E D I T O R I A L C O M M E N TA R Y
Human Immunodeficiency Virus, Mycobacterium Tuberculosis, and Pregnancy: A Deadly Combination Lynne M. Mofenson1 and Barbara E. Laughon2 1
Pediatric, Adolescent, and Maternal AIDS Branch, Center for Research on Mothers and Children, National Institute of Child Health and Human Development, and Complications and Co-Infections Research Branch, Therapeutics Research Program, Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland
2
(See the article by Gupta et al. on pages 241–9)
Mycobacterium tuberculosis is estimated to infect 30% of the world population, with 95% of tuberculosis (TB) cases and 98% of TB deaths occurring in resource-limited countries [1]. Superimposed on this burden of TB is HIV infection, which has reached pandemic proportions in areas where TB is endemic. TB and HIV are inextricably linked. The development of TB disease has been linked to increased HIV replication and reduced CD4 cell counts, potentially contributing to the progression of HIV infection [2]. In the Women’s Interagency HIV Study, which has followed a cohort of HIV-infected women in the United States for a median of 6 years, the development of TB disease was associated with a 4-fold increase in AIDS-related mortality [3]. Moreover, immunodeficiency induced by HIV fuels TB resurgence and increases TB incidence and mortality in areas where TB is highly prevalent; HIV infection is associated with a Received 2 April 2007; accepted 2 April 2007; electronically published 4 June 2007. Reprints or correspondence: Dr. Lynne M. Mofenson, Pediatric, Adolescent, and Maternal AIDS Branch, Center for Research on Mothers and Children, National Institute of Child Health and Human Development, National Institutes of Health, 6100 Executive Blvd., Rm. 4B11, Bethesda, MD 20892 (
[email protected]). Clinical Infectious Diseases 2007; 45:250–3 This article is in the public domain, and no copyright is claimed. 1058-4838/2007/4502-0017 DOI: 10.1086/518975
⭓20-fold increased risk of reactivation of latent TB [4, 5] and is thought to account for much of the increase in the global burden of TB observed over the past 2 decades [6–8]. Both TB and HIV infection are major health problems for women. Globally, 17.7 million of the 37.2 million adults with HIV infection are women, comprising nearly 50% of all persons with HIV infection worldwide [9]. Although the prevalence of TB in adults is higher among men than among women, women of reproductive age have higher rates of progression from TB infection to disease than do men in this age group [10–12]. In resource-limited countries, there is an overlap of the age ranges during which TB and HIV infection are most prevalent; like HIV infection, the greatest burden of TB disease in women occurs during the childbearing years (15–49 years of age). Eighty percent of all mortality due to TB in women occurs in this age group [13]. Worldwide, TB, like HIV infection, is a leading infectious cause of death among women, killing 11 million women each year [14]. In communities where TB and HIV infection are endemic, pregnant women are at high risk of acquiring both infections. From 1996 through 1998, in Durban, South Africa, a dramatic increase in the case load of TB disease in pregnant women
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was observed; 72% of these cases were attributable to HIV infection [15]. The rate of TB disease among HIV-infected pregnant women was ∼10 times higher than that among HIV-uninfected pregnant women. Although, historically, it had been thought that a woman with latent TB becoming pregnant was associated with an increased risk of development of active TB disease, the most recent data do not indicate that pregnancy increases risk of disease in either HIV-uninfected or HIV-infected women [16, 17]. However, HIV infection and TB during pregnancy are a particularly deadly combination and are independent risk factors for maternal mortality [8, 15, 18]. In a study of maternal mortality in South Africa, there was a 3.2-fold increase in the relative risk of death in mothers with TB-HIV coinfection, compared with HIV-uninfected mothers with TB infection, and 54% of maternal deaths caused by TB were attributable to coinfection with HIV [18]. In Zambia, TB accounts for 25% of all nonobstetric maternal deaths, most of these among women with TB-HIV coinfection [19]. In some tertiary care hospitals in South Africa, TB-HIV coinfection accounts for 14%–15% of all maternal mortality [18]. In this issue of Clinical Infectious Dis-
