Serum Level of Maternal Human Immunodeficiency Virus (HIV) RNA, Infant Mortality, and Vertical Transmission of HIV in Zimbabwe
Mục lục
Abstract
Maternal human immunodeficiency virus (HIV) RNA load, vertical transmission of subtype C HIV, and infant mortality were examined in 251 HIV-seropositive women and their infants in Zimbabwe. Demographic characteristics, health and medical histories, serum HIV RNA loads, and CD4+ lymphocyte counts for mothers were examined by logistic regression analysis to determine significant risk factors and their odds ratios for transmission and infant mortality. Tenfold (1 log10) incremental increases in maternal HIV RNA were associated with a 1.9-fold increase (95% confidence interval [CI], 1.2–2.9) in transmission and a 2.1-fold increase (95% CI, 1.3–3.5) in infant mortality (P < .01). Maternal CD4 cell counts and demographic and medical characteristics were not significant predictors of transmission. However, maternal CD4 cell counts below the median (400/mm3) were significantly associated with infant mortality (P = .035, Fisher’s exact test). The maternal level of serum HIV is an important determinant of vertical transmission and infant mortality in subtype C infection in Zimbabwe.
In sub-Saharan Africa, the increasing prevalence of human immunodeficiency virus (HIV) infection among women and the subsequent mother-to-child transmission of disease are having a profound effect on child survival. HIV infection rates among infants born to seropositive women in Africa range from 16% to 150% [1]. In Zimbabwe, recent studies show that > 30% of women of childbearing age attending antenatal care clinics in the capital city of Harare are HIV seropositive [2, 3]. Infant mortality due to HIV infection has reversed many of the gains in child survival that were achieved in recent decades. In Harare, which had an infant mortality rate of < 15/1000 before the HIV epidemic, it is now expected that infant mortality will increase at least 5-fold to 75/1000 because of HIV infection among women and reduced survival of children born to infected women [1, 3].
Mother-to-child transmission of HIV infection in the United States and Europe has been associated with lower maternal CD4+ cell counts, prolonged rupture of membranes, and high levels of maternal HIV plasma RNA [4–8]. Among HIV-infected infants in the United States and Europe, up to 50% develop AIDS within the first 5 years of life, with a median survival of 9.4 years [9, 10]. In sub-Saharan Africa, rates of infant mortality may approach 50% in the first 2 years of life among infants born to HIV-seropositive women [11–13]. In a study of > 300 infants born to seropositive women in Harare, almost 20% died before 2 years of age, and 70% of these infants had evidence of HIV infection prior to death. Among 27 infants for whom samples were available from their first day of life, 19 (70%) had evidence of in utero infection [14]. Additional studies of infants born to HIV-seropositive women in Zimbabwe suggest that most of those ultimately infected have evidence of HIV infection at birth [15]. Increasing rates of infant mortality, associated with an increasing prevalence of HIV among adults, including childbearing women, is expected to reduce population growth and will lead to a net decline in population in countries hardest hit by the AIDS pandemic [16].
In the AIDS Clinical Trial Group (ACTG) 076 study [17] and a recent study of short-course zidovudine in Thailand [18], treatment of women with zidovudine reduced infection among infants by 66% and 50%, respectively. In both settings, risk of transmission was increased among women with higher virus loads. In the ACTG 076 study, only a small fraction of the decline in mother-to-infant transmission following zidovudine therapy was explained by a decrease in maternal viremia, whereas among Thai women, prenatal zidovudine treatment resulted in a mean 0.5-log (70%) decrease in maternal virus load in the 4 weeks prior to delivery [19, 20]. The significance of maternal virus load and the optimal use and timing of antiretroviral drugs to reduce transmission of HIV from women to their infants have not been clearly defined.
In sub-Saharan Africa, non-subtype B viruses, particularly subtypes A, C, and D, account for the majority of HIV-1 infections. In Zimbabwe and much of southern Africa, HIV infection is predominantly due to subtype C virus [21]. Patterns of mother-to-child transmission among women with non-subtype B infection have not been well described. In this study, risk factors for mother-to-child transmission of HIV and infant mortality in a cohort of mothers and infants in Zimbabwe, before the introduction of antiretroviral drugs, were studied to determine the impact of maternal HIV RNA load and postpartum CD4+ cell count on mother-to-child transmission of HIV and on child survival.
