HIV seroconversion in the third trimester of pregnancy: using raltegravir to prevent mother-to-child transmission

Introduction

Maternal acquisition of HIV during pregnancy has been previously associated with higher rates of HIV mother-to-child transmission (MTCT). ¹ In some populations incident HIV cases in pregnancy occur more frequently than in non-pregnant women^2,3 and it has been postulated that this may be due to the upregulation of CCR5 HIV-1 co-receptor expression in pregnancy and other high progesterone states. ⁴ Higher viral loads are seen during acute HIV infection ⁵ and maternal viral load at delivery is strongly correlated with the risk of MTCT. ⁶ In resource-rich settings where routine antenatal screening for HIV occurs, a substantial proportion of residual vertical HIV transmission may be from subsequent maternal seroconversion in pregnancy. ⁷

The HIV-1 integrase inhibitor raltegravir has been shown to have rapid antiretroviral activity with shorter times to achieving virological suppression when used in combination treatments than conventional combination antiretroviral therapy.^8,9 Raltegravir demonstrates a favourable pharmacokinetic profile with a terminal elimination half-life between 7 and 12 hours and a time to steady state of approximately two days. ¹⁰ Although unlicensed in pregnancy, it has been used in patients who present late in pregnancy with high viral loads when it is critical to reduce the viral load to undetectable levels by the time of delivery. ¹¹ In addition to its other properties we have previously demonstrated effective transplacental transfer and the persistence of therapeutic levels of raltegravir in neonates for several days post-delivery. ¹²

Case Report

A 28-year-old West African woman presented 28 weeks and two days into a planned pregnancy with fever, cough and shortness of breath. Chest X-ray was normal. Prior to this presentation her pregnancy had been uneventful and she had received routine antenatal care, which had included a negative HIV test at 12 weeks gestation. Over the course of a week she became increasingly tachypnoeic and hypoxic (partial pressure of oxygen [pO₂] = 9.6 on 60% O₂). Repeat chest X-ray showed bilateral perihilar infiltrates.

An urgent HIV test was carried out within 24 hours of admission and this was positive for p24 antigen but negative for HIV antibody, supporting the diagnosis of acute seroconversion. HIV viral load was 7.24 log copies/mL (1.74 × 10⁷ copies/mL) and her CD4 count was 200 cells/μL (13%). Baseline resistance test showed wild-type virus of subtype CRF02_AG.

A chest computed tomography scan showed patchy areas of ground glass shadowing predominantly in the upper lobes and a provisional diagnosis of Pneumocystis jirovecii pneumonia (PCP) was made. She was treated with high dose co-trimoxazole and oral prednisolone and made a rapid clinical recovery. Multiple induced sputum samples cultured negative for tuberculosis and showed no evidence of P. jirovecii. Plasma cytomegalovirus (CMV) viral load was undetectable.

Three days into her PCP treatment a decision was made to start antiretroviral therapy and our standard regimen for pregnant women at the time consisting of tenofovir/emtricitabine and twice daily ritonavir-boosted saquinavir was started in accordance with local guidelines. Raltegravir at a dose of 400 mg once daily was added at the same time to lower the viral load as rapidly as possible. She was discharged from hospital four days later to continue her treatment as an outpatient. She tolerated antiretroviral therapy well and 18 days into treatment her HIV viral load had dropped to 4.24 log copies/mL (17,400 copies/mL) and CD4 count had increased to 427 cells/μL (31%).

At 39 weeks gestation (71 days after first starting antiretroviral therapy) her viral load was 2.32 log copies/mL (208 copies/mL) and an elective lower segment Caesarean section was carried out under intravenous zidovudine cover. She delivered a healthy baby boy who received four weeks of postnatal antiretroviral prophylaxis with zidovudine, lamivudine and nevirapine. HIV RNA and proviral DNA polymerase chain reaction (PCR) tests were negative in the baby at birth, and at one month and 18 months post-partum.

Discussion

There are few case reports of treating HIV seroconversion in pregnancy and to our knowledge this is the first reported case where raltegravir was used to rapidly decrease the HIV viral load in a pregnant woman presenting with acute HIV in the third trimester. We observed a striking 4.9 log drop in HIV viral load within 10 weeks of starting antiretroviral therapy in this patient.

It is possible the magnitude of this drop may have been partly exaggerated by the natural course of acute HIV infection. ⁵ However the use of raltegravir is likely to have significantly contributed to the extent and rapidity of this virological response, and similarly rapid declines in HIV viral load in patients with established HIV infection have been observed elsewhere in late pregnancy. ¹³

Around 54% of women with an HIV viral load greater than 32,640 copies/mL starting antiretroviral therapy after 20 weeks gestation are unlikely to achieve an undetectable viral load by the time of delivery, ¹⁴ which often precludes vaginal delivery. More rapid reduction of HIV viral load using raltegravir may help obviate the need for Caesarean section and other additional interventions in these women. The risk of HIV MTCT is known to be markedly reduced at HIV viral loads <1000 copies/mL and this risk may also be increased in preterm infants. ¹⁵ Additionally, absorption of orally administered drugs is unpredictable in neonates due to immature gastroinstestinal tract and parenteral antiretroviral options are limited. ¹⁶

Raltegravir may have an important role to play in HIV PMTCT when mothers present late in pregnancy with a high viral load.