Rapid Decline in HIV Viral Load When Introducing Raltegravir-Containing Antiretroviral Treatment Late in Pregnancy

Abstract

Antenatal screening program for HIV has been in use in Sweden since 1987 with a 95–98% acceptance rate. Screening is performed during gestational week 10–12 and antiretroviral treatment (ART) to prevent mother-to-child transmission (MTCT) is initiated at gestational week 14–18. However, some women present with HIV in late pregnancy and additional treatment are wanted to achieve viral suppression before delivery. The integrase inhibitor raltegravir has a favorable pharmacokinetic profile and a capacity to rapidly decrease the viral load (VL). We describe four women presenting as HIV positive late in pregnancy, their ART, and outcome for the mother and child. Four women were discovered as HIV positive late in pregnancy, of 7 discovered in the antenatal screening programme in Stockholm County Council during 2011. Raltegravir was added to standard ART. The mean VL at presentation was 217,000 copies per milliliter (range, 65,000–637,000). A rapid decline of HIV RNA was observed in all cases, one woman treated with ART for only 8 days prior to delivery. The mean VL decline per week was 1.12 log (range, 0.94–1.22), which is estimated to occur (based on literature) after 1–2 months with standard ART. No side effects due to raltegravir were observed in mothers or infants. Caesarean section was performed in all cases, and the women did not breastfeed. No infant was infected. This report suggests that raltegravir added to standard antiretroviral treatment would be an option for women presenting with HIV in late pregnancy.

Introduction

A n antenatal screening program for HIV has been in use in Sweden since 1987 with a 95–98% acceptance rate. Normally the screening is performed during gestational week 10–12. The mother-to-child transmission (MTCT) prevention program including antiretroviral therapy (ART) to the pregnant woman, delivery by cesarean section if viral load (VL) is greater than 50 HIV RNA copies per milliliter, antiretroviral prophylaxis to the child, and no breastfeeding, have resulted in a reduction of the HIV MTCT to less than 1%.^1,2 At Karolinska University Hospital/Huddinge, where almost all deliveries in HIV-positive women in Stockholm County Council are carried out, 30–40 HIV-positive women deliver each year. Approximately 80% are previously known HIV-infected women and the remaining 20% are found in the screening program.

According to the Swedish MTCT prevention program treatment of HIV-positive women during pregnancy consists of two nucleoside reverse transcriptase inhibitors (NRTIs) combined with a protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI), starting at week 14–18 of pregnancy (for those not already on ART).^1,3 However, some women present with HIV in late pregnancy when initiation of ART makes it less probable to achieve the treatment goal; VL less than 50 copies per milliliter before the time of delivery. Recently it was reported that initiation of ART after gestational week 20 affected the likelihood to achieve VL less than 50 copies per milliliter before delivery if VL at baseline was greater than 10,000 copies per milliliter and furthermore if VL was greater than 100,000 copies per milliliter.⁴ In those late presenters additional treatment options are wanted to increase the probability to achieve the treatment goal HIV RNA less than 50 copies per milliliter before delivery.

The integrase inhibitor raltegravir was introduced in 2007, is not approved for use during pregnancy, but has a demonstrated rapid antiviral activity with a mean viral load reduction of 1.7–2.2 log copies per milliliter by day 10 after initiation of raltegravir monotherapy in different doses.⁵ In addition, raltegravir is known to be well tolerated and have few side effects,⁶ which makes it appealing to use during pregnancy.

Methods

We present our experience of raltegravir in four cases of women presenting with HIV in late pregnancy in 2011. All four women were refugees or immigrants, recently arrived to Sweden and diagnosed in the Swedish pregnancy screening program. They were previously ART naïve.

Results

Patient 1

A 25-year-old woman, expecting her fourth child, came to the Department of Obstetrics due to contractions and anemia in gestational week 37. HIV screening test was positive (HIV-1, A1). CD4 cell count was 570×10⁶ cells per liter and HIV RNA 65,600 copies per milliliter. She was antiretroviral naïve.

Antiretroviral treatment with tenofovir/emtricitabine (TDF/FTC), lopinavir/r (LPV/r) twice daily, and raltegravir (RAL) was initiated immediately. After 8 days on antiretroviral treatment a planned cesarean section was performed in gestational week 39+1. Zidovudine (ZDV) IV was given to the women during delivery as well as single-dose nevirapine (NVP); HIV RNA had declined to 2700 copies per milliliter at that time. The infant had negative HIV RNA tests at 2 days, 6 weeks, and 6 months of age, is growing well, developing normally, and is considered HIV uninfected.