Methods
Subjects
Pregnant women were enrolled in a World Health Organization-sponsored study of perinatal HIV transmission, which was conducted from 1991 through 1995. A total of 367 HIV-positive women consented to participate at their first antenatal visit at three polyclinics in Harare, Zimbabwe. Serum samples from 36 weeks of gestation were available for 251 (67%) of the 367 women, and postpartum CD4+ cell counts were obtained for 121 (48%) of the 251 women. Heel-prick blood samples were obtained from neonates within 1 day of birth and at 2, 4, 6, and 14 weeks; thereafter, they were obtained at 12-week intervals at regular clinic visits.
Serum HIV RNA measurements
HIV RNA concentrations were measured in serum samples obtained at gestational age of 36 weeks from 291 women (251 from the HIV-seropositive women plus 40 seronegative samples). Sera were separated and stored at −70°C within 6 h of collection. HIV RNA was determined by use of the Amplicor Monitor 1.0 assay (Roche Diagnostics, Branchburg, NJ). Values < 2.6 log10 (400 copies/mL) were considered below the level of detection according to the test kit manufacturer’s instructions, and values > 400 copies/mL were log-transformed for analysis.
CD4+ lymphocyte measurements
CD4+ and CD8+ cells were enumerated in whole blood samples from 121 of the seropositive women 6–12 months after delivery, when a flow cytometer (FACSCount; Becton-Dickinson, Mountain View, CA) was introduced for CD4+ cell determinations. The 121 women with CD4+ results were among the 251 seropositive women for whom predelivery serum samples were available. Results were reported as CD4+ cells per cubic millimeter, with a lower limit of quantification of 50 cells/mm3.
Statistical analysis
HIV RNA levels, measured in copies per milliliter, and CD4+ cell numbers per cubic millimeter were transformed into log10 values to generate odds ratios (ORs) with logistic models; all calculations were carried out on log-transformed values. Women with < 50 CD4+ cells/mm3 were assigned a value of 49 for determination of mean and geometric mean (GM) values. The HIV RNA levels were normally distributed and ranged from 2.6 to 6.0 log10 (400–1,000,000) copies/mL. Mothers who were positive for HIV (as determined by ELISA) and who had < 400 HIV RNA copies/mL (as determined by polymerase chain reaction [PCR]) were assigned a value of 2.3 log10 (200) copies/mL. The 233 women with > 400 copies/mL were arranged into 4 quartile groups on the basis of serum HIV RNA values: group 1, ⩾2.6–3.6 log10 (400–4000) copies/mL; group 2, > 3.7–4.2 log10 (> 4000–15,840) copies/mL; group 3, > 4.2−4.6 log10 (15,840−39,800) copies/mL; and group 4, > 4.6−5.93 log10 (39,800–851,140) copies/mL. ORs were calculated, with group 1 as the reference to which each group was compared. ORs, confidence intervals (CIs), frequency tables, and general statistics were generated by use of computer programs (SAS, Cary, NC, and Epi-Info version 5; Centers for Disease Control and Prevention, Atlanta).
Results
Mortality and transmission rates
Among the 251 children born to HIV-seropositive mothers, there was an infant mortality rate of 19% (47 deaths) and a mother-to-child transmission rate of 17% (35 of the surviving 204 infants were HIV seropositive after 15 months of age). HIV DNA PCR analysis of blood samples from the 47 children who died revealed that 32 (68%) had evidence of HIV infection and 15 (32%) had negative results twice before death [14].
Overall, 67 (27%) of the 251 children became infected. Maternal demographic characteristics and infant outcomes were similar for the 367 seropositive women, the 251 with samples available for HIV RNA assays, and the subset of 121 (48%) of the 251 with postpartum CD4+ cell counts (table 1).
Table 1
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Characteristics for a cohort of 367 HIV-seropositive Zimbabwe women, a subset of 251 of the women for whom HIV RNA levels from 36 weeks of gestation were available, and a subset of 121 of the 251 women for whom postpartum CD4+ cell counts were obtained.
Maternal HIV RNA levels
HIV RNA levels > 400 copies/mL were detected in sera from 233 (93%) of the 251 HIV antibody-positive women but in none of the samples from 40 seronegative women. All 35 women whose children were HIV positive as determined by ELISA and alive at 2 years and 47 women whose children died in the first 2 years of life had serum HIV RNA levels > 400 copies/mL. GM serum HIV RNA levels among transmitters (4.4 ± 0.58 log10 copies/mL) and among women whose children died (4.3 ± 0.73 log10 copies/mL) were significantly greater than the GM value among 169 women who did not transmit HIV (4.1 ± 0.69 log10 copies/mL; P = .003 and .04, respectively).
