Intensification of antiretroviral treatment with raltegravir

for late-presenting HIV-infected pregnant women

Nattawan Thepnarong, Thanyawee Puthanakit, Surasith Chaithongwongwatthana, Suvaporn Anugulruengkitt, Orawan Anunsittichai ,Tuangtip Theerawit, Sasiwimol Ubolyam,

Chitsanu Pancharoen, Praphan Phanuphak

9th International Workshop on HIV Pediatrics , Paris, France

Short-course AZT WHO option A(AZT+single dose NVP)

WHO option B(HAART)

WHO option B+(lifelong HAART)

*2001-2007: estimates of MTCT transmission for women not reported in PHOMS; 2008-2012: global AIDS response report 2008-2012; 2013-2015: SPECTRUM version 5.4

Mother to child HIV transmission rate in Thailand

Lolekha R, et al. MMWR. 2016;65(22):562-6.Phanuphak N., Phanuphak P. J Virus Erad. 2016;2:107–109.

Chart1

20012001

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20032003

20042004

20052005

20062006

20072007

20082008

20092009

20102010

20112011

20122012

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20142014

20152015

Adjusted MTCT rate*

MTCT rate by DNA PCR

Mother-to-child HIV transmission rate

0.112

0.086

0.104

0.074

0.102

0.081

0.049

0.032

0.045

0.028

0.039

0.026

0.053

0.03

0.046

0.038

0.039

0.032

0.034

0.033

0.031

0.024

0.027

0.021

0.023

0.017

0.02

0.02

0.019

0.016

Sheet1

Adjusted MTCT rate*MTCT rate by DNA PCR

20010.1120.086

20020.1040.074

20030.1020.081

20040.0490.032

20050.0450.028

20060.0390.026

20070.0530.03

20080.0460.038

20090.0390.032

20100.0340.033

20110.0310.024

20120.0270.021

20130.0230.017

20140.020.02

20150.0190.016

Standard risk (80%)

HIV Transmission rate (TR)< 0.5%

High risk (20%)Late ANC(ART

Integrase inhibitors in pregnancy • Raltegravir has more rapid HIV viral load decline than EFV or boosted PI.

• Raltegravir is recommended as a first-line ART in pregnant women.• Raltegravir has high maternal:cord blood ratio.

Stephan C. J Antimicrob Chemother. 2014;69:2809-18.Maliakkal A, et al. J Acquir Immune Defic Syndr. 2016;72:153-61.

*

Study objectives

• To describe HIV vertical transmission rate from pregnant women who received raltegravir intensification regimen

Secondary objective • To describe proportion of pregnant women who

achieve plasma HIV RNA < 50 and

Method: Study design Study design: Prospective cohortInclusion criteria: HIV-infected pregnant women

* Initiate ART at GA > 32 weeks* On ART but plasma HIV RNA @ GA 32-36 weeks >1000 c/ml

Sites

Method: Mother and Infant care HAART (TDF/3TC/EFV or AZT/3TC/LPV/r )

At delivery

AZT+3TC+NVP for 6 weeks

1 monthBirth 2 month 4 month

HIV DNA PCR

Raltegravir 400 mg q 12 hr

Plasma HIV RNA (GA > 32 weeks) At enrollment

Result: Demographics data

Characteristics (N=101) ResultsAge 22 years (19-29)Gestational age 34 weeks(33-37)CD4 count, (cells/mm3) 377 (195-553)

HIV viral load*, (log10copies/ml), (N= 91) 3.9 (3.3-4.6)

Initiate ART at GA > 32 weeks 74(74%) VL > 1,000 copies/ml GA 32-26 weeks 27(26%)ART regimen n (%)• EFV-based 50 (49%)• LPV/r-based 50 (49%)• ATV/r-based 1 (1%)

6%

1%36%

23%

15%

19%

February 2016 to June 2017: 101 pregnant women

* HIV RNA was done before or within 3 days after RAL

101 HIV-infected pregnant women

71 pregnant women gave birth during February 2016- April 2017

68 infants at 2 months of age

46 infants at 4 monthsLost to follow up (N= 7)

Death @ 7 days (N=1) Lost to follow-up (N=4)

73 infants (2 sets of twins)

Mothers-Infants Cascade

Not reach or pending results at 4 month (N=15)

Delivered May-June (N=17)Expecting (N=13)

Plasma HIV RNA pregnant women

2

4623

32

35

1340

8

0%

20%

40%

60%

80%

100%

At the time of enrollment At the time of delivery10,000

78% had HIV RNA

< 1,000 c/ml

(N=62) (N=69)

