require therapy for their own health the benefit of HAART for maternal health outweighs potential risks

These women are at highest risk for postnatal transmission and HAART may reduce this risk

NVP toxicity not a concern in women with low CD4

Research needed for women with high CD4

Overall Transmission

MITRA MITRA (Infant ART N=398)

MITRAMITRA--PlusPlus(Maternal ART N=440)

6 Weeks 38(20-56)

41(21-60)

6 Months 49(27-71)

50(32-70)

Increment MTCT6 weeks-6 months 11 09

No significant difference in terms of postnataltransmission between maternal or infant

prophylaxis strategies

MITRA (Infant ARV) vs MITRA-PLUS (Maternal HAART) to Prevent Postnatal MTCT Tanzania

Kilewo et al 4th IAS Sydney Australia 2007 Abs TuAX101

Kisumu Breastfeeding Study (KIBS) Maternal HAART for PMTCT in 500 Breastfeeding Mothers in Kenya Thomas T et al 15th CROI 2008 Boston MA Abs 45aLB

0-7 Days 6 Wks 3 Mos 6 Mos

Overall MTCT 24 39 41 50

Postnatal Tx +15 +17 +26

By CD4 count

CD4 lt250 34 43 52 52

CD4 gt250 21 38 38 49

For Women with CD4 gt350No Significant Difference in Postnatal MTCTKiBS (Maternal HAART) vs PEPI (Infant ARV)

(infants uninfected at birth)

KiBS PEPI

KiBSKiBS

interventionintervention

PEPI interventionPEPI intervention

Thomas T Fowler M and KiBS

study

team unpublished

Taha T Kumwenda N Hoover D and PEPI

study team unpublished

Postpartum Prophylaxis of Breast Milk MTCT

Issue of ARV Drug Resistancein Infants

Problem with Infant NVP Prophylaxis but also with Maternal HAART

NVP Resistance More Frequent in Infants Infected While Receiving Extended NVP but Not in Infants

Infected After Extended NVP was Stopped India SWEN Study Moorthy A et al PLosONE 20094e4096

92

38

15 15

0

20

40

60

80

100 SWEN sdNVP

Infants Diagnosed with HIV AfterAge 6 Weeks (Late BF MTCT)

Infants Diagnosed with HIVWithin the First 6 Weeks of Life

P=0002

P=10

Standard assay

Resistance in BF Infected Infants in KIBS (Maternal HAART Prophylaxis)

Zeh C et al 15th CROI 2008 Boston MA Abs 45aLB

First Positive Viral (PCR) Test

Wk 14 + 24 Specimen

Week PostpartumN

Not amplified

N resist N tested

N resistN tested

Delivery 12 3 09 11122 Wks 2 1 01 126 Wks 6 0 16 1614 Wks 2 0 22 2224 Wks 2 0 12 1236 - 72 Wks 5 1 04 NATotal 29 10 319 (16) 1624 (67)

Resistance not seen on first viral test but rather appears to haveemerged during breastfeeding period

Summary Breastfeeding and HIV Transmissionbull ARV prophylaxis of infant or the mother during

breastfeeding will likely both reduce postnatal MTCT possibly to a similar extent

bull Infants who become infected in both scenarios are likely to have resistant virus

bull Women who require treatment should receive HAART which will likely decrease PP MTCT

bull However the risks and benefits of infant vs maternal prophylaxis need to be compared for women with higher CD4

bull Longer interventions to permit safe prolonged breastfeeding need to be assessed

PROMISEPromoting Maternal Infant

Survival Everywhere

SubgroupInterrupted ART

pt (rate 100pt-yr)Continuous ART

pt (rate 100pt-yr)HazardRatio

Baseline CD4350-449 24 (32) 18 (22) 15450-549 27 (37) 7 (09) 41550-649 19 (35) 7 (13) 28gt650 50 (32) 15 (20) 32Duration ART0-lt3 yrs 23 (28) 7 (08) 163-5 yrs 30 (27) 8 (11) 155-lt7 yrs 27 (33) 15 (17) 18gt7 yrs 40 (36) 17 (15) 25Hx ART baselineNo 4 (27) 1 (05) 52Yes 22 (44) 9 (17) 26

Hazard Ratio for OIDeath Interrupted vs Continuous ART by Subgroup SMART

Lack of Long-Term Adverse Effects of AZT Prophylaxis in Women in PACTG 076

Bardeguez A et al JAIDS 200332170-81

7 915

18

3 2

1925

0

10

20

30

o

f Wom

en

Category Cdisease

CD4 lt200 Death OVERALLProgression

or death

AZT PL

No significant differences between AZT and Placebo Groups (overall progressiondeath p=028)

WITS Progression after Stopping ARV Prophylaxis Watts DH et al 12th CROI 2005 Los Angeles CA Abs S109

Among ART-naiumlve women entering pregnancy with a CD4 gt 350 and initiating ARV for PMTCT change in CD4 and HIV RNA were similar over the 1st year postpartum among women stopping or continuing therapy PP

No women in either group progressed to AIDS or death during the 1st year postpartum

However a non-significant trend to increased risk CDC Class B events (RR 29 06-134) andsignificant increase in activated CD8 cells (CD38+ DR+) was observed among women stopping compared to continuing ART PP

For Women with CD4 gt350Postnatal PMTCT via Breastfeeding

Infant ARV ProphylaxisVs

Maternal HAART

May Have Comparative Efficacyin Women with Higher CD4 Counts

IF ASSUME TREATMENT FOR ALL WITHPREGNANT WOMEN WITH CD4 lt350

In fan t Ag e

Prob

abili

ty o

f HIV

-1 In

fect

ion

1wk 9wk 6m o 9m o 12m o 15m o 18m o 24m o

000

005

010

015

020

025

030

C ontro lE xtended NV PE xtended NV P +ZD V

Age1

wk6

wks9

wks14

wks6

mos9

mos12

mos15

mos18

mos24

mosEstimates ()

