Maternal and Infant Outcomes With Concurrent Treatment of Tuberculosis and HIV Infection in Pregnant Women

To the Editors:

INTRODUCTION

HIV-associated tuberculosis (TB) has been a major cause of maternal morbidity and mortality in high HIV prevalence settings.^1,2 Maternal TB also poses a serious risk to the fetus and newborn, as congenital TB is associated with a high infant mortality rate.^2,3 Early screening, diagnosis, and treatment of both HIV and TB in pregnant women are important strategies to improve maternal and infant outcomes.

According to the 2009 World Health Organization (WHO) guidelines,⁴ HIV-infected pregnant women with TB are eligible for antiretroviral therapy (ART) irrespective of CD4⁺ cell count. However, published clinical data of concurrent treatment for TB and HIV infection during pregnancy are limited.⁵ Although concurrent treatment of TB and HIV has been shown to be associated with improved survival, it may be associated with drug-drug interactions, high pill burden, and overlapping toxicities, which may limit the effectiveness and tolerability of available regimens in resource-limited countries.⁶ We describe maternal and infant outcomes for 33 pregnant women treated concurrently for TB and HIV infection.

METHODS

The MTCT-Plus (Mother to Child Transmission-Plus) Initiative provided support in Cameroon, Cote d'Ivoire, Kenya, Mozambique, Rwanda, South Africa, Thailand, Uganda, and Zambia to implement HIV care and treatment to HIV-infected women and their families identified through perinatal HIV-related services.⁷ At program entry and each clinical visit, patients had a physical examination including WHO clinical staging. CD4⁺ cell count was performed upon entry and every 6 months thereafter. ART eligibility was determined according to national guidelines. Patients on ART had clinical visits at least monthly. Pregnancy status was noted at every visit. At each clinical visit, women were screened for cough, fever, weight loss, and night sweats. Women suspected of TB were referred to the local TB clinic for evaluation and management according to national guidelines. Clinic visit attendance was tracked, and outreach was done to enhance program retention. The Institutional Review Board of Columbia University approved the MTCT-Plus Initiative as a service delivery program.

This analysis includes all women who received concurrent ART and TB treatment during pregnancy, defined as taking ART and TB medications at 2 or more consecutive visits from January 1, 2003, through March 31, 2008, when data collection ended.

The following data were reviewed: women's demographic and clinical characteristics, including age, gestational age, and WHO clinical stage at initiation of the combined use of ART and TB treatment, treatment regimens, single antiretroviral drug substitutions due to medication side effects during pregnancy, CD4⁺ cell count during pregnancy (baseline), first CD4⁺ cell count recorded postpartum, vital status during treatment, pregnancy outcome (live birth, pregnancy loss/stillbirth), and infant HIV status.

DNA polymerase chain reaction (PCR) and HIV antibody tests were used to determine infant HIV status. Infant HIV status was recorded as “HIV infected”, if >1 positive PCR test or antibody positive after breastfeeding cessation with the infant at least 9 months of age; “HIV negative” if antibody negative after breastfeeding cessation; and “inconclusive” if still breastfeeding at time of last negative test or test results were not recorded.

The Kruskal-Wallis test was used to compare median CD4⁺ cell count across groups. Data were analyzed using SAS version 9.1 (SAS Institute, Inc, Cary, NC).

RESULTS

A total of 4266 HIV-infected pregnant women enrolled in the MTCT-Plus Initiative between 2003 and 2008. Of 1536 women who received ART during pregnancy, 33 (2.1%) received TB treatment concurrently for a median of 6 weeks [interquartile range (IQR) 3-12] antepartum. At the start of concurrent treatment, women's median age was 29 years (IQR: 27-31), median gestational age was 33 weeks (IQR: 27-37), and median CD4⁺ cell count was 97 cells per cubic millimeter (IQR: 48-196). Ten women (30.3%) were WHO Stage 4. Thirty-two women were on rifampin-based TB treatment, and 1 received treatment for multidrug-resistant TB (Table 1).

TABLE 1: Description of 33 Pregnant Women on Concurrent ART and TB Treatment

TABLE 1: (continued) Description of 33 Pregnant Women on Concurrent ART and TB Treatment

Nineteen women (57%) started TB treatment and ART at the same visit. Nine women started TB treatment first [median 14 days (IQR: 10-25) before ART] and 5 started ART first [median 23 days (IQR: 14-315)]. Women who started ART first had a higher median CD4⁺ cell count at concurrent treatment initiation (387 cells/mm³) compared with women who started TB treatment first (75 cells/mm³) or both treatments concurrently (97 cells/mm³), but this difference did not reach statistical significance (P = 0.07). During pregnancy, 4 women (12.1%) had a single antiretroviral drug substitution.

Among 28 women with both an antepartum and postpartum CD4⁺ cell count all but 1 woman had a postpartum increase in CD4⁺ count, with a median increase of 104 cells per cubic millimeter (IQR: 56-235) at a median of 4 months postpartum (IQR: 3-6).

Of the 33 women, there was 1 maternal death. Her baseline CD4⁺ cell count was 6 cells per cubic millimeter, and she died of unknown causes at 24 weeks gestation after 6 weeks of concurrent treatment. One woman was lost to follow-up by 6 months postpartum. At the end of the data collection period, the remaining 31 women were alive and on ART.

