aDepartment of Rheumatology and Clinical Immunology, Germany
bDepartment of Gynecology and Obstetrics, Germany
cInstitute of Virology, Germany
dDepartment of Gastroenterology, University Hospital Freiburg, Freiburg, Germany.
Received 21 December, 2007
Revised 11 January, 2008
Accepted 10 January, 2008
Hepatitis E (HEV), which causes water-borne epidemics and sporadic acute often self-limiting hepatitis, is a major public health disease in developing countries . HEV spreads mainly by faeco-oral transmission. Secondary cases among household members of patients occur in approximately 1–2% of cases . Although nonendemic in the industrialized world, anti-HEV antibodies are detected in the general population . HEV represents a rare but important differential diagnosis of hepatitis in pregnancy . Infection in the last trimester results in high rates of preterm labour and maternal mortality of 15–26.9% [3,5,6] compared with a case fatality of between 0.2 and 4% during epidemics . In the case of HIV coinfection, complications and mortality rates are unknown.
We describe the case of a 32-year-old HIV-positive Nigerian woman living in Germany for 2 years before she presented at the 27th week of pregnancy with a 1-week history of fatigue, malaise, abdominal pain and jaundice. HIV had been diagnosed in the first trimester of pregnancy and treated with zidovudine, lamivudine and nelfinavir (NFV) for maternal indication (245/μl (14%) CD4+ lymphocytes). The differential diagnosis and follow-up of the hepatitis are described (Fig. 1).
The initial laboratory studies showed signs of severe hepatitis [alanine aminotransferase (ALT) 1683 IU/l (10–35 IU/l), bilirubin 43 mg/dl (0–1.2 mg/dl)], beginning liver failure [international normalized ratio 1.2 (0.85–1.15)] and haemolysis [haptoglobin <5 mg/dl (30–200 mg/dl), lactate dehydrogenase 1099 IU/l (135–214 IU/l), reticulocytes 7.2% (0.8–2.2%)]. Hepatitis A, B and C were excluded by serology and PCR; HEV-IgG revealed a borderline result, but PCR was negative. Other important causes of pregnancy-related hepatitis such as HELLP-syndrome, preeclampsia, acute fatty liver or thrombotic disease as well as autoimmune hepatitis were ruled out. At that time, the HIV infection was well controlled with an increased CD4+ cell count and <40 copies/ml viral load. HIV medication was stopped immediately for potential toxicity even though uncommon for the current regimen. On days 4 and 5 after admission, betamethasone was given intramuscularly (2 × 12 mg) to induce foetal lung maturation and stop haemolysis. Transaminases and bilirubin improved during the course and the patient was discharged on day 10 (ALT 372 IU/l; bilirubin 19.5 mg/dl). Due to an HIV load of 106 copies/ml, therapy was restarted on day 17, but after a rise in transaminases (ALT 691 IU/l) on day 23, NFV was exchanged for tenofovir (TDF). With this regimen and possibly betamethasone, liver enzymes and haemolysis normalized by day 56, it was virologically effective. Repeated HIV resistance testing showed no new or TDF-related mutations. HEV-IgG was repeated during follow-up on day 17 and was now positive. The patient delivered a healthy child at week 36 by Caesarean section.
The present case represents the first documented HIV-positive pregnant woman surviving acute HEV infection. HEV is a rare cause of hepatitis in HIV-positive pregnant women in nonendemic regions and without travel history. Due to a short viraemia, HEV-PCR in serum or faeces is often negative . Only seroconversion during repeated serology will confirm the diagnosis.
The impact of HIV infection on maternal mortality is difficult to quantify because the HIV status of pregnant women is often unknown. HIV incidence in pregnant women ranges from below 1% to more than 40% in different countries. HIV impacts on direct (obstetrical) causes of maternal mortality by an associated increase in pregnancy complications such as anaemia, haemorrhage and puerperal sepsis, as well as indirect causes of maternal mortality by an increased incidence of opportunistic infections . In HIV/HEV coinfection, a high maternal mortality must be assumed.
Treatment of HEV is supportive. Administration of steroids and the switch to a triple nucleoside reverse transcriptase inhibitor (NRTI) regimen might have benefited the outcome of hepatitis and haemolysis in our patient. Haemolysis is described in acute hepatitis  and in HEV in combination with glucose-6-phosphate dehydrogenase deficiency, which was ruled out here . The relapse after reexposure to NFV and improvement after exchange for TDF suggests an increased drug-related toxicity, which otherwise is uncommon for this drug. It needs to be mentioned that, soon after this episode, NFV was withdrawn from the European market for possible contamination with ethyl mesylate.
Triple NRTI regimens are not approved for use in pregnancy, the use of TDF during pregnancy is discussed controversially, and some international guidelines suggest avoiding TDF because of insufficient data . In our case, the regimen was shown to be well tolerated and effective without evolution of new resistance mutations despite a very high viral load at time of switching. Both mother and child are well, the child is developing normally.
We thank Dr Georg Härter, University Hospital Ulm, Germany, for his input in this case.
1. Reyes GR. Overview of the epidemiology and biology of the hepatitis E virus. In: Willson RA, editor. Viral hepatitis. New York: Marcel Dekker; 1997. pp. 239–258.
2. Khuroo MS. Study of an epidemic of non-A, non-B hepatitis. Possibility of another human hepatitis virus distinct from posttransfusion non-A, non-B type. Am J Med 1980; 68(Suppl 6):818–824.
3. Thomas DL, Yarbough PO, Vlahow D, Tsarev SA, Nelson KE, Saah AJ, et al
. Seroreactivity to hepatitis E virus in areas where the disease is not endemic. J Clin Microbiol 1997; 35:1244–1247.
4. Sookoian S. Liver disease during pregnancy: acute viral hepatitis. Ann Hepatol 2006; 5(Suppl 3):231–236.
5. Khuroo MS, Teli MR, Skidmore S, Sofi MA, Khuroo MI. Incidence and severity of viral hepatitis in pregnancy. Am J Med 1981; 70(Suppl 2):252–255.
6. Kumar A, Beniwal M, Kar P, Sharma JB, Murthy NS. Hepatitis E in pregnancy. Int J Gynaecol Obstet 2004; 85(Suppl 3):240–244.
7. Worm HC, van der Poel WH, Brandstätter G. Hepatitis E: an overview. Microbes Infect 2002; 4(Suppl 6):657–666.
8. Khuroo MS, Saleem M, Teli MR, Sofi MA. Failure to detect chronic liver disease after epidemic non-A, non-B hepatitis. Lancet 1980; 2:97.
9. McIntyre J. Mothers infected with HIV. Br Med Bull 2003; 67:127–135.
10. Chau TN, Lai ST, Lai JY, Yuen H. Haemolysis complicating acute viral hepatitis in patients with normal or deficient glucose-6-phosphate dehydrogenase activity. Scand J Infect Dis 1997; 29(Suppl 6):551–553.
11. Abid S, Khan AH. Severe hemolysis and renal failure in glucose-6-phosphate dehydrogenase deficient patients with hepatitis E. Am J Gastroenterol 2002; 97(Suppl 6):1544–1547.
12. European AIDS Clinical Society (EACS). Guidelines for the clinical management and treatment of HIV infected adults in Europe 2007. www.eacs.eu