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The intersection of HIV and tuberculosis (TB) poses a serious threat to HIV-infected women and their children1,2. The majority of TB patients in sub-Saharan Africa are infected with HIV, and together the overlapping epidemics synergistically accelerate illness and death3,4. Escalating case rates, increased mortality, and the recent emergence of extensively drug-resistant (XDR) TB highlights how catastrophic a once-preventable and curable disease has become among people with HIV/AIDS5. The HIV epidemic requires new strategies to control TB in high-burden areas6 especially as women of reproductive age are disproportionately affected by the epidemic. Intensified case finding for TB has the potential to reduce morbidity and mortality for people living with HIV, especially pregnant women, their families and infants7,8.
Women of reproductive age bear a disproportionate burden of TB case notification rates in sub-Saharan Africa relative to their population, and pregnant HIV-infected women who have active TB disease are at higher risk for mortality9,10. Khan and colleagues documented a more than three-fold increase in maternal mortality for mothers with both TB and HIV infection11. Among African women in the early reproductive years, case detection rates of sputum smear-positive TB are 1.6 – 2.4 times higher than in women age 44 and older (Fig 1)10. In 15-24 year olds, there is marked gender disparity; women experience TB rates 1.5-2 times higher than men in the same age group in areas of high HIV prevalence (Fig 2)10. At all ages women have a higher prevalence of HIV compared to men in many African and Asian countries12,13,14 (Table 1). This disproportionate impact of HIV on women affects maternal mortality rates, a sensitive indicator of women’s health; HIV-infected mothers are at a 1.5-2 times greater risk of dying during or after pregnancy compared to uninfected women15,16,17.
The impact of TB and HIV on maternal health is dramatic. In Durban, South Africa, Pillay and colleagues assessed the difference between rates of TB and death amongst 50,000 deliveries. Of women who were HIV negative at the time of delivery, the incidence of TB was 72.9/100,000 compared to a rate of 774.5/100,000 in those HIV seropositive at the time of delivery, a more than 10-fold increased incidence18. Another recent study from Pune, India, by Gupta and associates showed that 22/627 HIV-infected women who had recently delivered developed active TB, or 4.6/100 postpartum person years (4,600/100,000)19. The median time to development of active TB postpartum was 3 months.
In addition, women with TB have a high probability of transmitting TB infection to their infants, increasing the risk of child mortality, especially in children who are HIV-infected. In the Pune study, TB increased the probability of death 2.2-fold for HIV-infected women and 3.4-fold for their infants compared to HIV-infected women who did not develop TB19. Infants born to women with TB face the threat of both vertical and horizontal transmission of TB, as well as higher rates of intrauterine growth retardation, premature birth, and low birth weight.
The trends of infection, morbidity, and mortality attributable to TB in children for the most part follow those of adults, but are compounded by the complexity of confirming a diagnosis of TB in infants born to HIV-infected mothers20. In a study of 126 children with TB in the Democratic Republic of Congo, 65% had HIV coinfection21. Mortality and relapse rates are higher among HIV-infected children who have active TB than in HIV-uninfected children22. Anti-TB drugs are not specifically formulated for children, making treatment challenging. A recent review concludes that in most developing countries there are few TB medications designed for children,; using tablets in place of stable syrups increases the potential for inaccurate dosing, resulting in toxicity or the emergence of drug-resistance23. In a cohort of 213 HIV infected children from the West Indies (all of whom were on combination antiretroviral therapy), there were 24 cases of culture-confirmed TB. Among this group 3/24 had drug resistant TB and 20% (5/24) of children died24. These data underscore the imperative of finding TB in women of childbearing age as a way to protect their children and prevent mortality.
There is a strong evidence base for screening pregnant HIV-infected women for TB as part of antenatal care. Intensified case finding for tuberculosis can reduce morbidity and mortality and prevent transmission of TB in families, the community and health care settings. Delaying the diagnosis of active TB significantly increases the proportion of infected contacts 25. By finding existing TB that would otherwise go undetected or only be detected by passive case finding at a later time, spread of TB is interupted. If the cycle of transmission of TB from adults to children is to be interrupted, those with active TB, particularly parents, need to be detected and treated as early in the course of their illness as possible.
