JAIDS Journal of Acquired Immune Deficiency Syndromes:
Brief Report: Epidemiology and Prevention
Antiretroviral Treatment Initiation Among HIV-Infected Pregnant Women with Low CD4+ Cell Counts in Gaborone, Botswana
Chen, Jennifer Y MD*; Ogwu, Anthony C MD†; Svab, Petr MD‡; Lockman, Shahin MD, MSc§‖; Moffat, Howard J MBChB, FRCP¶; Gaolathe, Tendani MD#; Moilwa, Shana RN‡; Størdal, Ketil MD, PhD‡; Dryden-Peterson, Scott MD†**; Moffat, Claire MD, MPH†; Makhema, Joseph MBChB†; Essex, M DVM, PhD‖; Shapiro, Roger L MD, MPH‖††
From the *Harvard Medical School, Boston, MA; †Botswana Harvard AIDS Institute, Bontleng, Gaborone, Botswana; ‡Princess Marina Hospital, Gaborone, Botswana; §Brigham and Women's Hospital, Infectious Disease Unit, Boston, MA; ∥Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA; ¶Botswana Ministry of Health, Health Inspectorate, Gaborone, Botswana; #Botswana Harvard PEPFAR Master Trainer Program, Gaborone, Botswana; **Infectious Disease Unit, Massachusetts General Hospital, Boston, MA; and ††Division of Infectious Diseases, Beth Israel Deaconess Medical Center, Boston, MA.
Received for publication June 16, 2009; accepted September 9, 2009.
Supported by Funding from the Doris Duke Charitable Research Foundation, through a Clinical Research Fellowship awarded to J.Y.C.
Presented in part as: Chen JY, Ribaudo H, Ogwu A, Svab P, Wester C, Tumbare E, Moffat H, Makhema J, Essex M, Shapiro RL. Risk factors for adverse pregnancy outcomes among HIV-infected women in Gaborone, Botswana. at the 16th Conference on Retroviruses and Opportunistic Infections, February 8-11, 2009, Montreal, Canada. Abstract 949.
No authors have a commercial or other association that might pose a conflict of interest (eg, pharmaceutical stock ownership, consultancy, advisory board membership, relevant patents, or research funding).
Correspondence to: Roger L. Shapiro, MD, MPH, Division of Infectious Diseases, Beth Israel Deaconess Medical Center, 110 Francis Street, Suite GB, Boston, MA 02215 (e-mail: firstname.lastname@example.org).
Background: Botswana has the most comprehensive public program in Africa for providing antiretroviral therapy to treat HIV and prevent mother-to-child transmission (PMTCT). Botswana guidelines prioritize CD4+ cell count testing during pregnancy and initiation of highly active antiretroviral treatment (HAART) for women who qualify for treatment. We analyzed rates of HIV testing, CD4+ cell count testing, and HAART initiation during pregnancy.
Methods: From October 2007 through June 2008, we reviewed obstetric and laboratory records of women at Princess Marina Hospital in Gaborone, Botswana.
Results: We recorded information from 3056 women. Of 2675 women eligible for the PMTCT program, 2623 (98%) had a documented HIV status, of whom 793 (30%) were HIV infected. Among women who were treatment naive at pregnancy conception, 397 (59%) had recorded CD4+ cell counts, of whom 62 (16%) had a CD4+ cell count <200 cells per cubic millimeter. Among this subset, 23 (37%) initiated HAART during pregnancy, 26 (42%) received zidovudine prophylaxis, and 13 (21%) received no therapy.
Conclusions: We observed low rates of CD4+ cell count testing and HAART initiation during pregnancy. Antenatal clinics should prioritize CD4+ cell count testing and referral of women who qualify for HAART to maximize benefits of maternal treatment and PMTCT.