Control 03 51 74 84 101 106 115 124 139 145

Extended NVP 01 17 26 28 40 52 70 78 101 112

Extended NVP+ZDV 02 16 24 28 52 64 81 87 102 123

14 Week Extended ARV Prophylaxis Significantly Reduces Postnatal HIV Infection PEPI Malawi

Kumwenda N et al NEJM 2008359119-29

Maternal Antiretroviral Prophylaxis of Breast Milk HIV Transmission

Observational suggest maternal HAART during lactation may reduce transmission

For women who require therapy for their own health the benefit of HAART for maternal health outweighs potential risks

These women are at highest risk for postnatal transmission and HAART may reduce this risk

NVP toxicity not a concern in women with low CD4

Research needed for women with high CD4

Overall Transmission

MITRA MITRA (Infant ART N=398)

MITRAMITRA--PlusPlus(Maternal ART N=440)

6 Weeks 38(20-56)

41(21-60)

6 Months 49(27-71)

50(32-70)

Increment MTCT6 weeks-6 months 11 09

No significant difference in terms of postnataltransmission between maternal or infant

prophylaxis strategies

MITRA (Infant ARV) vs MITRA-PLUS (Maternal HAART) to Prevent Postnatal MTCT Tanzania

Kilewo et al 4th IAS Sydney Australia 2007 Abs TuAX101

Kisumu Breastfeeding Study (KIBS) Maternal HAART for PMTCT in 500 Breastfeeding Mothers in Kenya Thomas T et al 15th CROI 2008 Boston MA Abs 45aLB

0-7 Days 6 Wks 3 Mos 6 Mos

Overall MTCT 24 39 41 50

Postnatal Tx +15 +17 +26

By CD4 count

CD4 lt250 34 43 52 52

CD4 gt250 21 38 38 49

For Women with CD4 gt350No Significant Difference in Postnatal MTCTKiBS (Maternal HAART) vs PEPI (Infant ARV)

(infants uninfected at birth)

KiBS PEPI

KiBSKiBS

interventionintervention

PEPI interventionPEPI intervention

Thomas T Fowler M and KiBS

study

team unpublished

Taha T Kumwenda N Hoover D and PEPI

study team unpublished

Postpartum Prophylaxis of Breast Milk MTCT

Issue of ARV Drug Resistancein Infants

Problem with Infant NVP Prophylaxis but also with Maternal HAART

NVP Resistance More Frequent in Infants Infected While Receiving Extended NVP but Not in Infants

Infected After Extended NVP was Stopped India SWEN Study Moorthy A et al PLosONE 20094e4096

92

38

15 15

0

20

40

60

80

100 SWEN sdNVP

Infants Diagnosed with HIV AfterAge 6 Weeks (Late BF MTCT)

Infants Diagnosed with HIVWithin the First 6 Weeks of Life

P=0002

P=10

Standard assay

Resistance in BF Infected Infants in KIBS (Maternal HAART Prophylaxis)

Zeh C et al 15th CROI 2008 Boston MA Abs 45aLB

First Positive Viral (PCR) Test

Wk 14 + 24 Specimen

Week PostpartumN

Not amplified

N resist N tested

N resistN tested

Delivery 12 3 09 11122 Wks 2 1 01 126 Wks 6 0 16 1614 Wks 2 0 22 2224 Wks 2 0 12 1236 - 72 Wks 5 1 04 NATotal 29 10 319 (16) 1624 (67)

Resistance not seen on first viral test but rather appears to haveemerged during breastfeeding period

Summary Breastfeeding and HIV Transmissionbull ARV prophylaxis of infant or the mother during

breastfeeding will likely both reduce postnatal MTCT possibly to a similar extent

bull Infants who become infected in both scenarios are likely to have resistant virus

bull Women who require treatment should receive HAART which will likely decrease PP MTCT

bull However the risks and benefits of infant vs maternal prophylaxis need to be compared for women with higher CD4

bull Longer interventions to permit safe prolonged breastfeeding need to be assessed

PROMISEPromoting Maternal Infant

Survival Everywhere

Lack of Long-Term Adverse Effects of AZT Prophylaxis in Women in PACTG 076

Bardeguez A et al JAIDS 200332170-81

7 915

18

3 2

1925

0

10

20

30

o

f Wom

en

Category Cdisease

CD4 lt200 Death OVERALLProgression

or death

AZT PL

No significant differences between AZT and Placebo Groups (overall progressiondeath p=028)

WITS Progression after Stopping ARV Prophylaxis Watts DH et al 12th CROI 2005 Los Angeles CA Abs S109

Among ART-naiumlve women entering pregnancy with a CD4 gt 350 and initiating ARV for PMTCT change in CD4 and HIV RNA were similar over the 1st year postpartum among women stopping or continuing therapy PP

No women in either group progressed to AIDS or death during the 1st year postpartum

However a non-significant trend to increased risk CDC Class B events (RR 29 06-134) andsignificant increase in activated CD8 cells (CD38+ DR+) was observed among women stopping compared to continuing ART PP

For Women with CD4 gt350Postnatal PMTCT via Breastfeeding

Infant ARV ProphylaxisVs

Maternal HAART

May Have Comparative Efficacyin Women with Higher CD4 Counts

IF ASSUME TREATMENT FOR ALL WITHPREGNANT WOMEN WITH CD4 lt350

In fan t Ag e

Prob

abili

ty o

f HIV

-1 In

fect

ion

1wk 9wk 6m o 9m o 12m o 15m o 18m o 24m o

000

005

010

015

020

025

030

C ontro lE xtended NV PE xtended NV P +ZD V

Age1

wk6

wks9

wks14

wks6

mos9

mos12

mos15

mos18

mos24

mosEstimates ()

Control 03 51 74 84 101 106 115 124 139 145

Extended NVP 01 17 26 28 40 52 70 78 101 112

Extended NVP+ZDV 02 16 24 28 52 64 81 87 102 123

14 Week Extended ARV Prophylaxis Significantly Reduces Postnatal HIV Infection PEPI Malawi

Kumwenda N et al NEJM 2008359119-29

Maternal Antiretroviral Prophylaxis of Breast Milk HIV Transmission

Observational suggest maternal HAART during lactation may reduce transmission

For women who require therapy for their own health the benefit of HAART for maternal health outweighs potential risks

These women are at highest risk for postnatal transmission and HAART may reduce this risk

