Rapid Reduction in HIV Viral Load in Late Pregnancy with Raltegravir

Abstract

The use of raltegravir (RAL) is not preferred to prevent perinatal transmission in pregnancy due to lack of safety and pharmacokinetic data in this population. Data have been limited to few case reports of patients who present for treatment late in pregnancy, have multidrug resistance, or have poor adherence, requiring an additional class such as an integrase inhibitor to further lower viral load. This case report describes and supports the initiation of RAL in very late pregnancy (week 33) to rapidly decrease viral load and successfully prevent perinatal transmission. By increasing the efficacy and safety data of RAL use in pregnancy, we believe this report can help provide some guidance on the management of complex cases.

Introduction

In the United States, vertical transmission of HIV from mother to infant has declined to less than 2% as a result of universal prenatal HIV testing, combination antenatal antiretroviral therapy, cesarean sections for mothers with elevated viral loads, and the avoidance of breast-feeding. ¹ To further reduce the risk of transmission, scheduled cesarean delivery is recommended at week 38 for patients with HIV RNA >1000 copies/mL. For HIV-infected pregnant women, the Department of Health and Human Services guidelines recommend antiretroviral (ARV) medications consisting of a 3-drug combination for prophylaxis of perinatal transmission consisting of 2 nucleoside reverse transcriptase inhibitors (NRTIs) plus a protease inhibitor (PI) or non-nucleoside reverse transcriptase inhibitors (NNRTI). ¹ The preferred ARV regimen in pregnancy is zidovudine/lamivudine (ZDV/3TC), along with lopinavir/ritonavir, riton-avir-boosted atazanavir (ATV/r), or nevirapine (NVP). The NVP should not be considered as a first-line agent if the CD4 count is >250 cells/mm³. Alternative ARV agents include tenofovir (TDF), emtricitabine (FTC), abacavir (ABC), ritonavir-boosted darunavir (DRV/r), or ritonavir-boosted saquinavir (SQV/r). When viral suppression is not achieved by the third trimester, an additional class may be considered, such as an integrase inhibitor.

In the BENCHMRK trials, raltegravir (RAL), an integrase inhibitor, was combined with optimized background therapy (OBT) in patients with resistance to at least 1 drug in each of the 3 classes of ARVs: NRTI, NNRTI, and PI. The integrase inhibitor combination was shown to be highly effective in achieving viral suppression in patients with drug resistance. ^{2 –5} The STARTMRK trial, in which ART-naive patients were treated with either RAL or efavirenz (EFV), both combined with TDF and FTC demonstrated a more rapid decline in viral load in the RAL-treated group. ^2,4–5 There is currently no recommendation for RAL use in pregnancy due to insufficient safety and pharmacokinetic data. Nevertheless, data suggesting faster time to viral suppression with an RAL-based ARV regimen offer a potential option for pregnant women who have failed therapy with other classes of ARV drugs or require rapid viral load reduction in an attempt to reduce the risk of vertical transmission. This case describes the use of RAL in late pregnancy to rapidly decrease viral load prior to delivery.

Patient Case Report

A 30-year-old female with a past medical history of HIV infection and depression had a viral load of 60 copies/mL during her seventh week of pregnancy while on coformulated TDF/FTC and ATV/r. This once-daily regimen had been selected due to previous adherence issues on twice-daily (BID) combinations. She reported experiencing metallic taste, and the regimen was switched to coformulated ZDV/3TC and LPV/r BID in week 10 of pregnancy. The patient’s viral load on this regimen increased to 8860 copies/mL at week 15 of pregnancy; and after additional adherence counseling, the viral load decreased to 720 copies/mL by week 18. However, it increased again to 10 630 copies/mL by week 23 due to poor adherence. The patient reported that she was forgetting to take some of her doses due to stress caused by caring for her 3 children. Despite aggressive adherence counseling efforts, her viral load increased sharply to 122 070 copies/mL at week 29. Genotypic testing revealed a pan-sensitive virus.