HIV transmission and maternal HIV RNA levels
Of the 251 HIV-seropositive women, 67 (27%) transmitted virus to their children (transmitters), and 184 (73%) did not transmit virus (nontransmitters). Within the group of women with HIV RNA levels > 4.6 log10 copies/mL, 24 (41%) of 59 transmitted HIV infection to their infants, compared with 6 (11%) of 55 women with the lowest detectable HIV RNA levels (2.6–3.7 log10 copies/mL; table 2). The GM level of serum HIV RNA among transmitters (4.4 log10 ±0.58 copies/mL) was significantly greater than the level for nontransmitters (4.1 log10± 0.69 copies/mL; P = .003).
Table 2
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Relationship of maternal levels of serum HIV RNA to mother-to-child HIV transmission and infant mortality, Zimbabwe.
Among the 204 seropositive women whose children were alive 2 years after birth, 35 (17%) were transmitters and 169 (83%) were nontransmitters. ORs for transmission were significantly greater among the women with higher serum loads of HIV RNA. The GM HIV RNA level among transmitters (4.32 log10 ±0.68 copies/mL) was significantly higher than that among nontransmitters (4.06 log10 ±0.49 copies/mL; P = .03).
Infant mortality and maternal HIV RNA levels
Among the 251 infants, 47 (19%) died, primarily due to respiratory infection, and 204 (81%) were alive after 2 years [14]. The overall risk for mortality within the first 2 years of life was increased by 2.1 (95% CI, 1.3–3.5; P< .01) for every log10 increase in maternal HIV RNA. However, when stratified according to maternal virus load, the ORs for infant mortality were significantly greater only for children of women with the highest levels of HIV RNA (group 4; OR, 3.52; CI, 1.24–10.30; P = .008); infant mortality levels were relatively similar for children of mothers with lower levels of HIV RNA (table 2). The GM level of serum HIV RNA was significantly higher in women whose children died (4.34 ± 0.73 log10 copies/mL) compared with levels in women whose children survived (4.11 ± 0.65 log10 copies/mL; P = .04). Of the 47 seropositive mothers whose children died, 15 (32%) were nontransmitters, and 32 (68%) were transmitters. The GM level of HIV RNA among women whose children died with evidence of HIV transmission was 4.4 ± 0.67 log10 copies/mL, which was not significantly different from levels in women whose infants died without evidence for transmission (4.2 ± 0.86 log10 copies/mL; P = .44).
CD4+ lymphocytes
Postpartum CD4+ cell counts were obtained for 121 women. The characteristics and outcomes among these women were similar to those in the larger group of 251 mothers (table 1). Maternal CD4+ counts were not normally distributed. Mean CD4+ cell counts were skewed by a small number of high CD4+ cell counts, and results < 50 cells/mm3 were censored. Thus, log-transformed and GM log CD4+ cell counts were used to compare CD4+ cell counts for 95 non-transmitting and 26 transmitting mothers (table 3). Mothers with CD4+ cell counts above or below the median value (390 CD4+ cells/mm3) had nearly equal rates of transmission (15/60 vs. 11/61, respectively). However, GM CD4+ lymphocyte numbers were significantly lower among 17 mothers of infants who died, compared with 104 mothers with infants who survived (P = .035), and mortality was significantly greater among infants born to women with CD4+ cell counts below the median value (13/60 vs. 4/61; P = .02, Fisher’s exact test).
Table 3
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Mean and geometric mean (GM) log-transformed CD4+ cell counts for 121 HIV-seropositive mothers who did or did not transmit virus to their infants and whose infants died or survived, Zimbabwe.
Logistic regression models, using mortality or transmission as an outcome, were used to examine CD4+ cell counts above and below the median value. The model for mortality demonstrated an OR of 3.3 (95% CI, 1.2–8.9; P = .02) for mortality associated with a CD4+ cell count below the median, whereas the OR for transmission was 1.4 (95% CI, 0.6–2.8; P = .35). Multivariate proportional hazards models were constructed with maternal values for virus load and CD4+ cell counts (each included in the models as log10 values). These demonstrated a significant association between virus load and transmission (OR, 3.04; 95% CI, 1.6–5.8; P = .0007). When mortality was used as an outcome, only lower CD4+ cell counts were significantly associated with infant mortality (OR, 11; 95% CI, 1.5–8.4; P = .02).
Maternal and obstetric characteristics
Demographic, medical, and obstetric variables that were examined by regression analysis were not associated with either transmission or mortality at levels of significance < .1. The onset of labor and rupture of membranes were recorded by date, and thus precise duration could not be determined. We specifically examined the rates of transmission associated with the mode of delivery as recorded for 242 women. Cesarean section was performed in 20 women (8.3%), usually after prolonged labor without progress or because of breech presentation. Eight (40%) of 20 infants delivered by cesarean section were infected with HIV, compared with 59 (27%) of 222 infants delivered vaginally (P = .2, Fisher’s exact test).