NVP toxicity not a concern in women with low CD4

Research needed for women with high CD4

Overall Transmission

MITRA MITRA (Infant ART N=398)

MITRAMITRA--PlusPlus(Maternal ART N=440)

6 Weeks 38(20-56)

41(21-60)

6 Months 49(27-71)

50(32-70)

Increment MTCT6 weeks-6 months 11 09

No significant difference in terms of postnataltransmission between maternal or infant

prophylaxis strategies

MITRA (Infant ARV) vs MITRA-PLUS (Maternal HAART) to Prevent Postnatal MTCT Tanzania

Kilewo et al 4th IAS Sydney Australia 2007 Abs TuAX101

Kisumu Breastfeeding Study (KIBS) Maternal HAART for PMTCT in 500 Breastfeeding Mothers in Kenya Thomas T et al 15th CROI 2008 Boston MA Abs 45aLB

0-7 Days 6 Wks 3 Mos 6 Mos

Overall MTCT 24 39 41 50

Postnatal Tx +15 +17 +26

By CD4 count

CD4 lt250 34 43 52 52

CD4 gt250 21 38 38 49

For Women with CD4 gt350No Significant Difference in Postnatal MTCTKiBS (Maternal HAART) vs PEPI (Infant ARV)

(infants uninfected at birth)

KiBS PEPI

KiBSKiBS

interventionintervention

PEPI interventionPEPI intervention

Thomas T Fowler M and KiBS

study

team unpublished

Taha T Kumwenda N Hoover D and PEPI

study team unpublished

Postpartum Prophylaxis of Breast Milk MTCT

Issue of ARV Drug Resistancein Infants

Problem with Infant NVP Prophylaxis but also with Maternal HAART

NVP Resistance More Frequent in Infants Infected While Receiving Extended NVP but Not in Infants

Infected After Extended NVP was Stopped India SWEN Study Moorthy A et al PLosONE 20094e4096

92

38

15 15

0

20

40

60

80

100 SWEN sdNVP

Infants Diagnosed with HIV AfterAge 6 Weeks (Late BF MTCT)

Infants Diagnosed with HIVWithin the First 6 Weeks of Life

P=0002

P=10

Standard assay

Resistance in BF Infected Infants in KIBS (Maternal HAART Prophylaxis)

Zeh C et al 15th CROI 2008 Boston MA Abs 45aLB

First Positive Viral (PCR) Test

Wk 14 + 24 Specimen

Week PostpartumN

Not amplified

N resist N tested

N resistN tested

Delivery 12 3 09 11122 Wks 2 1 01 126 Wks 6 0 16 1614 Wks 2 0 22 2224 Wks 2 0 12 1236 - 72 Wks 5 1 04 NATotal 29 10 319 (16) 1624 (67)

Resistance not seen on first viral test but rather appears to haveemerged during breastfeeding period

Summary Breastfeeding and HIV Transmissionbull ARV prophylaxis of infant or the mother during

breastfeeding will likely both reduce postnatal MTCT possibly to a similar extent

bull Infants who become infected in both scenarios are likely to have resistant virus

bull Women who require treatment should receive HAART which will likely decrease PP MTCT

bull However the risks and benefits of infant vs maternal prophylaxis need to be compared for women with higher CD4

bull Longer interventions to permit safe prolonged breastfeeding need to be assessed

PROMISEPromoting Maternal Infant

Survival Everywhere

WITS Progression after Stopping ARV Prophylaxis Watts DH et al 12th CROI 2005 Los Angeles CA Abs S109

Among ART-naiumlve women entering pregnancy with a CD4 gt 350 and initiating ARV for PMTCT change in CD4 and HIV RNA were similar over the 1st year postpartum among women stopping or continuing therapy PP

No women in either group progressed to AIDS or death during the 1st year postpartum

However a non-significant trend to increased risk CDC Class B events (RR 29 06-134) andsignificant increase in activated CD8 cells (CD38+ DR+) was observed among women stopping compared to continuing ART PP

For Women with CD4 gt350Postnatal PMTCT via Breastfeeding

Infant ARV ProphylaxisVs

Maternal HAART

May Have Comparative Efficacyin Women with Higher CD4 Counts

IF ASSUME TREATMENT FOR ALL WITHPREGNANT WOMEN WITH CD4 lt350

In fan t Ag e

Prob

abili

ty o

f HIV

-1 In

fect

ion

1wk 9wk 6m o 9m o 12m o 15m o 18m o 24m o

000

005

010

015

020

025

030

C ontro lE xtended NV PE xtended NV P +ZD V

Age1

wk6

wks9

wks14

wks6

mos9

mos12

mos15

mos18

mos24

mosEstimates ()

Control 03 51 74 84 101 106 115 124 139 145

Extended NVP 01 17 26 28 40 52 70 78 101 112

Extended NVP+ZDV 02 16 24 28 52 64 81 87 102 123

14 Week Extended ARV Prophylaxis Significantly Reduces Postnatal HIV Infection PEPI Malawi

Kumwenda N et al NEJM 2008359119-29

Maternal Antiretroviral Prophylaxis of Breast Milk HIV Transmission

Observational suggest maternal HAART during lactation may reduce transmission

For women who require therapy for their own health the benefit of HAART for maternal health outweighs potential risks

These women are at highest risk for postnatal transmission and HAART may reduce this risk

NVP toxicity not a concern in women with low CD4

Research needed for women with high CD4

Overall Transmission

MITRA MITRA (Infant ART N=398)

MITRAMITRA--PlusPlus(Maternal ART N=440)

6 Weeks 38(20-56)

41(21-60)

6 Months 49(27-71)

50(32-70)

Increment MTCT6 weeks-6 months 11 09

No significant difference in terms of postnataltransmission between maternal or infant

prophylaxis strategies

MITRA (Infant ARV) vs MITRA-PLUS (Maternal HAART) to Prevent Postnatal MTCT Tanzania

Kilewo et al 4th IAS Sydney Australia 2007 Abs TuAX101

Kisumu Breastfeeding Study (KIBS) Maternal HAART for PMTCT in 500 Breastfeeding Mothers in Kenya Thomas T et al 15th CROI 2008 Boston MA Abs 45aLB