Because the viral load was still 106 110 copies/mL at week 33 of pregnancy, the patient was scheduled to deliver via cesarean section at week 38, and RAL was added to her ARV regimen in an attempt to rapidly decrease the viral load. Adherence was reinforced by calling the patient BID, providing a BID pillbox, and setting alarms on her partner’s cellular phone. By week 35, the patient’s viral load dramatically decreased to 820 copies/mL; the viral load further declined to 200 copies/mL during week 37, reflecting a 2.7 log₁₀ reduction over 4 weeks of therapy with the addition of RAL.

After 5 weeks with RAL added to OBT, peripartum ZDV infusion was started and the patient delivered a healthy newborn via cesarean section. The infant received postnatal prophylaxis with ZDV 2 mg/kg orally every 6 hours as an inpatient and then continued to receive ZDV 4 mg/kg orally every 12 hours at home for a total of 6 weeks. The infant received an HIV polymerase chain reaction (PCR) test at birth, which was negative. Additional HIV PCR testing was repeated at weeks 2, 4, 8, and 16, and all results remained negative for HIV. The final determination of HIV status was negative with the concluding test at 18 months.

Discussion

Very limited literature exists regarding the use of RAL in pregnant patients. ^6,7,8 In a retrospective chart review of 2 cases by Jaworsky et al, both pregnant women were highly treatment experienced and were already on DRV/r, RAL, and etravirine. ⁶ They continued this regimen throughout the pregnancy due to lack of ARV options and both safely delivered without transmitting the virus. The next 2 reports are more similar to our case as they document use of RAL late in the third trimester. In a case report by Pinnetti et al, a woman coinfected with HIV and hepatitis C virus was treated with RAL and TDF at 38 weeks of pregnancy. ⁷ At the start of her unplanned pregnancy, her viral load was undetectable while on TDF/FTC plus RAL. However, after the diagnosis of pregnancy at 8 weeks, ART was changed to ZDV/3TC plus DRV/r. The patient experienced poor adherence to that regimen due to increased nausea and vomiting. At 38 weeks of pregnancy, the patient was hospitalized with an HIV viral load of 75 584 copies/mL, and RAL and TDF were added to her regimen. After 9 days of therapy, a 2.4 log reduction in viral burden was observed, and the viral load was 260 copies/mL at delivery. She delivered a healthy newborn with negative PCR tests reported at birth and 1 month. In a retrospective review of 5 cases in Austria presented by Taylor et al, all patients presented for initiation of therapy at week 33 or 34 of pregnancy. ⁸ Prior to cesarean delivery, the median length of exposure to RAL was 23 days. Two patients with low-level viremia became undetectable by delivery. Greater than a 2 log reduction of viral load occurred in the remaining 3 patients prior to delivery, and none of the 5 infants were HIV infected. Similarly, our patient experienced a rapid 2.7 log reduction over 4 weeks with the addition of RAL to ZDV/3TC and LPV/r, and delivered a healthy baby with negative HIV PCR tests at birth, 2 weeks, 4 weeks, 2 months, and 4 months.

Summary

Although the use of ART has led to a significant decrease in vertical transmission from mother to infant over the past 25 years in the United States, there are limited drug options for patients who present with certain circumstances. Patients who present for treatment late in pregnancy, have multidrug resistance, or have poor adherence may require an additional class such as an integrase inhibitor to help lower their viral load and ultimately reduce the risk of mother-to-infant transmission. The RAL has been shown to improve both virologic and immunologic outcomes in treatment-experienced HIV-infected patients with viral resistance and has also demonstrated the ability to very rapidly lower viral loads in treatment-naive patients. ^2,4,5,9 Limited data currently exist regarding the use of RAL in the pregnant population, especially in the United States; however, case reports, including our patient, suggest that RAL is an appropriate option for pregnant patients who require additional and rapid viral load reduction in late stages of pregnancy. Further investigations on safety and the pharmacokinetics of RAL use in pregnancy are warranted before it can be considered a standard of care in this patient population.