Of 32 women who survived, 25 had known live births, 1 underwent a voluntary termination of pregnancy, 5 (15.2%) experienced pregnancy losses or stillbirths (3 in women who started ART and TB treatment concurrently and 2 in women who started ART first), and 1 infant outcome was unknown. In contrast, of the 1503 women in the MTCT-Plus Initiative who started ART alone (with no documented TB treatment) during pregnancy at a median gestational age of 30 weeks (IQR: 21-35) and with a median CD4⁺ count of 174 cells per cubic millimeter (IQR: 116-266), 88 women (5.9%) experienced a pregnancy loss or stillbirth.

Of the 25 live births, 1 infant was determined to be HIV infected, 20 were HIV negative, and 4 had an inconclusive HIV status. Of the latter 4, 1 child died at 2.5 months with 1 known negative HIV DNR PCR, but no confirmatory test, one died at 5 months with no results noted, and the other 2 voluntarily withdrew from the program at 5 months and 3.5 years of age with no HIV test results recorded.

DISCUSSION

We describe herein the clinical outcomes of a series of HIV-infected women who received TB treatment and ART concurrently during pregnancy. One of 33 women died during pregnancy, whereas 94% were alive and in care 6 months postpartum, with an overall median increase in CD4⁺ cell count of 104 cells per cubic millimeter. Concurrent treatment was generally well tolerated, with only 12.1% of women requiring single antiretroviral drug substitutions during pregnancy due to a medication side effect.

Pregnancy outcomes were less encouraging. The rate of pregnancy loss/stillbirth (15.2%) in this case series was more than twice that observed among women receiving ART alone during pregnancy in the MTCT-Plus Initiative. Similarly, in the observational arm of the Botswana Mma Bana study, the stillbirth rate among 170 women with a CD4⁺ cell count <200 cells per cubic millimeter who initiated ART during pregnancy was 6.5%.⁸ A number of factors may have contributed to the poor pregnancy outcomes observed in our case series. Not only did the women in this case series have more advanced HIV disease but they also had TB, both serious conditions requiring immediate treatment with multidrug regimens. Among the infants that survived, only 1 was determined to be HIV infected.

WHO guidelines for concurrent treatment of HIV and TB recommend efavirenz or abacavir as a substitute for nevirapine⁹ as pharmacokinetic drug-drug interactions between rifampin and nevirapine may lead to decreased plasma concentrations of nevirapine, with possible loss of antiretroviral efficacy. There was considerable heterogeneity in the ART regimens prescribed to women in this case series, with 33% receiving a nevirapine-containing regimen and another 33% receiving abacavir-containing regimens. Regardless of the ART regimen received, all but 1 woman experienced an increase in CD4⁺ cell count. However, postpartum hemoconcentration may have contributed to this observed increase.¹⁰

Our findings underscore the importance of early diagnosis and treatment of TB in HIV-infected pregnant women. Antenatal clinics with prevention of mother-to-child transmission programs are an important setting to implement active TB case finding. The feasibility of such an approach was demonstrated in 2 antenatal clinics in South Africa, where lay counselors used a TB symptom questionnaire to screen pregnant women for TB.¹¹ They reported a TB prevalence rate among HIV-infected women enrolled in a prevention of mother-to-child transmission program of 2.2%, which is similar to the rate of 2.1% we found among women who received ART during pregnancy in the MTCT-Plus Initiative.

In summary, we found that concurrent treatment for TB and HIV infection during pregnancy is feasible and well tolerated, with good short-term maternal outcomes, although pregnancy losses and stillbirths were high. Further research is needed to determine the best practices for treating TB and HIV disease concurrently during pregnancy to improve maternal outcomes and ensure infant HIV-free survival.

ACKNOWLEDGMENTS

The authors wish to thank the colleagues from the MTCT-Plus Initiative: ACONDA FSU and Abobo clinics, Cote d'Ivoire (Dr Siaka Toure); Cameroon Baptist Convention Clinics, Cameroon (Dr Pius Tih); Moi University College of Health Sciences Clinics, Kenya (Drs Robert Einterz and Joseph Mamlin); Nyanza Provincial General Hospital Clinic, Kenya (Dr Juliana Otieno); Beira and Chimoio Clinics, Mozambique (Health Alliance International); Treatment and Research AIDS Center, Rwanda (Dr Anita Assimwe); Cato Manor Clinic of UKZN, South Africa (Dr Anna Coutsoudous); Langa Health Clinic of Western Cape, South Africa (Dr Ivan Toms); Perinatal HIV Research Unit of University of Witswatersrand, South Africa (Dr James McIntyre); Thai Red Cross Clinic, Thailand (Dr Praphan Phanuphak); MU-JHU Cares Clinic, Uganda (Dr Philippa Musoke); St. Francis Hospital Clinic, Uganda (Dr Pius Okong); and Mtendere and Chelstone Health Clinics, Zambia (Dr Elizabeth Stringer).

Patricia L. Toro, MD, MPH*

Karen L. Schneider, PhD†

Rosalind J. Carter, PhD*

Elaine J. Abrams, MD*‡

Wafaa M. El-Sadr, MD, MPH*‡

Andrea A. Howard, MD, MS*

*International Center for AIDS Care and Treatment Programs (ICAP), Columbia University Mailman School of Public Health New York, NY

†John Snow, Inc, Boston, MA

‡Harlem Hospital, New York, NYHarlem Hospital and College of Physicians & Surgeons, Columbia University, New York, NY.