0-7 Days 6 Wks 3 Mos 6 Mos

Overall MTCT 24 39 41 50

Postnatal Tx +15 +17 +26

By CD4 count

CD4 lt250 34 43 52 52

CD4 gt250 21 38 38 49

For Women with CD4 gt350No Significant Difference in Postnatal MTCTKiBS (Maternal HAART) vs PEPI (Infant ARV)

(infants uninfected at birth)

KiBS PEPI

KiBSKiBS

interventionintervention

PEPI interventionPEPI intervention

Thomas T Fowler M and KiBS

study

team unpublished

Taha T Kumwenda N Hoover D and PEPI

study team unpublished

Postpartum Prophylaxis of Breast Milk MTCT

Issue of ARV Drug Resistancein Infants

Problem with Infant NVP Prophylaxis but also with Maternal HAART

NVP Resistance More Frequent in Infants Infected While Receiving Extended NVP but Not in Infants

Infected After Extended NVP was Stopped India SWEN Study Moorthy A et al PLosONE 20094e4096

92

38

15 15

0

20

40

60

80

100 SWEN sdNVP

Infants Diagnosed with HIV AfterAge 6 Weeks (Late BF MTCT)

Infants Diagnosed with HIVWithin the First 6 Weeks of Life

P=0002

P=10

Standard assay

Resistance in BF Infected Infants in KIBS (Maternal HAART Prophylaxis)

Zeh C et al 15th CROI 2008 Boston MA Abs 45aLB

First Positive Viral (PCR) Test

Wk 14 + 24 Specimen

Week PostpartumN

Not amplified

N resist N tested

N resistN tested

Delivery 12 3 09 11122 Wks 2 1 01 126 Wks 6 0 16 1614 Wks 2 0 22 2224 Wks 2 0 12 1236 - 72 Wks 5 1 04 NATotal 29 10 319 (16) 1624 (67)

Resistance not seen on first viral test but rather appears to haveemerged during breastfeeding period

Summary Breastfeeding and HIV Transmissionbull ARV prophylaxis of infant or the mother during

breastfeeding will likely both reduce postnatal MTCT possibly to a similar extent

bull Infants who become infected in both scenarios are likely to have resistant virus

bull Women who require treatment should receive HAART which will likely decrease PP MTCT

bull However the risks and benefits of infant vs maternal prophylaxis need to be compared for women with higher CD4

bull Longer interventions to permit safe prolonged breastfeeding need to be assessed

PROMISEPromoting Maternal Infant

Survival Everywhere

For Women with CD4 gt350Postnatal PMTCT via Breastfeeding

Infant ARV ProphylaxisVs

Maternal HAART

May Have Comparative Efficacyin Women with Higher CD4 Counts

IF ASSUME TREATMENT FOR ALL WITHPREGNANT WOMEN WITH CD4 lt350

In fan t Ag e

Prob

abili

ty o

f HIV

-1 In

fect

ion

1wk 9wk 6m o 9m o 12m o 15m o 18m o 24m o

000

005

010

015

020

025

030

C ontro lE xtended NV PE xtended NV P +ZD V

Age1

wk6

wks9

wks14

wks6

mos9

mos12

mos15

mos18

mos24

mosEstimates ()

Control 03 51 74 84 101 106 115 124 139 145

Extended NVP 01 17 26 28 40 52 70 78 101 112

Extended NVP+ZDV 02 16 24 28 52 64 81 87 102 123

14 Week Extended ARV Prophylaxis Significantly Reduces Postnatal HIV Infection PEPI Malawi

Kumwenda N et al NEJM 2008359119-29

Maternal Antiretroviral Prophylaxis of Breast Milk HIV Transmission

Observational suggest maternal HAART during lactation may reduce transmission

For women who require therapy for their own health the benefit of HAART for maternal health outweighs potential risks

These women are at highest risk for postnatal transmission and HAART may reduce this risk

NVP toxicity not a concern in women with low CD4

Research needed for women with high CD4

Overall Transmission

MITRA MITRA (Infant ART N=398)

MITRAMITRA--PlusPlus(Maternal ART N=440)

6 Weeks 38(20-56)

41(21-60)

6 Months 49(27-71)

50(32-70)

Increment MTCT6 weeks-6 months 11 09

No significant difference in terms of postnataltransmission between maternal or infant

prophylaxis strategies

MITRA (Infant ARV) vs MITRA-PLUS (Maternal HAART) to Prevent Postnatal MTCT Tanzania

Kilewo et al 4th IAS Sydney Australia 2007 Abs TuAX101

Kisumu Breastfeeding Study (KIBS) Maternal HAART for PMTCT in 500 Breastfeeding Mothers in Kenya Thomas T et al 15th CROI 2008 Boston MA Abs 45aLB

0-7 Days 6 Wks 3 Mos 6 Mos

Overall MTCT 24 39 41 50

Postnatal Tx +15 +17 +26

By CD4 count

CD4 lt250 34 43 52 52

CD4 gt250 21 38 38 49

For Women with CD4 gt350No Significant Difference in Postnatal MTCTKiBS (Maternal HAART) vs PEPI (Infant ARV)

(infants uninfected at birth)

KiBS PEPI

KiBSKiBS

interventionintervention

PEPI interventionPEPI intervention

Thomas T Fowler M and KiBS

study

team unpublished

Taha T Kumwenda N Hoover D and PEPI

study team unpublished

Postpartum Prophylaxis of Breast Milk MTCT

Issue of ARV Drug Resistancein Infants

Problem with Infant NVP Prophylaxis but also with Maternal HAART

NVP Resistance More Frequent in Infants Infected While Receiving Extended NVP but Not in Infants

Infected After Extended NVP was Stopped India SWEN Study Moorthy A et al PLosONE 20094e4096

92

38

15 15

0

20

40

60

80

100 SWEN sdNVP

Infants Diagnosed with HIV AfterAge 6 Weeks (Late BF MTCT)

Infants Diagnosed with HIVWithin the First 6 Weeks of Life

P=0002

P=10

Standard assay

Resistance in BF Infected Infants in KIBS (Maternal HAART Prophylaxis)