The use of highly active antiretroviral therapy (HAART) has dramatically reduced the incidence of mother-to-child HIV transmission (MTCT) in regions of the world where it is available, and its use to prevent mother-to-child transmission (PMTCT) is widely regarded as one of the major medical breakthroughs in HIV prevention. The World Health Organization recommends the use of HAART as a combined treatment and PMTCT strategy for all pregnant women who require treatment for their own health.1 The benefits of this combined treatment and prevention strategy are clear among HIV-infected women with lower CD4+ cell counts. When maternal HAART is not available, the majority of maternal mortality and up to half of all MTCT may occur among those with CD4+ cell count below 200 cells per cubic millimeter.2-6 Unfortunately, this World Health Organization recommendation is rarely implemented in resource-poor settings: it is estimated that 11% of HIV-infected pregnant women in the developing world have access to antiretroviral drugs.7
In Botswana, where up to 32% of pregnant women are HIV infected8 and the majority of pregnant women access antenatal care,9 there exists an unique opportunity within Africa to implement the use of HAART as a combined treatment and PMTCT strategy. A successful national PMTCT program based on short-course maternal and infant zidovudine (ZDV) was established in 1999, with single-dose nevirapine added to the regimen in 2002. In 2004, routine noncompulsory (opt out) HIV testing was introduced, which resulted in dramatic increases in HIV testing rates.10 In 2002, a national antiretroviral treatment program was initiated for those with CD4 cell counts <200 cells per cubic millimeter or an AIDS-defining illness. This program was rapidly expanded across the country, and the Ministry of Health reported that by the end of December 2008, a total of 95,051 patients were receiving HAART.11,12 Recognizing the opportunity to maximize the benefits of HAART as a combined treatment and PMTCT strategy, Botswana PMTCT guidelines have prioritized CD4+ cell count testing during pregnancy and the rapid referral of women who qualify for treatment for HAART initiation at government treatment clinics since 2002.13,14
We sought to measure the rates of HIV testing, CD4+ cell count testing, and HAART initiation during pregnancy among women delivering at the largest public referral hospital in Botswana.
On a prospective basis, we identified women who delivered at a gestational age of 20 weeks or greater at Princess Marina Hospital (PMH) in the capital city of Gaborone. PMH is the main government referral center for southern Botswana, and approximately 85% of all births in Gaborone occur there. All pregnancies that ended between October 19, 2007, and June 30, 2008, were recorded. Data collection consisted of anonymous abstraction from obstetric records maintained in the postnatal maternity ward. Approval for this study was granted by human subjects committees in Botswana and at the Harvard School of Public Health.
Detailed demographic information included age, marital status, nationality, highest level of education obtained, parity, receipt of antenatal care, gestational age at first antenatal clinic visit, medical history, obstetrical risk factors, medications received during pregnancy, and HIV status. Among HIV-infected women, CD4+ cell count information was available from obstetric records. In addition, a computer database from PMH (which included all CD4s drawn at outlying government antenatal clinics in southern Botswana) was reviewed to identify CD4+ cell counts that were performed but not recorded in the obstetric records. We recorded antiretroviral drugs received during pregnancy from antenatal clinics and classified them as ZDV prophylaxis, HAART initiated during pregnancy, HAART continued from before the current pregnancy, or no antiretroviral therapy.
According to the government PMTCT guidelines at the time of the study, HIV-infected women with a CD4+ cell count <200 cells per cubic millimeter (changed to < 250 cells/mm3 in May 2008) or an AIDS-defining illness were eligible to receive HAART during pregnancy. HIV-infected women who did not meet criteria for HAART initiation (or if eligibility information was unknown) were recommended to initiate short-course ZDV prophylaxis. The PMTCT program recommends CD4+ cell count testing immediately after diagnosis of HIV infection, either onsite or at a referral center. The program is free for all Botswana citizens, and we calculated rates of HIV, CD4+ cell count testing, and HAART initiation during pregnancy among this subset of women eligible for the government PMTCT program. At the time of the study, a clinical trial was studying the efficacy of HAART for PMTCT among women with CD4+ cell counts ≥200 cells per cubic millimeter who did not qualify for HAART for maternal health. The study provided CD4+ cell count testing to determine eligibility. In addition, the trial included an observational group of women with CD4+ cell counts <200 cells per cubic millimeter for which study personnel ensured HAART initiation through the Botswana national program.
Statistical analyses were performed with the use of SAS, version 9.1 (SAS Institute, Cary, NC). All reported P values are based on 2-sided tests, and a P value of less than 0.05 was considered to indicate statistical significance. Differences between comparison groups were assessed using the χ2 test or Fisher exact test.
Between October 19, 2007, and June 30, 2008, we recorded data from 3056 deliveries at PMH at a gestational age of 20 weeks or greater. Based on data from the Botswana Ministry of Health, this represented approximately 80% of deliveries that occurred at PMH and 11% of deliveries that occurred in Botswana during the 8-month period (Moffat HJ, MBChB, PRCP, Personal Communications, May 2009).
Of the 3056 women who delivered at PMH, 2675 (88%) were citizens of Botswana. Table 1 shows the demographic information by HIV status for the 2675 Botswana citizens in our cohort. Statistical differences between HIV-infected and HIV-uninfected women were identified, but overall, the differences were small in magnitude. Ninety-nine percent of all citizens received antenatal care during their pregnancy. Women who were multiparous (P = 0.09) or received primary level or no education (P = 0.09) were more likely to have an unknown HIV status. Noncitizens comprised 11% of the total deliveries recorded at PMH, and Zimbabweans represented the majority of this subset (86%). Of the 331 noncitizens, 291 (88%) received antenatal care during their pregnancy.