eases, Gupta et al. [20] report the significant burden of TB disease in postpartum HIV-infected women and their infants in India. The study is part of an ongoing National Institutes of Health–sponsored phase III clinical trial of infant antiretroviral prophylaxis to prevent postnatal mother-to-child HIV transmission caused by breastfeeding. The incidence of TB disease in HIV-infected postpartum Indian women was 5 cases per 100 person-years, with cases occurring primarily during the early postpartum period (median time to incident TB was 3 months after delivery of the infant), suggesting that the women may have had subclinical TB during late pregnancy; 29% of cases occurred within the first 2 weeks after delivery. Twelve percent of women with TB-HIV coinfection died, compared with 1% of HIV-infected women without TB infection. In an analysis adjusting for other factors associated with mortality, HIV-infected women with incident TB had a 2.2-fold increased risk of death, compared with HIV-infected women without active TB. Maternal TB can also pose a serious risk of transmission of TB infection to the infant. Mother-to-child TB transmission can occur in utero, through hematogenous dissemination to the infant via the umbilical vein or aspiration or ingestion of infected amniotic fluid; intrapartum, through aspiration or ingestion of infected amniotic fluid or genital secretions during passage through the birth canal; or postpartum, through inhalation or ingestion of infectious respiratory droplets from the mother or ingestion of infected milk (e.g., from mothers with a breast abscess due to TB infection) [21]. In a study of 107 South African mothers with active TB during pregnancy, 77% of whom had HIV infection, mother-to-child TB transmission was detected in 15% of neonates [22]. Neonatal TB was associated with late diagnosis of TB in the mother and lack of TB treatment. In the current study by Gupta et al. [20], 2 (9%) of 23 women with incident TB appeared to transmit TB infection to their infant. In addition, in-
fants born to women with incident TB had a 3.4-fold increased risk of death, compared with infants born to mothers without TB. Congenital TB carries a high risk of infant death, with reported mortality rates of up to 38%; postnatal acquisition of TB infection by young infants is also associated with a high risk of disseminated and rapidly fatal TB disease [23–25]. Additionally, congenital TB may be associated with an increased risk of HIV transmission in mothers with TB-HIV coinfection. In the South African study described above, 11 of 16 newborns with congenital TB were also exposed to HIV; 64% of these infants also acquired HIV infection and died with rapidly progressive disease before 1 year of age [22]. The HIV infection status of the infants in the study by Gupta et al. [20] was not reported, because analysis in the parent perinatal clinical trial has not been completed. The study by Gupta et al. [20] in India, combined with previously published data from Africa, suggest that effective intervention strategies to lower maternal mortality in areas with high prevalence of HIV infection and TB infection should include prevention, diagnosis, and treatment of TB disease. Antenatal clinics in areas with high prevalence of TB infection and HIV infection could include screening for TB infection and HIV infection, as well as implementation of preventive therapy for HIV-infected pregnant women found to be infected with TB (after excluding active TB disease); coordination with local TB control services for diagnosis and treatment of TB disease in women with suspected symptoms should be ensured. There are some existing models for such programs. In an antenatal clinic in Johannesburg, South Africa, pregnant women found to have HIV infection during a routine antenatal care voluntary testing program were routinely screened for symptoms of TB disease by lay counselors during the postcounseling session, and women with symptoms were referred to nurses for further investigation; using only
symptom screening, the prevalence of active TB disease was 2.2% [26]. In a more recent study at the same perinatal HIV prevention program in Johannesburg, South Africa, 1400 HIV-infected pregnant women underwent tuberculin skin testing (TST); 49% of women were found to have positive skin test results, and 11% of these women were found to have active TB disease [27]. The standard for diagnosis of latent TB has been the intradermal TST. However, this test has lower sensitivity in individuals with HIV infection, particularly in those with a low CD4 cell count. In addition, intradermal TST requires at least 2 visits to apply and then read the skin test, and many patients may not return for the skin test reading. A whole blood IFN-g release assay has been developed, which also assesses cell-mediated immunity against TB, but the correlation between IFN-g release assay and skin testing has been low, and IFN-g release assay responses among HIVinfected individuals is diminished, making it less useful among this population [7, 28]. Improved assays to determine TB infection and to diagnose TB disease are urgently needed. A newer, single-tube version of the QuantiFeron-TB Gold assay has recently become available, appears to have greater specificity, and may provide practical advantages in developing countries [29]. It is important to note that the TST and newer immune assays cannot distinguish between latent infection and active disease. It is critical that all HIV-infected individuals, including pregnant women, are evaluated for symptoms of TB disease using appropriate diagnostic testing and that multidrug TB treatment is initiated if active disease is identified. In addition, infants with mothers with untreated smearpositive pulmonary TB disease should be evaluated for symptoms of active TB, and once disease is excluded, the World Health Organization recommends that isoniazid preventive therapy (IPT) be administered to the infant for 6 months, followed by bacille Calmette-Gue´rin vaccination [30].