Zeh C et al 15th CROI 2008 Boston MA Abs 45aLB

First Positive Viral (PCR) Test

Wk 14 + 24 Specimen

Week PostpartumN

Not amplified

N resist N tested

N resistN tested

Delivery 12 3 09 11122 Wks 2 1 01 126 Wks 6 0 16 1614 Wks 2 0 22 2224 Wks 2 0 12 1236 - 72 Wks 5 1 04 NATotal 29 10 319 (16) 1624 (67)

Resistance not seen on first viral test but rather appears to haveemerged during breastfeeding period

Summary Breastfeeding and HIV Transmissionbull ARV prophylaxis of infant or the mother during

breastfeeding will likely both reduce postnatal MTCT possibly to a similar extent

bull Infants who become infected in both scenarios are likely to have resistant virus

bull Women who require treatment should receive HAART which will likely decrease PP MTCT

bull However the risks and benefits of infant vs maternal prophylaxis need to be compared for women with higher CD4

bull Longer interventions to permit safe prolonged breastfeeding need to be assessed

PROMISEPromoting Maternal Infant

Survival Everywhere

In fan t Ag e

Prob

abili

ty o

f HIV

-1 In

fect

ion

1wk 9wk 6m o 9m o 12m o 15m o 18m o 24m o

000

005

010

015

020

025

030

C ontro lE xtended NV PE xtended NV P +ZD V

Age1

wk6

wks9

wks14

wks6

mos9

mos12

mos15

mos18

mos24

mosEstimates ()

Control 03 51 74 84 101 106 115 124 139 145

Extended NVP 01 17 26 28 40 52 70 78 101 112

Extended NVP+ZDV 02 16 24 28 52 64 81 87 102 123

14 Week Extended ARV Prophylaxis Significantly Reduces Postnatal HIV Infection PEPI Malawi

Kumwenda N et al NEJM 2008359119-29

Maternal Antiretroviral Prophylaxis of Breast Milk HIV Transmission

Observational suggest maternal HAART during lactation may reduce transmission

For women who require therapy for their own health the benefit of HAART for maternal health outweighs potential risks

These women are at highest risk for postnatal transmission and HAART may reduce this risk

NVP toxicity not a concern in women with low CD4

Research needed for women with high CD4

Overall Transmission

MITRA MITRA (Infant ART N=398)

MITRAMITRA--PlusPlus(Maternal ART N=440)

6 Weeks 38(20-56)

41(21-60)

6 Months 49(27-71)

50(32-70)

Increment MTCT6 weeks-6 months 11 09

No significant difference in terms of postnataltransmission between maternal or infant

prophylaxis strategies

MITRA (Infant ARV) vs MITRA-PLUS (Maternal HAART) to Prevent Postnatal MTCT Tanzania

Kilewo et al 4th IAS Sydney Australia 2007 Abs TuAX101

Kisumu Breastfeeding Study (KIBS) Maternal HAART for PMTCT in 500 Breastfeeding Mothers in Kenya Thomas T et al 15th CROI 2008 Boston MA Abs 45aLB

0-7 Days 6 Wks 3 Mos 6 Mos

Overall MTCT 24 39 41 50

Postnatal Tx +15 +17 +26

By CD4 count

CD4 lt250 34 43 52 52

CD4 gt250 21 38 38 49

For Women with CD4 gt350No Significant Difference in Postnatal MTCTKiBS (Maternal HAART) vs PEPI (Infant ARV)

(infants uninfected at birth)

KiBS PEPI

KiBSKiBS

interventionintervention

PEPI interventionPEPI intervention

Thomas T Fowler M and KiBS

study

team unpublished

Taha T Kumwenda N Hoover D and PEPI

study team unpublished

Postpartum Prophylaxis of Breast Milk MTCT

Issue of ARV Drug Resistancein Infants

Problem with Infant NVP Prophylaxis but also with Maternal HAART

NVP Resistance More Frequent in Infants Infected While Receiving Extended NVP but Not in Infants

Infected After Extended NVP was Stopped India SWEN Study Moorthy A et al PLosONE 20094e4096

92

38

15 15

0

20

40

60

80

100 SWEN sdNVP

Infants Diagnosed with HIV AfterAge 6 Weeks (Late BF MTCT)

Infants Diagnosed with HIVWithin the First 6 Weeks of Life

P=0002

P=10

Standard assay

Resistance in BF Infected Infants in KIBS (Maternal HAART Prophylaxis)

Zeh C et al 15th CROI 2008 Boston MA Abs 45aLB

First Positive Viral (PCR) Test

Wk 14 + 24 Specimen

Week PostpartumN

Not amplified

N resist N tested

N resistN tested

Delivery 12 3 09 11122 Wks 2 1 01 126 Wks 6 0 16 1614 Wks 2 0 22 2224 Wks 2 0 12 1236 - 72 Wks 5 1 04 NATotal 29 10 319 (16) 1624 (67)

Resistance not seen on first viral test but rather appears to haveemerged during breastfeeding period

Summary Breastfeeding and HIV Transmissionbull ARV prophylaxis of infant or the mother during

breastfeeding will likely both reduce postnatal MTCT possibly to a similar extent

bull Infants who become infected in both scenarios are likely to have resistant virus

bull Women who require treatment should receive HAART which will likely decrease PP MTCT

bull However the risks and benefits of infant vs maternal prophylaxis need to be compared for women with higher CD4

bull Longer interventions to permit safe prolonged breastfeeding need to be assessed

PROMISEPromoting Maternal Infant

Survival Everywhere

Maternal Antiretroviral Prophylaxis of Breast Milk HIV Transmission

Observational suggest maternal HAART during lactation may reduce transmission

For women who require therapy for their own health the benefit of HAART for maternal health outweighs potential risks

These women are at highest risk for postnatal transmission and HAART may reduce this risk

NVP toxicity not a concern in women with low CD4

Research needed for women with high CD4

Overall Transmission

MITRA MITRA (Infant ART N=398)

MITRAMITRA--PlusPlus(Maternal ART N=440)

6 Weeks 38(20-56)

41(21-60)

6 Months 49(27-71)

50(32-70)