Active, intensified TB case finding is a powerful tool for TB control even without new drugs and diagnostic tests. As documented in a 2005 review, case-finding in conjunction with a strong DOTS program has the potential to significantly reduce TB incidence25. Active case finding through house-to-house surveys and enhanced case finding strategies in clinical settings that focus on increasing TB awareness have been demonstrated as effective in diverse settings.
By utilizing existing points of care, such as antenatal, family planning or immunization clinics large numbers of women could be opportunistically screened both for HIV and for TB as they receive routine health services, making active TB case finding cost-effective and sustainable. Pregnant women are tested for HIV at antenatal clinics with prevention of mother to child transmission (PMTCT) programs, and many offer CD4 counts at the time of initial HIV diagnosis to identify women who would benefit from combination antiretroviral therapy rather than single or dual therapy for PMTCT. These programs offer a unique opportunity to evaluate women who are at increased risk of TB.
In 2004, a cross- sectional study was carried out in 2 community antenatal clinics in Soweto, South Africa, a setting of high HIV seroprevalence where 30,000 women receive antenatal voluntary counseling and testing (VCT) each year7. In Soweto, over 97% of pregnant women accept VCT and receive post-test counseling, 31% are HIV seropositive and 90% seropositive women are given treatment to prevent mother-to-child-transmission of HIV. HIV-infected pregnant women enrolled during their post-test counseling session, and lay counselors screened patients for TB symptoms using a simple questionnaire with symptomatic patients referred to a primary health care nurse. The symptom screen was positive if there was one or more major TB symptoms (cough longer than two weeks, cough producing sputum, blood in sputum, and night sweats), or two or more minor symptoms (shortness of breath, fever, chest pain, weight loss, loss of appetite, or fatigue). Of 370 participants screened, 120 (32%) had symptoms and 8 patients were diagnosed with active TB (2.1%) by sputum culture; all cases were sputum smear-negative7. As sputum smear is the most common method of diagnosis in South Africa, none of these patients would have been detected if smear was used alone. The TB screening survey – which was performed by lay VCT counselors - added an average of just three additional minutes to the VCT session. Early detection of active TB resulted in earlier treatment and prevented exposure to infectious TB in the infants subsequently born to these women. Other studies have documented the benefit of using a symptom screen to diagnose TB, though sensitivity and specificity vary26,27,28,29.
Another South African study in a group of HIV–infected postpartum women used tuberculin skin tests (TST) to screen for TB. 438 women were enrolled, 72% returned for a skin test reading, and 49% had reactions ≥5 mm8. Active TB was found 11% of those completing screening (3% of the total), including 9 with extrapulmonary TB.
Although there is a wealth of evidence suggesting that screening for active TB during routine antenatal care would be a beneficial intervention, especially in places with efficient PMTCT program, no country programs have implemented this strategy as part of best practices. Finding TB in patients who are the most vulnerable, such as HIV-infected women in reproductive ages, is an urgent priority. Because PMTCT services are widely utilized and promoted, they can serve as an excellent venue to enhance TB screening services in both HIV- infected and uninfected women.
Operational research on case finding strategies should be performed to develop best and most cost effective practices for women, their children and communities. In addition, serious consideration should be given to prevention of TB in women for whom active TB has been excluded by use of isoniazid preventive therapy (IPT). Guidelines in the United States recommend the use of IPT for HIV-infected pregnant women30. Few if any PMTCT programs in developing settings offer IPT.
A research agenda for TB screening and prevention in antenatal settings must include studying alternative PMTCT regimens for pregnant women on TB treatment, examining the sensitivity and specificity of symptom based screening for early TB, active case finding at every pre-test counseling session and early antenatal visit, and IPT for pregnant women with latent tuberculosis infection. While the reality of the existing situation must be taken in to consideration—including low coverage of PMTCT services focused on preventing transmission of HIV, and the limits of antenatal clinics—targeted TB interventions should be incorporated into comprehensive women’s health services.
Funding sources: Bill and Melinda Gates Foundation, National Institute of Allergy and Infectious Diseases, USAID