An increasing number of infants are now exposed to antiretroviral medication to reduce the risk of the vertical transmission of HIV [1]. Data on short and long-term toxicity are, however, scarce [2]. Recent epidemiological studies and anecdotal case reports suggest an association between exposure to antiretroviral drugs during pregnancy and mitochondrial toxicity in uninfected children [3,4] as well as cardiovascular complications [5,6]. We report a pair of dizygotic twins born to an HIV-infected mother treated with HAART who developed severe bradycardia as a result of a complete heart block and dilated cardiomyopathy. Case report A 33-year-old HIV-1-positive gravida 2 para 0 became pregnant with dichorionic twins after in-vitro fertilization. She was first treated with efavirenz, stavudine and didanosine, which was changed to lopinavir/ritonavir, lamivudine and tenofovir because of virological failure, most likely because of non-compliance. During the infertility treatment and subsequent pregnancy she was maintained on this therapy (including tenofovir) because of the suspected resistance mutations. Good viral suppression was maintained (viral load < 40 copies/ml) throughout her pregnancy with a CD4 cell count higher than 400 cells/μl (nadir 130). At 27 weeks' gestation, premature rupture of the membranes occurred and antenatal steroids were administered. One week later, two preterm infants were born through spontaneous vaginal delivery. The first-born infant was a boy and weighed 1083 g. The second-born infant was a girl and weighed 990 g. HIV postexposure prophylaxis (PEP) was started in both infants directly after birth, consisting of zidovudine 4 mg/kg per day and lamivudine 4 mg/kg per day to which lopinavir 460 mg/m2 per day and ritonavir 115 mg/m2 per day was added because of likely (archived) resistance mutations in the maternal HIV strain. On day 3 the boy developed arrhythmias, consisting of a complete heart block with a ventricular rate between 50 and 60 bpm. Echocardiography showed dilated cardiomyopathy. Inotropic support was increased and antiretroviral medication was discontinued. Transesophageal pacing was attempted, but without success. On day 4, thoracotomy for temporary external epicardial pacing was performed. During and after the operation, resuscitation with heart massage and several intravenous injections of adrenaline were required because of low cardiac output. External ventricular pacing was successful and heart rhythm increased to 100 bpm. Two days later, spontaneous sinus rhythm reoccurred and pacing was no longer required. In the second-born infant, echocardiography was performed on day 4 because of the cardiac disorders of her twin brother and showed no signs of cardiomyopathy. On day 6, however, she developed the same symptoms as her twin brother with a complete heart block (Fig. 1) and dilated cardiomyopathy. Inotropic support was started and antiretroviral medication was discontinued. Again, transesophageal pacing was unsuccessful. This time, thoracotomy for temporary external pacing was not performed because of the severe peri and postoperative course observed in her brother and the rapid spontaneous recovery after cessation of the antiretroviral medication. One day later, her heart rhythm returned to normal sinus rhythm with gradual resolution of the cardiomyopathy, as seen in her brother.Fig. 1: Oesophageal electrophysiological analysis using leads V2 and V5. Atrial (A) contraction with an A–A interval of 56 ms (heart rate of 107 bpm) and ventricular (V) contraction with a V–V interval of 112 ms (heart rate of 53.5 bpm).Laboratory investigations in both infants showed normal full blood counts. Phosphate and calcium levels in both infants were within the normal range. Lactate levels increased to a maximum value of 6.3 mmol/l (day 3) in the first-born infant and 2.1 mmol/l (day 6) in the second-born infant, respectively, and gradually regressed to normal values. Screening for metabolic disorders was normal. HIV-1 polymerase chain reaction at birth and 5 weeks later was negative. We report two cases of dilated cardiomyopathy and complete atrioventricular heart block in a pair of dyzigotic twins treated antenatally and postnatally with antiretroviral drugs, including lopinavir/ritonavir from conception up to the first days postpartum. These rare cardiac symptoms could not be explained by prematurity, asphyxia, pharmacokinetic interactions or other somatic or metabolic disorders. In both infants, the cardiac symptoms disappeared between one and 2 days after discontinuation of the antiretroviral medication. HIV-uninfected infants born to seropositive mothers may develop cardiovascular complications (such as hypertrophic cardiomyopathy) as a result of antiretroviral toxicity [7,8]. Complete heart block with dilated cardiomyopathy as a result of antiretroviral toxicity has not previously been reported. Exposure to HAART during pregnancy has been associated with various neonatal toxic side effects, including mitochondrial toxicity [4,6,9,10]. This association is controversial, is rare with lamivudine and tenofovir and is generally related to prolonged exposure to nucleoside analogues [11]. Discontinuation of therapy usually leads to resolution of the symptoms, but the toxic effects can also be permanent [3,12]. As HAART remains crucial in the reduction of vertical HIV transmission, infants who are exposed to antiretroviral drugs should be vigorously monitored for toxicities.
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Aug 27, 2021
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