Increment MTCT6 weeks-6 months 11 09

No significant difference in terms of postnataltransmission between maternal or infant

prophylaxis strategies

MITRA (Infant ARV) vs MITRA-PLUS (Maternal HAART) to Prevent Postnatal MTCT Tanzania

Kilewo et al 4th IAS Sydney Australia 2007 Abs TuAX101

Kisumu Breastfeeding Study (KIBS) Maternal HAART for PMTCT in 500 Breastfeeding Mothers in Kenya Thomas T et al 15th CROI 2008 Boston MA Abs 45aLB

0-7 Days 6 Wks 3 Mos 6 Mos

Overall MTCT 24 39 41 50

Postnatal Tx +15 +17 +26

By CD4 count

CD4 lt250 34 43 52 52

CD4 gt250 21 38 38 49

For Women with CD4 gt350No Significant Difference in Postnatal MTCTKiBS (Maternal HAART) vs PEPI (Infant ARV)

(infants uninfected at birth)

KiBS PEPI

KiBSKiBS

interventionintervention

PEPI interventionPEPI intervention

Thomas T Fowler M and KiBS

study

team unpublished

Taha T Kumwenda N Hoover D and PEPI

study team unpublished

Postpartum Prophylaxis of Breast Milk MTCT

Issue of ARV Drug Resistancein Infants

Problem with Infant NVP Prophylaxis but also with Maternal HAART

NVP Resistance More Frequent in Infants Infected While Receiving Extended NVP but Not in Infants

Infected After Extended NVP was Stopped India SWEN Study Moorthy A et al PLosONE 20094e4096

92

38

15 15

0

20

40

60

80

100 SWEN sdNVP

Infants Diagnosed with HIV AfterAge 6 Weeks (Late BF MTCT)

Infants Diagnosed with HIVWithin the First 6 Weeks of Life

P=0002

P=10

Standard assay

Resistance in BF Infected Infants in KIBS (Maternal HAART Prophylaxis)

Zeh C et al 15th CROI 2008 Boston MA Abs 45aLB

First Positive Viral (PCR) Test

Wk 14 + 24 Specimen

Week PostpartumN

Not amplified

N resist N tested

N resistN tested

Delivery 12 3 09 11122 Wks 2 1 01 126 Wks 6 0 16 1614 Wks 2 0 22 2224 Wks 2 0 12 1236 - 72 Wks 5 1 04 NATotal 29 10 319 (16) 1624 (67)

Resistance not seen on first viral test but rather appears to haveemerged during breastfeeding period

Summary Breastfeeding and HIV Transmissionbull ARV prophylaxis of infant or the mother during

breastfeeding will likely both reduce postnatal MTCT possibly to a similar extent

bull Infants who become infected in both scenarios are likely to have resistant virus

bull Women who require treatment should receive HAART which will likely decrease PP MTCT

bull However the risks and benefits of infant vs maternal prophylaxis need to be compared for women with higher CD4

bull Longer interventions to permit safe prolonged breastfeeding need to be assessed

PROMISEPromoting Maternal Infant

Survival Everywhere

Overall Transmission

MITRA MITRA (Infant ART N=398)

MITRAMITRA--PlusPlus(Maternal ART N=440)

6 Weeks 38(20-56)

41(21-60)

6 Months 49(27-71)

50(32-70)

Increment MTCT6 weeks-6 months 11 09

No significant difference in terms of postnataltransmission between maternal or infant

prophylaxis strategies

MITRA (Infant ARV) vs MITRA-PLUS (Maternal HAART) to Prevent Postnatal MTCT Tanzania

Kilewo et al 4th IAS Sydney Australia 2007 Abs TuAX101

Kisumu Breastfeeding Study (KIBS) Maternal HAART for PMTCT in 500 Breastfeeding Mothers in Kenya Thomas T et al 15th CROI 2008 Boston MA Abs 45aLB

0-7 Days 6 Wks 3 Mos 6 Mos

Overall MTCT 24 39 41 50

Postnatal Tx +15 +17 +26

By CD4 count

CD4 lt250 34 43 52 52

CD4 gt250 21 38 38 49

For Women with CD4 gt350No Significant Difference in Postnatal MTCTKiBS (Maternal HAART) vs PEPI (Infant ARV)

(infants uninfected at birth)

KiBS PEPI

KiBSKiBS

interventionintervention

PEPI interventionPEPI intervention

Thomas T Fowler M and KiBS

study

team unpublished

Taha T Kumwenda N Hoover D and PEPI

study team unpublished

Postpartum Prophylaxis of Breast Milk MTCT

Issue of ARV Drug Resistancein Infants

Problem with Infant NVP Prophylaxis but also with Maternal HAART

NVP Resistance More Frequent in Infants Infected While Receiving Extended NVP but Not in Infants

Infected After Extended NVP was Stopped India SWEN Study Moorthy A et al PLosONE 20094e4096

92

38

15 15

0

20

40

60

80

100 SWEN sdNVP

Infants Diagnosed with HIV AfterAge 6 Weeks (Late BF MTCT)

Infants Diagnosed with HIVWithin the First 6 Weeks of Life

P=0002

P=10

Standard assay

Resistance in BF Infected Infants in KIBS (Maternal HAART Prophylaxis)

Zeh C et al 15th CROI 2008 Boston MA Abs 45aLB

First Positive Viral (PCR) Test

Wk 14 + 24 Specimen

Week PostpartumN

Not amplified

N resist N tested

N resistN tested

Delivery 12 3 09 11122 Wks 2 1 01 126 Wks 6 0 16 1614 Wks 2 0 22 2224 Wks 2 0 12 1236 - 72 Wks 5 1 04 NATotal 29 10 319 (16) 1624 (67)

Resistance not seen on first viral test but rather appears to haveemerged during breastfeeding period

Summary Breastfeeding and HIV Transmissionbull ARV prophylaxis of infant or the mother during

breastfeeding will likely both reduce postnatal MTCT possibly to a similar extent

bull Infants who become infected in both scenarios are likely to have resistant virus

bull Women who require treatment should receive HAART which will likely decrease PP MTCT

bull However the risks and benefits of infant vs maternal prophylaxis need to be compared for women with higher CD4

bull Longer interventions to permit safe prolonged breastfeeding need to be assessed

