To the Editors:
Chronic hepatitis B virus (HBV) infection is an important public health problem in sub-Saharan Africa.1 Infection is thought to occur predominantly in early childhood through horizontal transmission. Clearance of infection at a young age is uncommon; most infected children remain chronically infected and at risk for HBV sequelae. HBV immunization protocols in Africa are based on data obtained in the pre-HIV era showing that perinatal transmission was rare.2 However, the immune paresis associated with HIV infection may increase HBV infectivity in pregnant women. HIV-HBV–coinfected patients may be more likely to be HBeAg seropositive,3 have higher HBV viral loads,4,5 are less likely to clear infection,6 are more likely to reactivate, have a higher risk for HBeAg seroreversion,7 and are more likely to have occult HBV infection8 than monoinfected patients. The aim of this study was to determine the prevalence and character of HBV infection in HIV-infected pregnant women attending a large tertiary hospital in Cape Town, South Africa, in order to determine whether HIV increases the risk of HBV transmission from mother to child.
The participants in this study were HIV-infected pregnant women who attended Tygerberg Hospital for their delivery between July 2008 and October 2009 and who had residual plasma samples stored in the Division of Medical Virology, Tygerberg. Epidemiological data collected on these women included age, parity, CD4 count, antiretroviral treatment status, complications at delivery and infant birth weight. Ethical approval was obtained from the University of Stellenbosch Health Research Ethics Committee.
The samples were anonymized and then tested for HBsAg and anti-HBc on the Abbott AxSYM (Abbott, Chicago, IL). Low level HBsAg reactivity was confirmed by neutralization (Diasorin, Saluggia, Italy), and if confirmed positive, the samples were tested for HBeAg and anti-HBe by Abbott AxSYM (Abbott, Chicago, IL). HBV viral load testing, genotyping, and sequence analysis using DNASTAR (version 9) were performed as described previously.9,10
Data were analyzed using Statistica (StataSoft Inc, version 9). We compared all variables between HBsAg sero-positive and sero-negative women using χ2 tests for categorical variables and t tests for continuous variables. We log-transformed the absolute CD4 counts and HBV viral loads for analysis.
A total of 1661 HIV-infected women attended Tygerberg Hospital for their antenatal care between July 2008 and October 2009. Of 219 samples stored at the Division of Medical Virology, 17 had insufficient volume for further testing. The remaining 202 samples identified the women who were included in the study. Their median age was 28 years (interquartile range: 24–32 years). Their median CD4 count was 198 cells per microliter (interquartile range: 117–329 cells/μL), and 96/202 (47.5%) of the women were on combination antiretroviral therapy (ART).
Twelve samples reactive for HBsAg were confirmed positive on neutralization resulting in a HBsAg prevalence in this population of 5.9%. Five of the HBsAg-positive samples also contained HBeAg, the remainder all contained anti-HBe. Of 10 samples available for HBV viral load testing, six had viral loads greater than 104 IU/mL and four of six had viral loads greater than 106IU/ml. Sequencing was successful on eight of these samples; seven were genotype A1, and 1 genotype D. No significant surface or polymerase gene mutations were detected. No significant association was found between CD4 count and HBsAg status (P = 0.36), HBV viral load (P = 0.34) or HBeAg (P = 0.21) status. Seven of the 12 HBsAg-seropositive patients were on ART, and the remainder were unbooked pregnancies (ie, presented to medical services in labor). All 12 delivered at term with no complications. Of 178 HBsAg-negative samples with sufficient residual sample for further testing, 75 (42.1%) were found to contain anti-HBc.
This study presents clinical and virological data regarding HBV infection among HIV-infected pregnant African women. Although the sample size is small and may be subject to sampling bias, it suggests that a proportion of women in a South African community are at risk of transmitting HBV infection perinatally to their babies and developing the complications of HIV-HBV coinfection.