In total, among the 2675 citizens who were eligible for the free PMTCT program, 2623 (98%) had a documented HIV status, of whom 793 (30%) were HIV infected (Fig. 1). Among the 758 HIV-infected women with a recorded testing date, 267 (35%) received a diagnosis of HIV before the current pregnancy and 491 (66%) tested positive during the current pregnancy.
Among 668 HIV-infected citizens who were treatment naive at the time of conception, 397 (59%) had a CD4+ cell count measured during pregnancy. Of the 397 women who received a CD4+ cell count during pregnancy, 102 (26%) received their CD4+ cell count screening through testing provided by the ongoing clinical trial (Shapiro RL, MD, MPH, unpublished data, May 2009). In the overall cohort of 668 HIV-infected treatment-naive women, 112 (17%) initiated HAART; 460 (69%) initiated ZDV for PMTCT; and 96 (14%) received no antiretroviral therapy during pregnancy.
The median CD4+ cell count was 382 cells per cubic millimeter (range 28-1481 cells per cubic millimeter, interquartile range: 260-536 cells/mm3) for women tested during pregnancy, and the median gestational age at the time of CD4+ cell count testing was 25 weeks (range: 0.1-43 weeks, interquartile range: 20-30 weeks). Women who were unemployed (P = 0.02) or who attended their first visit to an antenatal clinic at ≥20 weeks gestation (P = 0.02) were less likely to have a recorded CD4+ cell count during pregnancy. Of note, we did not observe limited access to other laboratory testing among this cohort of 668 HIV-infected treatment naive women: 601 (90%) had a measured hemoglobin value during pregnancy, similar to the rate observed in the overall study population.
Among the 397 treatment-naive HIV-infected women with a documented CD4+ cell count, 62 (16%) had a CD4+ cell count <200 cells per cubic millimeter and therefore qualified for HAART (Fig. 1). Of these 62 women, 23 (37%) initiated HAART for maternal health and PMTCT, 26 (42%) initiated ZDV for PMTCT, and 13 (21%) received no antiretroviral therapy during pregnancy. Women who attended their first visit to an antenatal clinic at ≥20 weeks were less likely to initiate HAART (P = 0.08).
By extrapolating the percentage of women with CD4+ cell counts <200 cells per cubic millimeter to the remaining 271 HIV-infected treatment-naive women without a documented CD4+ cell count during pregnancy, we estimated there to be an additional 40 women with a CD4+ cell count <200 cells per cubic millimeter. When we compared HIV-infected women who received a CD4 test with those who did not, we did not observe significant differences with respect to age, parity, educational background, marital status, alcohol use, and smoking. To calculate the excess MTCT from lack of HAART initiation, we assumed similar rates of receipt of HAART, ZDV, or no ART use as for those with documented CD4+ cell counts and estimated the following rates of MTCT at 1 month in this largely formula-feeding population: 1% for women receiving HAART during pregnancy15-17; 11% for women with CD4+ cell counts <200 cells per cubic millimeter receiving ZDV prophylaxis3,18-22; and 25% for women with CD4+ cell counts <200 cells per cubic millimeter receiving no therapy during pregnancy.15,17,22 By these estimates, approximately 9 excess infant HIV infections may have occurred at PMH among these 668 HIV-infected treatment-naive women during this 8-month period because of the lack of HAART initiation during pregnancy (Fig. 2).
As an additional analysis, we calculated rates of HIV testing, CD4+ cell count testing, and HAART initiation among the subset of noncitizens who delivered at PMH. Of 331 noncitizens, 217 (66%) had a documented HIV test, of whom 50 (23%) were HIV infected and treatment naive. Among the 50 noncitizens, only 2 (4%) had a recorded CD4+ cell count during pregnancy, of whom 1 had a CD4+ cell count <200 cells per cubic millimeter (and did not receive antiretroviral drugs).
We evaluated HIV testing, CD4+ cell count testing, and HAART initiation during pregnancy at the largest maternity ward in Botswana. Our study supports previous findings of excellent HIV testing rates during pregnancy, but reveals the need for improved CD4+ cell count testing and antenatal HAART initiation among eligible women.
The HIV testing rate of 98% was high and consistent with data previously reported.10 The success of HIV testing during pregnancy has been attributed to the introduction of optout testing; integration of PMTCT into existing maternal and child health services; and expansion of government-sponsored HIV care and treatment facilities.10,23 Of note, recent data from Botswana revealed an HIV incidence rate of 1.3% during pregnancy,24 and in 2008, the Ministry of Health adopted the policy of retesting at or after 36 weeks or at delivery (Moffat HJ, Personal Communications, 2009).