PROMISEPromoting Maternal Infant

Survival Everywhere

Kisumu Breastfeeding Study (KIBS) Maternal HAART for PMTCT in 500 Breastfeeding Mothers in Kenya Thomas T et al 15th CROI 2008 Boston MA Abs 45aLB

0-7 Days 6 Wks 3 Mos 6 Mos

Overall MTCT 24 39 41 50

Postnatal Tx +15 +17 +26

By CD4 count

CD4 lt250 34 43 52 52

CD4 gt250 21 38 38 49

For Women with CD4 gt350No Significant Difference in Postnatal MTCTKiBS (Maternal HAART) vs PEPI (Infant ARV)

(infants uninfected at birth)

KiBS PEPI

KiBSKiBS

interventionintervention

PEPI interventionPEPI intervention

Thomas T Fowler M and KiBS

study

team unpublished

Taha T Kumwenda N Hoover D and PEPI

study team unpublished

Postpartum Prophylaxis of Breast Milk MTCT

Issue of ARV Drug Resistancein Infants

Problem with Infant NVP Prophylaxis but also with Maternal HAART

NVP Resistance More Frequent in Infants Infected While Receiving Extended NVP but Not in Infants

Infected After Extended NVP was Stopped India SWEN Study Moorthy A et al PLosONE 20094e4096

92

38

15 15

0

20

40

60

80

100 SWEN sdNVP

Infants Diagnosed with HIV AfterAge 6 Weeks (Late BF MTCT)

Infants Diagnosed with HIVWithin the First 6 Weeks of Life

P=0002

P=10

Standard assay

Resistance in BF Infected Infants in KIBS (Maternal HAART Prophylaxis)

Zeh C et al 15th CROI 2008 Boston MA Abs 45aLB

First Positive Viral (PCR) Test

Wk 14 + 24 Specimen

Week PostpartumN

Not amplified

N resist N tested

N resistN tested

Delivery 12 3 09 11122 Wks 2 1 01 126 Wks 6 0 16 1614 Wks 2 0 22 2224 Wks 2 0 12 1236 - 72 Wks 5 1 04 NATotal 29 10 319 (16) 1624 (67)

Resistance not seen on first viral test but rather appears to haveemerged during breastfeeding period

Summary Breastfeeding and HIV Transmissionbull ARV prophylaxis of infant or the mother during

breastfeeding will likely both reduce postnatal MTCT possibly to a similar extent

bull Infants who become infected in both scenarios are likely to have resistant virus

bull Women who require treatment should receive HAART which will likely decrease PP MTCT

bull However the risks and benefits of infant vs maternal prophylaxis need to be compared for women with higher CD4

bull Longer interventions to permit safe prolonged breastfeeding need to be assessed

PROMISEPromoting Maternal Infant

Survival Everywhere

For Women with CD4 gt350No Significant Difference in Postnatal MTCTKiBS (Maternal HAART) vs PEPI (Infant ARV)

(infants uninfected at birth)

KiBS PEPI

KiBSKiBS

interventionintervention

PEPI interventionPEPI intervention

Thomas T Fowler M and KiBS

study

team unpublished

Taha T Kumwenda N Hoover D and PEPI

study team unpublished

Postpartum Prophylaxis of Breast Milk MTCT

Issue of ARV Drug Resistancein Infants

Problem with Infant NVP Prophylaxis but also with Maternal HAART

NVP Resistance More Frequent in Infants Infected While Receiving Extended NVP but Not in Infants

Infected After Extended NVP was Stopped India SWEN Study Moorthy A et al PLosONE 20094e4096

92

38

15 15

0

20

40

60

80

100 SWEN sdNVP

Infants Diagnosed with HIV AfterAge 6 Weeks (Late BF MTCT)

Infants Diagnosed with HIVWithin the First 6 Weeks of Life

P=0002

P=10

Standard assay

Resistance in BF Infected Infants in KIBS (Maternal HAART Prophylaxis)

Zeh C et al 15th CROI 2008 Boston MA Abs 45aLB

First Positive Viral (PCR) Test

Wk 14 + 24 Specimen

Week PostpartumN

Not amplified

N resist N tested

N resistN tested

Delivery 12 3 09 11122 Wks 2 1 01 126 Wks 6 0 16 1614 Wks 2 0 22 2224 Wks 2 0 12 1236 - 72 Wks 5 1 04 NATotal 29 10 319 (16) 1624 (67)

Resistance not seen on first viral test but rather appears to haveemerged during breastfeeding period

Summary Breastfeeding and HIV Transmissionbull ARV prophylaxis of infant or the mother during

breastfeeding will likely both reduce postnatal MTCT possibly to a similar extent

bull Infants who become infected in both scenarios are likely to have resistant virus

bull Women who require treatment should receive HAART which will likely decrease PP MTCT

bull However the risks and benefits of infant vs maternal prophylaxis need to be compared for women with higher CD4

bull Longer interventions to permit safe prolonged breastfeeding need to be assessed

PROMISEPromoting Maternal Infant

Survival Everywhere

Postpartum Prophylaxis of Breast Milk MTCT

Issue of ARV Drug Resistancein Infants

Problem with Infant NVP Prophylaxis but also with Maternal HAART

NVP Resistance More Frequent in Infants Infected While Receiving Extended NVP but Not in Infants

Infected After Extended NVP was Stopped India SWEN Study Moorthy A et al PLosONE 20094e4096

92

38

15 15

0

20

40

60

80

100 SWEN sdNVP

Infants Diagnosed with HIV AfterAge 6 Weeks (Late BF MTCT)

Infants Diagnosed with HIVWithin the First 6 Weeks of Life

P=0002

P=10

Standard assay

Resistance in BF Infected Infants in KIBS (Maternal HAART Prophylaxis)

Zeh C et al 15th CROI 2008 Boston MA Abs 45aLB

First Positive Viral (PCR) Test

Wk 14 + 24 Specimen

Week PostpartumN

Not amplified

N resist N tested

N resistN tested

Delivery 12 3 09 11122 Wks 2 1 01 126 Wks 6 0 16 1614 Wks 2 0 22 2224 Wks 2 0 12 1236 - 72 Wks 5 1 04 NATotal 29 10 319 (16) 1624 (67)

