Is tenofovir/emtricitabine teratogenic?

Abstract

The Truvada^® (tenofovir/emtricitabine) and nevirapine combination is increasingly being prescribed for prevention of mother-to-child HIV transmission. There is presently no documented evidence of teratogenicity of either tenofovir/emtricitabine or nevirapine. We report two cases of spina bifida in infants of mothers on this drug combination.

Introduction

Prevention of mother-to-child HIV transmission (PMTCT) is an integral part of comprehensive HIV care. It involves the initiation or continuation of antiretroviral (ARV) drugs and optimal management of labour. In Nigeria, the national guideline for PMTCT recommends that patients on ARV drugs prior to conception should continue their medications. However, efavirenz, due to its known teratogenicity, is often substituted with nevirapine in the first trimester [Federal Ministry of Health, 2010]. Currently, the Truvada® (tenofovir/emtricitabine) and nevirapine combination (Gilead, Foster City, CA, USA) is increasingly being prescribed in pregnancy.

There is no literature evidence of teratogenicity of either tenofovir or emtricitabine alone, or in a fixed-dose combination. The US Food and Drug Administration categorizes Truvada as a category B drug, which implies that animal reproduction studies have not demonstrated foetal risk and there are no adequate controlled studies in pregnant women. Determination of teratogenicity of drugs from population studies is difficult. Much of what is known of the safety of tenofovir/emtricitabine in pregnancy emanates from animal studies and evaluation of birth registers. Animal studies have not shown any evidence of teratogenicity even at very high doses [Gilead, 2012]. The paucity of evidence to support the safety or otherwise of tenofovir/emtricitabine in pregnancy thus heightens the need for vigilance.

Alnoury Hospital, located in the city of Kano in Nigeria, started treating HIV patients in October 2005 with support from AIDSrelief, a consortium that includes the Institute of Human Virology at the University of Maryland, College Park, MD, USA, Catholic Relief Services and Constella Futures. It is an antiretroviral therapy programme funded by the President’s Emergency Plan for AIDS Relief. This partnership was transferred to the Institute of Human Virology Nigeria on October 2012.

The ARV register of the specialist Alnoury Hospital has a total of 2711 enrolled HIV patients of which 1698 are on ARV treatment as at March 2012. A total of 353 patients on the register had taken various ARV regimens during the first trimester of pregnancy, of which 44 received tenofovir/emtricitabine and nevirapine in 58 deliveries. We present case reports of two neonates with spina bifida born in March 2012 by mothers on the tenofovir/emtricitabine and nevirapine regimen. Both mothers are from a low socio-economic background. Other major regimens used in the hospital include Combivir® (zidovudine/lamivudine)/ nevirapine, Combivir®/efavirenz, Combivir®/Aluvia® (lopinavir/ritonavir), Truvada®/efavirenz and Truvada®/Aluvia® and others.

Case 1

A 29-year-old HIV positive woman (Para 4⁺⁴, 2 alive), who has been on tenofovir/emtricitabine and nevirapine for 7 years prior to index pregnancy, delivered a live 2.6 kg male infant via spontaneous vaginal delivery (SVD) at a gestational age of 39 weeks 6 days. The infant was delivered at home and was immediately brought to the hospital following an observed deformity on his back. A diagnosis of spina bifida was made. Antenatal pelvic ultrasound scan carried out at 16 weeks of gestation did not reveal any anomaly. Maternal red blood cell (RBC) folate postpartum was 1.3 ηg/ml (3–17 ηg/ml). She had daily folic acid from 13 weeks; other drugs taken were multivitamins and an iron supplement. She received sulphadoxine/pyrimethamine prophylaxis for malaria at 24 weeks and 32 weeks. No other medication was taken during this gestation. She had four previous first trimester spontaneous abortions, none of which was investigated for congenital anomaly at the hospital where she was managed. None of her other two living children had a neural tube defect (NTD). The infant was referred to a nearby teaching hospital but died 4 months postpartum before surgical repair could be done.