Median duration of raltegravir = 21 days (IQR 8-34)

75% had HIV RNA >1,000 c/ml

Characteristics ResultsMedian GA at birth 38 weeks (IQR 38-39)Mode of delivery (n=71)• Normal labor 41 (57%)• Cesarean section* 30 (43%)Infant outcomes (n=73)*Low birth weight

HIV Status of infants HIV status of infants Number (%)

N=73 95% CI

HIV Infection(2 positive HIV DNA PCR tests)

2 (2.7%) 0.3-9.5%

Definitely uninfected( > 2 negative HIV DNA PCR up to 4 month of age)

44 (60.3%) 48.1-71.5%

Presumptively uninfected(negative HIV DNA PCR up to 2 month of age)

22 (30.1%) 19.9-42.0%

Possible uninfected*(negative HIV DNA PCR only at birth)

5 (6.9%) 2.3-15.3%

One child was died at home on day 7th of life. He was born full-term 2990 gm. Maternal plasma HIV RNA 192 copies/ml at delivery.

HIV infected infants #1 in utero infection #2 peripartum infection

Maternal age 20 years G1P0 16 years G1P0ARV regimen TDF/3TC/EFV @ 20 weeks TDF/3TC/LPV/r @ 33 weeksCD4 T lymphocyte 302 cell/mm3 596 cell/mm3GA, duration Raltegravir 34 weeks/ 14 days 34 weeks/ 29 daysHIV RNA at Raltegravir 5,833 copies/ml 1,514 copies/mlHIV RNA at birth 1,848 copies/ml < 40 copies/mlMode of delivery Elective cesarean section Emergency cesarean section Infants birth weight 2,690 gm (GA 36 week) 2,860 gm (GA 38 week)Neonatal regimen AZT/3TC/NVP 24 days AZT 28 daysHIV DNA PCR @ birth: positive

@ day 24: positive@ birth: negative

@ day 69, 83: positive

Systematic Review * Our studyNumber 11 studies: 131 cases 73 infantsYear 2001-2015 2016-2017HIV transmission rate 1.5 % (95% CI 0.2-5.4) 2.7% (95%CI 0.3-9.5)Duration of RAL range 1-12 weeks median 3 weeks (IQR 1-5)HIV RNA < 50 copies/ml 67% 46%Cesarean section 79% 43%

* Maliakkal A, et al. J Acquir Immune Defic Syndr. 2016;72:153-61.

Discussions (I)

*Include only 11 from 26 studies that use Raltegravir after GA 28 week

Discussions (II)• Effect of raltegravir to prevent HIV vertical transmission

– Reduce maternal plasma HIV RNA level at delivery• 78% had plasma HIV RNA < 1000 copies/ml

– Transplacental transfer to prevent newborn during the first week of life

• Drug cost of the raltegravir intensitification strategies– HIV risk reduction from 7.4% to 2.7% (Number need to treat = 21) – Raltegravir cost in this pilot program 5000 USD to prevent 1 HIV infection – Drug cost should be reduced in a large-scale national program.

Clarke DF, et al. J Acquir Immune Defic Syndr. 2014;67(3):310-315.

Strengths and Limitations Strengths

• Pilot program in real-life clinical setting, use practical approach.

• Documented a HIV viral decay in pregnant women.

Limitations• Infants lost to follow-up

before 4 months of age was 14%.

• Implementation barriers: raltegravir twice daily dosing and high drug cost.

Conclusions• With risk-based approach for perinatal HIV transmission,

high-risk women who received raltegravir intensification ART can achieved VL suppression.

• HIV vertical transmission rate is reduced to 2.7%.• This strategy should be considered for program aiming for

born-free HIV generation.

Acknowledgements

Funding1. Princess Soamsawali PMTCT Fund 2. Ratchadapiseksompotch Fund, Faculty of Medicine, Chulalongkorn University (RA 59/032)3. Thailand Research Fund, Department of Pediatrics, Faculty of Medicine, ChulalongkornUniversity (IRG 5780015)

Intensification of antiretroviral treatment with raltegravir �for late-presenting �HIV-infected pregnant women Dianummer 2Dianummer 3Integrase inhibitors in pregnancy Study objectivesMethod: Study design Method: Mother and Infant care Result: Demographics dataMothers-Infants CascadePlasma HIV RNA pregnant womenDianummer 11HIV Status of infants HIV infected infants Discussions (I)Discussions (II)Strengths and Limitations ConclusionsAcknowledgements