Resistance not seen on first viral test but rather appears to haveemerged during breastfeeding period

Summary Breastfeeding and HIV Transmissionbull ARV prophylaxis of infant or the mother during

breastfeeding will likely both reduce postnatal MTCT possibly to a similar extent

bull Infants who become infected in both scenarios are likely to have resistant virus

bull Women who require treatment should receive HAART which will likely decrease PP MTCT

bull However the risks and benefits of infant vs maternal prophylaxis need to be compared for women with higher CD4

bull Longer interventions to permit safe prolonged breastfeeding need to be assessed

PROMISEPromoting Maternal Infant

Survival Everywhere

NVP Resistance More Frequent in Infants Infected While Receiving Extended NVP but Not in Infants

Infected After Extended NVP was Stopped India SWEN Study Moorthy A et al PLosONE 20094e4096

92

38

15 15

0

20

40

60

80

100 SWEN sdNVP

Infants Diagnosed with HIV AfterAge 6 Weeks (Late BF MTCT)

Infants Diagnosed with HIVWithin the First 6 Weeks of Life

P=0002

P=10

Standard assay

Resistance in BF Infected Infants in KIBS (Maternal HAART Prophylaxis)

Zeh C et al 15th CROI 2008 Boston MA Abs 45aLB

First Positive Viral (PCR) Test

Wk 14 + 24 Specimen

Week PostpartumN

Not amplified

N resist N tested

N resistN tested

Delivery 12 3 09 11122 Wks 2 1 01 126 Wks 6 0 16 1614 Wks 2 0 22 2224 Wks 2 0 12 1236 - 72 Wks 5 1 04 NATotal 29 10 319 (16) 1624 (67)

Resistance not seen on first viral test but rather appears to haveemerged during breastfeeding period

Summary Breastfeeding and HIV Transmissionbull ARV prophylaxis of infant or the mother during

breastfeeding will likely both reduce postnatal MTCT possibly to a similar extent

bull Infants who become infected in both scenarios are likely to have resistant virus

bull Women who require treatment should receive HAART which will likely decrease PP MTCT

bull However the risks and benefits of infant vs maternal prophylaxis need to be compared for women with higher CD4

bull Longer interventions to permit safe prolonged breastfeeding need to be assessed

PROMISEPromoting Maternal Infant

Survival Everywhere

Resistance in BF Infected Infants in KIBS (Maternal HAART Prophylaxis)

Zeh C et al 15th CROI 2008 Boston MA Abs 45aLB

First Positive Viral (PCR) Test

Wk 14 + 24 Specimen

Week PostpartumN

Not amplified

N resist N tested

N resistN tested

Delivery 12 3 09 11122 Wks 2 1 01 126 Wks 6 0 16 1614 Wks 2 0 22 2224 Wks 2 0 12 1236 - 72 Wks 5 1 04 NATotal 29 10 319 (16) 1624 (67)

Resistance not seen on first viral test but rather appears to haveemerged during breastfeeding period

Summary Breastfeeding and HIV Transmissionbull ARV prophylaxis of infant or the mother during

breastfeeding will likely both reduce postnatal MTCT possibly to a similar extent

bull Infants who become infected in both scenarios are likely to have resistant virus

bull Women who require treatment should receive HAART which will likely decrease PP MTCT

bull However the risks and benefits of infant vs maternal prophylaxis need to be compared for women with higher CD4

bull Longer interventions to permit safe prolonged breastfeeding need to be assessed

PROMISEPromoting Maternal Infant

Survival Everywhere

Summary Breastfeeding and HIV Transmissionbull ARV prophylaxis of infant or the mother during

breastfeeding will likely both reduce postnatal MTCT possibly to a similar extent

bull Infants who become infected in both scenarios are likely to have resistant virus

bull Women who require treatment should receive HAART which will likely decrease PP MTCT

bull However the risks and benefits of infant vs maternal prophylaxis need to be compared for women with higher CD4

bull Longer interventions to permit safe prolonged breastfeeding need to be assessed

PROMISEPromoting Maternal Infant

Survival Everywhere

PROMISEPromoting Maternal Infant

Survival Everywhere

PROMISE General Overview Sequential Randomized 2x2 Factorial Trial

Women with CD4 gt350AP 28-term

Continue HAART

Stop All ARVs

Mother

Randomize

AZTAZT +

SD NVP+7d TRV

HAART HAARTRandomize

Infant(if

uninfected and lt12

mos old attime of

weaning)

CTX to 18

months

No CTX

Randomize

Infant uninfected at birth

Late presenters

No ARV

MaternalAZT +

SD NVP+7d TRV

IP PP for Duration BF After Weaning

Infant dailyNVP

HAART

Infant SD NVP + AZT x1 wk

Randomize

Infant SD NVP + AZT x1 wk

Antepartum PostpartumInfant Health

Maternal Health

Antepartum

AZTsdNVP (TRV 1 week tail)AZT3TCLPV-r

TRVLPV-r

HAART If HBsAg+

Postpartum

HAART TRVLPV-r (all regardless HBV status)

Infant NVP

Antiretroviral Regimens in PROMISE and Renal and Bone Safety Study of TDF

TDF SubstudyDexa scans mothers and infantsInfant growthCa P creatinineRenal tubular functionMarkers of bone growthInflammatory cytokinesTDF levels in breast milk infant

AZT3TCLPV-r

Thank You ForYour Attention

Antepartum

AZTsdNVP (TRV 1 week tail)AZT3TCLPV-r

TRVLPV-r

HAART If HBsAg+

Postpartum

HAART TRVLPV-r (all regardless HBV status)

Infant NVP

Antiretroviral Regimens in PROMISE and Renal and Bone Safety Study of TDF

TDF SubstudyDexa scans mothers and infantsInfant growthCa P creatinineRenal tubular functionMarkers of bone growthInflammatory cytokinesTDF levels in breast milk infant

AZT3TCLPV-r

Thank You ForYour Attention

Thank You ForYour Attention