Patient 2

A 28-year-old woman, who was expecting her second child, was discovered HIV positive (HIV-1, CRF 01AE) at screening test in gestational week 30. HIV RNA on admission was 69,600 copies per milliliter and CD4 cell count were 180×10⁶ cells per liter. ART with zidovudine and lamivudine (3TC), atazanavir/r (ATV/r) was started at once and raltegravir was added after 10 days due to high HIV viral load on admission. After 15 days on raltegravir, HIV RNA had declined to 142 copies per milliliter, at planned cesarean section in gestational week 37+3 HIV RNA was less than 20 copies per milliliter. The infant had negative HIV RNA tests at 2 days, 8 weeks, and 4 months of age, is growing well, developing normally, and is considered HIV uninfected.

Patient 3

A 16-year-old woman, pregnant for the first time, presented HIV positive (HIV-1, F1) in gestational week 37. ART was initiated immediately in the form of tenofovir/emtricitabine, atazanavir/r and raltegravir. HIV RNA was 96,100 copies per milliliter and CD 4 counts 230×10⁶ cells per liter on admission. After 12 days a planned cesarean section was performed in gestational week 38+5. Zidovudine was administrated intravenously at delivery, and single-dose NVP. HIV RNA had declined to 831 copies per milliliter at that time. The infant had negative HIV RNA tests at 2 days, 5 weeks, and 4 months of age, is growing well, developing normally, and is considered HIV uninfected.

Patient 4

A 29-year-old woman, expecting her second child, was discovered HIV positive (HIV-1, C) in pregnancy week 34. Antiretroviral treatment with tenofovir/emtricitabine, and atazanavir/r, and raltegravir was initiated immediately. HIV RNA at that time was 637,000 copies per milliliter and CD 4 cell count 40×10⁶ cells per liter. After 6 days HIV RNA had declined to 35,600 copies per milliliter and after 22 days an emergency cesarean section was performed due to ruptured membranes in gestational week 37+5. HIV RNA at delivery was 691 copies per milliliter. Zidovudine was given intravenously during delivery. The infant had negative HIV RNA tests at 2 days, 7 weeks, and 4 months of age, is growing well, developing normally, and is considered HIV uninfected. The patients were strongly advised not to breastfeed. Additional data for the women and infants are presented in Table 1 and Table 2.

Table 1.

Characteristics of Four Pregnant Women Presenting as HIV Positive Late in Pregnancy

Case	1	2	3	4
Age	25	28	16	29
Gestational age at presentation	37	30	37	34
HIV subtype	HIV-1, A 1	HIV-1, CRF 01AE	HIV-1, F1	HIV-1, C
HIV RNA (copies/per milliliter) at presentation	65,600	69,600	96,100	637,000
CD 4 counts at presentation (×10⁶ cells/per liter)	570	180	230	40
ART	TDF/FTC/LPV/r/RAL	ZDV/3TC/ATV/r/RAL	TDF/FTC/ATV/r/RAL	TDF/FTC/ATV/r/RAL
Zidovudine intravenously	Yes	No	Yes	Yes
Single-dose nevirapine (NVP) before delivery	Yes	No	Yes	No
Mode of delivery	Planned cesarean section	Planned cesarean section	Planned cesarean section	Emergency cesarean section
Days on raltegravir	8	49	12	22
HIV RNA (copies/per milliliter) of the mother at delivery	2700	<20	837	691
Decline of HIV RNA (log) from presentation to delivery	1.39	3.56	2.06	2.96

TDF/FTC, tenofovir/emtricitabine; LPV/r, lopinavir/r; ATV/r, atazanavir/r; RAL, raltegravir; nevirapine, (NVP); ZDV, zidovudine.

Table 2.