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In the study by Gupta et al. [20], although only 37.5% of HIV-infected women with active TB disease had positive TST results at the time of delivery, skin test positivity was an independent predictor of progression to disease. IPT has been shown in a number of studies to reduce TB incidence by 38%–42% in HIV-infected individuals overall and by 60% in HIV-infected persons with positive TST results [31, 32]. In a recent report from the Swiss HIV Cohort Study, no cases of TB disease developed in 193 HIV-infected individuals with positive TST results who received preventive therapy, compared with 16 (6.5%) of 246 individuals with positive TST results who did not receive preventive treatment [33]. Provision of IPT prophylaxis during pregnancy to either all HIV-infected pregnant women or targeted to those HIV-infected women with positive TST results could have significantly decreased postpartum progression to TB disease and its associated maternal and infant mortality. The most important adverse effect associated with IPT is hepatitis; the rate of symptomatic hepatitis in the general population is estimated to be 0.1%–0.3%, with a risk of death of 0.001%. Pregnancy has been cited as a risk factor for IPT-induced hepatotoxicity; however, this concern appears to be based on a single retrospective study, in which the difference between the study group and previously collected data on nonpregnant women was not statistically significant [34–36]. On the basis of this study, IPT is often delayed until 3–6 months after delivery in pregnant women with latent TB infection [17]. Such delay in initiation of preventive therapy often results in no preventive therapy being given, because appropriate linkage to follow-up is often lacking, or appointments are not kept, even in developed countries such as the United States [37]. In a Markov decision analysis model, Boggess et al. [38] found that antepartum IPT administered to pregnant women with latent TB infection prevented more cases of active TB disease, was more cost-effective, and
increased life expectancy (because of the prevented cases of TB disease and related mortality, despite potential cases of IPTrelated hepatitis and related mortality), compared with postpartum treatment or no treatment. Although IPT prophylaxis is effective in reducing the incidence of TB disease in HIV-infected individuals, most studies have found that IPT prophylaxis does not appear to prevent the progression of HIV disease [31, 39], and HIV-infected pregnant women should receive urgent evaluation to assess the need for antiretroviral treatment for their own health. Combination antiretroviral therapy has been shown in several studies to reduce the incidence of TB in HIV-infected individuals, with the greatest effect occurring among those experiencing more-severe immunosuppression [33, 40–42]. However, TB incidence remains high, even among individuals receiving antiretroviral treatment [3, 6]. HIV-infected patients receiving antiretroviral therapy who have latent TB infection still have a 15-fold increased risk of developing TB disease than do individuals without HIV infection. Additionally, TB can occur in individuals prior to development of severe immunosuppression that would require initiation of antiretroviral therapy. Thus, antiretroviral therapy cannot be substituted for IPT in HIV-infected individuals with latent TB infection. Given data showing that (1) TB-HIV coinfection is frequent in many resourcelimited settings, (2) HIV infection is the strongest risk factor for progression of latent TB to active TB disease, (3) tests are available to identify TB infection, (4) there is an intervention available that is effective in preventing progression from infection to disease, (5) and the development of TB disease in HIV-infected pregnant and postpartum women is associated with significant maternal and infant mortality, routine screening of HIV-infected pregnant and postpartum women for latent TB infection and disease and provision of IPT prophylaxis for women with latent TB
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seem to be logical interventions to reduce maternal mortality. In areas where TB is highly endemic, a comparison of targeted preventive therapy for HIV-infected women who had positive TST results with administration of IPT to all HIV-infected pregnant women (after screening for symptoms to rule out active TB), would be important to determine the safety, efficacy, and cost-effectiveness of a more simplified approach to prevent the development of TB disease in HIV-infected pregnant women. Acknowledgments Potential conflicts of interest. L.M.M. and B.E.L.: no conflicts.
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