Case 2

A 26-year-old HIV positive woman (Para 4⁺¹, 3 alive), who had been on ARV regimen of tenofovir/emtricitabine and nevirapine for 4 years prior to index pregnancy, delivered via SVD a live male infant weighing 2.8 kg at a gestational age of 39 weeks 5 days. The infant was diagnosed with spina bifida and was subsequently referred for neurosurgical care. The infant died a day after the surgery. During the index pregnancy, the mother had continued with her prescribed ARV drugs. She commenced folate supplementation at about 13 weeks of gestation and also received iron and multivitamin supplements. She received malaria prophylaxis of sulphadoxine/pyrimethamine at 20 weeks and 32 weeks. No other drug was taken during pregnancy. She had three previous live births and a spontaneous abortion at 16 weeks. The single miscarriage was managed at another hospital and was not investigated for congenital abnormality. None of her previous children had birth defects. Pelvic ultrasound scan carried out at 21 weeks of gestation did not show any anomaly. RBC folate of the mother carried out postpartum was 5.27 ηg/ml (3–17 ηg/ml).

Discussion

NTD is an umbrella name for a group of developmental disorders that includes spina bifida, anencephaly and encephalocoele. These disorders occur as a result of the failure of closure of the neural tube within the first few weeks of embryonic life [Padmanabhan, 2006]. In the two cases reported, tenofovir/emtricitabine and nevirapine were continued throughout the first trimester. Given that several other factors could also potentially predispose to teratogenicity during this period, it is difficult to ascribe the observed defects to the tenofovir/emtricitabine and nevirapine regimen. Although folic acid deficiency is associated with higher incidence NTD [Kirke and Molloy, 1993], the contrasting picture of maternal RBC folate values in both cases underscores the difficulty with identifying aetiology. In the first case, maternal folate was low (1.3 ηg/ml), while result of the second case was within the normal limit (5.27 ηg/ml). Both mothers in these reports commenced folate supplementation after 13 weeks, rather than the periconceptional period when such supplementation can protect against NTD [MRC Vitamin Study Research Group, 1991].

We have reported two cases of NTDs in 58 live births of mothers on a tenofovir/emtricitabine and nevirapine combination regimen. This incidence is higher than the background rate of NTD in northern Nigeria. Evaluation of 13,619 live births registered at a major teaching hospital in Kano, Nigeria between 1998 and 2004 showed an incidence of NTD of 0.8/1000 live births [Yola et al. 2005]. Another review of the birth register at the National Hospital in Abuja, Nigeria reported only two cases of open NTD in 3632 live births (0.5/1000 live births) [Audu et al. 2004].

Data from the Antiretroviral Pregnancy Registry (APR) from 1989 to January 2012 shows that none of the component drugs in the tenofovir/emtricitabine and nevirapine combination regime predispose to birth defects [Antiretroviral Pregnancy Registry, 2012]. As at July 2011, the APR register shows that birth defects occurred in 18 out of 764 (2.4%) live births for emtricitabine-containing regimens and 27 out of 1219 (2.2%) live births for tenofovir-containing regimens after first trimester exposure. These figures did not differ considerably from the background rate of 2.7% recorded in the general population [Gilead, 2012]. Neither emtricitabine nor tenofovir alone, or as a fixed combination, are known to be foetotoxic [Szczech et al. 2003; Khun and Bulterys, 2012; Gibb et al. 2012]. Nevirapine is also not toxic to the foetus, and studies have shown that it is not a cause of congenital malformation [Ekouevi et al. 2011].

While these case reports do not indict any of the component drugs in the tenofovir/emtricitabine and nevirapine combination regimen, it nevertheless underscores the need for continued evaluation of the risks and benefits of these drugs during the first trimester. It is also important to increase the coverage of periconceptional folate supplementation among women receiving tenofovir/emtricitabine and nevirapine in pregnancy. Despite the limitations of registers, they still provide reliable supplemental information to animal toxicology studies and clinical trials. Therefore, in addition to information from various birth registers, cohort studies and randomized trials of pregnant women on tenofovir/emtricitabine are needed to determine drug safety in pregnancy.