Characteristics of the Infants to Four Women Presenting as HIV Positive Late in Pregnancy

Case	1	2	3	4
Birth weight (g)	3585	2552	3096	3375
Apgar score (1’, 5’, 10’)	7, 3, 8	9, 10, 10	10, 10, 10	9, 10, 10
Prophylactic treatment to the infant	ZDV 4 weeks	ZDV 4 weeks	ZDV 4 weeks	ZDV 4 weeks
	3TC 4 weeks		3TC 4 weeks	3TC 4 weeks
	NVP 2 weeks		NVP 2 weeks	NVP 2 weeks
Breastfed	No	No	No	No
Infant HIV RNA (copies/per milliliter) 2 days after delivery	<20	<20	<20	<20
Infant HIV RNA (copies/per milliliter) at 5–8 weeks	<20	<20	<20	<20
Infant HIV RNA (copies/per milliliter) at 4–6 months	<20	<20	<20	<20
HIV status of the infant	HIV negative	HIV negative	HIV negative	HIV negative

Viral load

The mean VL at presentation was 217,000 copies per milliliter (range, 65,000–637,000). One patient reached undetectable level of VL (<20 copies per milliliter) before delivery. The mean VL decline per week before delivery in the remaining three patients was 1.12 log (range, 0.94–1.22; Table 1).

Discussion

Raltegravir has a favorable pharmacokinetic profile and a capacity to rapidly decrease the HIV RNA load. Raltegravir penetrates well in to the cervix with a ratio cervicovaginal fluid/blood plasma of 2.3,⁷ and high transfer across the placenta barrier has been reported.^8,9

In this case series we report four women presenting late in pregnancy as HIV positive, all antiretroviral naïve, where raltegravir was added to standard ART. In all cases a rapid decline in HIV RNA was seen. There were no maternal or infant side effects observed, and no child was infected. One child was delivered after only 8 days on ART (including raltegravir). The mean HIV RNA decline, in the three mothers who did not reach VL less than 20 copies per milliliter, was 1.12 log/week (range, 0.94–1.22), estimated to occur after 1–2 months with standard ART. Previously, a few case reports of the use of raltegravir in pregnant patients^9

–12 have been published, mainly due to resistance to other ART or other reasons to nonadherence.¹³ Our report is focusing on the possible use of raltegravir when HIV is diagnosed late in pregnancy to achieve a rapid decline in VL before delivery.

Raltegravir is so far not licensed for use during pregnancy. Studies from rats have shown an increased incidence of super numeral ribs in treated animals compared to controls. The exposure was threefold the human exposure at the recommended human dose. Insufficient numbers of first trimester exposure in human pregnancies have been monitored to detect a twofold increase in risk of overall birth defects. Among 61 exposures of any raltegravir containing regimens during first trimester 1 birth defect was reported and among 53 exposures during second/third trimester 3 birth defects were reported.¹⁴ However, the number is too small to draw any conclusion from, but there is no indication that raltegravir is teratogenic. Current treatment guidelines for nonpregnant adults and adolescents with HIV have resulted in an altered drug exposure profile at conception. Drugs not recommended as first line of choice by current guidelines for use of antiretroviral drugs in pregnancy are now commonly used. Exposure to raltegravir during pregnancy was recently presented as infrequent but significantly rising in an Italian report.¹⁵

This report suggests that raltegravir added to standard antiretroviral treatment would be an option for women presenting with HIV in late pregnancy to achieve as low VL as possible before delivery and thereby protecting the infant from HIV infection. It is also a possibility to achieve HIV RNA less than 50 copies per milliliter, below which no further MTCT risk reduction has been able to detect with planned caesarean section delivery.¹⁶ This would also increase the possibility for a number of HIV-infected women to deliver vaginally as several European guidelines recommend this option at VL less than 50 copies per milliliter at the time of delivery.¹

In total, 7 pregnant women were discovered as HIV positive in the screening program in Stockholm County Council during 2011. Four of them (57%), all immigrants and reported in this article, were presenting late in pregnancy. WHO wants to reduce the MTCT of HIV to below 5% in a breastfeeding population, and to below 2% in a non-breastfeeding population until 2015. There is a need for additional ART, and raltegravir might play a role for those women presenting as HIV positive late in pregnancy.

Footnotes

Author Disclosure Statement

K.W. has received research grants from Janssen/Tibotec. She has received honoraria as speaker and/or advisor from Abbott, Gilead Sciences, Bristol-Myers Squibb, and Janssen/Tibotec. L.N. has received honoraria as speaker from Abbott and GlaxoSmithKline. K.P. and A.K. have no conflicts of interest.

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