Discussion
In this study, maternal HIV RNA load predicted mother-to-child transmission of infection and mortality among infants born to HIV-seropositive women in Zimbabwe. For every 10-fold increase in maternal HIV RNA, there was a 2-fold increase in risk for mother-to-child transmission. The clinical ramification of this observation is that 91% (61/67) of transmission events occurred in mothers with > 5000 HIV RNA copies/mL serum. Similarly, infant mortality increased 2-fold for every 10-fold increase in maternal HIV RNA. Overall, 34% of children born to women with virus loads of > 40,000 HIV RNA copies/mL died within 2 years, nearly 3 times the death rate (13%) among children born to women with < 4000 copies/mL. Multivariate models including CD4+ cell numbers suggest that the level of maternal HIV RNA is independently associated with transmission, whereas lower (postpartum) maternal CD4+ cell counts are significantly associated with infant mortality.
The high rate of mortality (20%) among infants born to HIV-infected women in Zimbabwe may be attributed, in part, to in utero transmission of HIV, as suggested by HIV DNA PCR evidence of infection at birth in many of the infants [14, 15]. There were few cases of documented perinatal and late (breast-feeding—associated) acquisition of infection; therefore, we could not evaluate timing of transmission in relation to maternal virus load and CD4+ cell count. Increased maternal HIV RNA levels and low CD4+ cell numbers, independent factors in risk of disease progression in adults and children [22-25], were associated with an increased risk for infant mortality in Zimbabwe. Progression of HIV infection in women may limit the care and nutritional support mothers can provide for their children, increasing the risk among infants for infection and mortality. Supportive postpartum care and treatment for HIV-infected women and their infants may be an additional intervention to increase child survival.
Studies in the United States have shown significant differences in HIV RNA levels of > 0.5 log (70%) between transmitting and nontransmitting women, with a risk ratio of ∼2 for each 10-fold increase in maternal HIV RNA [7, 8, 24, 25]. However, the significance of measurements of plasma or serum HIV RNA in mother-to-child transmission may depend on the sensitivity of the laboratory method used, the geographic origin of women, and subtype(s) of HIV infection. In subtype B infection, PCR amplification with the Amplicor Monitor test (Roche Diagnostics) provides for detection and quantitation of virus [26, 27]. Among some non-B HIV-1 subtypes, sequence diversity may reduce the efficiency of detection and quantification of viral RNA with assays that use reverse transcription and PCR amplification or hybridization [28, 29]. A striking example of this comes from a study including HIV-positive pregnant women from France and Africa [30]. In this study of maternal virus load and transmission, African women had significantly lower serum and plasma HIV RNA measurements. However, this finding is likely specific to subtype A virus, the predominant subtype among women of African origin in France [31] and the subtype that has presented the greatest difficulty for PCR-based assays.
A significant limitation of this study is the lack of precise information on timing of rupture of membranes and length of labor. Duration of ruptured membranes, in particular, has been shown to be important in other studies of vertical transmission of HIV [4, 32]. We observed a high rate of transmission (40%) among women with prolonged labor and rupture of membranes who underwent emergency cesarean section, providing further evidence for transmission in association with prolonged rupture of membranes.
The association between outcome in infants and maternal virus load in this study may be particularly important as antiretroviral drugs are introduced for prevention of mother-to-child transmission of HIV. Increased potency of antiretroviral drugs administered to mothers may be expected to reduce both maternal virus load and mother-to-child transmission of HIV. Subtype C viruses are susceptible to zidovudine and other antiretroviral drugs [33, 34]; however, the activity of short-course zidovudine on maternal virus load and on mother-to-child transmission in sub-Saharan Africa has not been reported. Further studies, including measurement of maternal HIV RNA in response to antiretroviral drugs, may provide more direct information on the role of maternal viremia in mother-to-child transmission of HIV and direct effective treatment of HIV-positive pregnant women and their infants.
Note Added in Proof
Since the submission of the manuscript, there have been several important study results that provide additional information on the relationship between maternal viremia, vertical transmission, and the efficacy of zidovudine in the reduction of vertical transmission. These include two publications from studies in Thailand that provide more extensive data on maternal virus load and vertical transmission of HIV [1] and an expanded analysis of the effects of zidovudine treatment on maternal virus load and transmission [2]. Recent studies from Africa, in the Ivory Coast and Burkina Faso, provide evidence for a significant effect of zidovudine on vertical transmission in breast-feeding African women [3, 4].
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Author notes
© 1999 by the Infectious Diseases Society of America