The HBsAg prevalence among these patients is similar to that in another sample of antenatal women in South Africa among whom the prevalence of HBsAg was 6.2%, and that of anti-HBc positivity was 37.3%.11 Few studies report on HBeAg status in African cohorts. HBeAg seropositivity has been reported to be associated with HIV infection, Oshitani et al3 reporting 25% HBeAg positivity in HIV-infected versus 12.3% in HIV-uninfected women. This association is important for pregnant women because the risk of vertical transmission is greater in women who are HBeAg positive.12 13 In sub-Saharan Africa, routine HBV immunization is commenced at 6 weeks of life, too late to prevent infection from exposure at delivery. HBeAg-seropositive chronic HBV infection is usually associated with a high viral load, which increases risk of transmission,14 but HBe antigenaemia may add additional risk because it may induce chronic infection in neonates. HBeAg is a small secreted antigen, which induces unresponsiveness of helper T cells to HBeAg and HB core antigen.15 The immune tolerance induced by HBeAg continues for years during the persistence of HBe antigenaemia. HBeAg-seropositive children are more likely to have higher viral loads16 and are therefore more likely to transmit virus to others.
The pregnant women in this study who were coinfected with HIV and HBV had low CD4 counts, a high prevalence of HBeAg seropositivity, and high HBV viral loads, confirming that HIV-HBV–coinfected pregnant women with low CD4 counts are at risk of transmitting HBV perinatally. This may compromise the effectiveness of current HBV immunization protocols across much of Africa because these commence more than 24 hours postdelivery. We believe that the time has come to consider changing policies in sub-Saharan African countries with high HIV-HBV coinfection rates to take account of the way in which HIV coinfection seems to alter the natural history of HBV. Further studies are needed to determine the incidence and effects of perinatal HBV infections in these countries.
1. Hoffmann CJ, Thio CL. Clinical implications of HIV and hepatitis B co-infection in Asia and Africa. Lancet Infect Dis. 2007;7:402–409.
2. Botha JF, Ritchie MJ, Dusheiko GM, et al.. Hepatitis B virus carrier state in black children in Ovamboland: role of perinatal and horizontal infection. Lancet. 1984;1:1210–1212.
3. Oshitani H, Kasolo FC, Mpabalwani M, et al.. Prevalence of hepatitis B antigens in human immunodeficiency virus type 1 seropositive and seronegative pregnant women in Zambia. Trans R Soc Trop Med Hyg. 1996;90:235–236.
4. Gilson RJ, Hawkins AE, Beecham MR, et al.. Interactions between HIV and hepatitis B virus in homosexual men: effects on the natural history of infection. AIDS. 1997;11:597–606.
5. Colin JF, Cazals-Hatem D, Loriot MA, et al.. Influence of human immunodeficiency virus infection on chronic hepatitis B in homosexual men. Hepatology. 1999;29:1306–1310.
6. Bodsworth NJ, Cooper DA, Donovan B. The influence of human immunodeficiency virus type 1 infection on the development of the hepatitis B virus carrier state. J Infect Dis. 1991;163:1138–1140.
7. Di MV, Thevenot T, Colin JF, et al.. Influence of HIV infection on the response to interferon therapy and the long-term outcome of chronic hepatitis B. Gastroenterology. 2002;123:1812–1822.
8. Mphahlele MJ, Lukhwareni A, Burnett RJ, et al.. High risk of occult hepatitis B virus infection in HIV-positive patients from South Africa. J Clin Virol. 2006;35:14–20.
9. Garson JA, Grant PR, Ayliffe U, et al.. Real-time PCR quantitation of hepatitis B virus DNA using automated sample preparation and murine cytomegalovirus internal control. J Virol Methods. 2005;126:207–213.
11. Burnett RJ, Ngobeni JM, Francois G, et al.. Increased exposure to hepatitis B virus infection in HIV-positive South African antenatal women. Int J STD AIDS. 2007;18(3):152–156.
12. Beasley RP, Trepo C, Stevens CE, et al.. The e antigen and vertical transmission of hepatitis B surface antigen. Am J Epidemiol. 1977;105:94–98.
13. Okada K, Kamiyama I, Inomata M, et al.. e antigen and anti-e in the serum of asymptomatic carrier mothers as indicators of positive and negative transmission of hepatitis B virus to their infants. N Engl J Med. 1976;294:746–749.
14. Burk RD, Hwang LY, Ho GY, et al.. Outcome of perinatal hepatitis B virus exposure is dependent on maternal virus load. J Infect Dis. 1994;170:1418–1423.
15. Hsu HY, Chang MH, Hsieh KH, et al.. Cellular immune response to HBcAg in mother-to-infant transmission of hepatitis B virus. Hepatology. 1992;15:770–776.
16. Chang MH. Natural history of hepatitis B virus infection in children. J Gastroenterol Hepatol. 2000;15(suppl):E16–E19.