We identified CD4+ cell counts performed during pregnancy among 59% of the HIV-infected treatment-naive women. One reason for the lack of CD4+ cell count testing was a reagent shortage that occurred from October 2007 to November 2007. We have observed additional structural barriers, including poor access to transportation, lost or insufficient specimens, and limited access to phlebotomy services, that may also account for some of the missing tests. In addition, missing tests may have occurred because of lack of referral, refusal of testing, or the inability to perform CD4+ cell count testing before delivery occurred. Although it is possible that additional CD4+ cell count testing occurred but was not recorded on the obstetric cards, we attempted to identify all samples by utilizing a laboratory database. We therefore believe that most missing CD4+ cell counts in this study were never drawn.
Of equal concern was the more definitive evidence for missed opportunities to initiate HAART among women with documented CD4+ cell counts <200 cells per cubic millimeter. This finding suggests difficulty in implementing government recommendations to start HAART during pregnancy for maternal health and for PMTCT. Although this study was unable to capture the reasons for not initiating HAART, possible reasons include delay in the receipt of CD4+ cell count results, delay in or lack of referral to the ART clinic, delay in starting HAART due to complex initiation procedures, or patient unwillingness to take HAART.
We observed lower rates of HIV testing, CD4+ cell count testing, and HAART initiation among noncitizens, which were not unexpected given their overall lower access to antenatal care and their limited access to free PMTCT services. In Botswana, noncitizens are eligible for free HIV testing during pregnancy at Voluntary Counseling and Testing Centers that are available in all population centers, but they are not eligible for free testing at health facilities. Noncitizens are also ineligible to receive free CD4+ cell count testing or free antiretroviral drugs (including ZDV prophylaxis and HAART) during pregnancy from the antenatal clinics.
The study had several limitations. First, the collection of data consisted of anonymous extraction at delivery, and we were unable to account for missing data or to record exact MTCT rates. We were unable to assess the rate of testing and referral among women who delivered at home (a group estimated to be approximately 5% of the population23) or in the private sector. In addition, we report data collected at a referral hospital in Gaborone, which differs from the other maternity clinics in volume and in the complexity of cases (all obstetric and neonatal complications that occur at the district maternity clinics are referred to PMH). However, surveillance at smaller maternity clinics in Gaborone and at a large district hospital near Gaborone revealed similar patterns of antiretroviral use during pregnancy (data not shown). Our estimation of the number of HIV-infected infants that resulted from the missed opportunity to initiate HAART may be inexact, as it is based on extrapolations of treatment patterns from the group of women with documented CD4+ cell counts and on MTCT rates reported for women with CD4+ cell counts <200 cells per cubic millimeter in the literature and in a recent clinical trial in Botswana. We did not capture differences in rates of CD4+ cell count testing and HAART initiation by antenatal clinic site and we had limited ability to identify clinical reasons for CD4+ cell count testing (eg, presence of clinical illness), and thus we could not account for potential selection biases that may have been present in this cohort. Finally, rates of CD4+ cell count testing and HAART referral may have been artificially higher during this study period because of an ongoing clinical trial that provided CD4+ cell count testing and rapid initiation of HAART for those who qualified for maternal treatment.
In summary, the high HIV testing rate and overall success of the PMTCT and antiretroviral therapy programs in Botswana create a unique opportunity for Botswana to be the first country in Africa to provide HAART to large numbers of pregnant women requiring treatment. As the first free PMTCT program in Africa, the Botswana program has achieved widespread success through strong political commitment, expansion of HIV care and treatment services, and increasing availability of rapid HIV testing. However, we identified low rates of CD4+ cell count testing and HAART initiation during pregnancy. Improvements to the current strategy for rapid CD4+ cell count testing and HAART referral may be needed for this selected population of HIV-infected women to maximize the benefits of HAART for maternal and infant health.
We gratefully acknowledge the contribution of our research assistants, Kelebogile Binda, Rehanna Matsebe, Koziba Malibala, and Aboleleng Ditsheko, and the nurses, counselors, obstetricians, pediatricians, and superintendents who worked at PMH. We are also grateful for the administrative support provided by the Botswana Harvard AIDS Institute and the statistical assistance provided by Marcus Bachhuber (CDC/BOTUSA). We are grateful to the institutional review boards at the Health Research Unit in the Botswana Ministry of Health, Harvard Medical School, and Harvard School of Public Health for reviewing this study.
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Botswana; CD4+ cell count testing; HAART initiation; pregnancy
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