The probabilities of peripartum and postnatal MTCT of HIV according to ARV regimen and maternal CD4 count among women with prevalent infection and among women with incident infection were reviewed for a meeting that aimed to update modelling approaches and assumptions used in Spectrum that was held in Washington, DC, September 2010. A process to agree on estimates of transmission probability was agreed by the authors following a critical review of available evidence. While the initial meeting was held in September 2010, data from studies reported in peer-reviewed journals from 1990 until the beginning of 2012 were considered for inclusion.
Studies included in the analysis
Data used for this analysis included published literature, conference presentations and data from personal communication with researchers when data were not otherwise available. The authors reviewed these data for quality, internal consistency and relevance. Data from randomised studies were prioritised but cohort and observational data were also included providing the reports indicated rigorous study methods, appropriate sample sizes and provided direct transmission estimates from relevant study populations. Details of these reports are summarised in an annotated bibliography (see working paper in online supplementary appendix).
Definitions and assumptions underlying estimates of HIV transmission probabilities
Peripartum HIV transmission reflects combined in utero and intrapartum transmission and is measured by HIV status of infants at 4–6 weeks of age. It assumes no additional early transmission due to breast feeding. In non-breastfed infants, HIV status of infants at 4–6 weeks or any time thereafter would represent peripartum transmission. In breastfed infants, any additional transmission that occurs after 6 weeks of age would be regarded as postnatal transmission and attributable to breast feeding.
Postnatal HIV transmission reflects infections in infants or children who were HIV uninfected through pregnancy and delivery (identified through a negative HIV test at 4–6 weeks) and who subsequently become HIV-infected while breast feeding.
Postnatal transmission rates captured for each study were either those directly reported by investigators, even if the age at which peripartum transmission was measured differed between studies namely 2, 4, 6 or 8 weeks post partum, or were calculated from data included in the reports. Some investigators reported point or cumulative transmission at birth, 6 weeks and other postnatal time points such as 3, 6, 12 and 18 months. In these situations, HIV transmission due to breast feeding was estimated by subtracting HIV infections (or transmission rates) among 6-week-old HIV-exposed infants from HIV infections (or transmission rates) among HIV-exposed breastfeeding infants identified any time thereafter.
Depending on data provided, monthly postnatal transmission probabilities were calculated by dividing the cumulative transmission per cent measured over a particular time interval by the number of months in that time period minus 4 weeks. Four weeks was deducted from the breastfeeding exposure period as HIV DNA laboratory assays only reliably detect infections that occur up to about 4 weeks prior to measurement. For example, if transmission was measured at 6 months, then the breastfeeding exposure period was deemed to be 1 month less, or 5 months. If the transmission rates at 6 weeks and 6 months were 5% and 8.5%, respectively, then 3.5% HIV transmission would be attributed to 5 months of breast feeding, or 0.7% per month of breast feeding.
Alternatively, if studies reported the median breastfeeding period as less than the time at which HIV status was determined, then the cumulative transmission per cent by the time of measurement was divided by the median duration of breast feeding. For example, if postnatal transmission was estimated to be 9% at 12 months with a median breastfeeding period of 7 months, then the monthly transmission probability associated with breast feeding would be 9/7=1.29% per month of breast feeding.
This simple, and easily applied, calculation does not account for the conditional probability of postnatal infection, for example, the conditional probability that the child is not infected in the previous month or at birth, which will have a significant impact when multiplied over several months of exposure or to large probabilities. Spectrum currently only includes two decimal spaces of accuracy for the monthly transmission probabilities. Thus, a more accurate calculation (see example in footnoteii
) would have no impact on the overall rates in the current model.
Incident infection refers to newly acquired infections in pregnant or lactating women. Methods used for identifying these women were different between studies and the investigators’ approach for inclusion of this population was accepted. Incident infection was usually identified through seroconversion of women who previously tested negative for HIV. Transmission probabilities were not disaggregated by maternal CD4 count as, although women with incident infection have high viral load similar to women with longstanding HIV infection, their CD4 counts are not depleted in the early stages of infection.
We did not estimate a monthly transmission probability for lactating women with incident HIV infection as the reported high risks of transmission, associated with high viral load in mothers during primary viraemia, may only be present for 1–2 months. It was considered inappropriate to apply an average monthly probability over a duration of breast feeding, whether long or short, within a model.
were defined according to WHO recommendations that were valid at the time of respective studies. The term WHO 2006 dual prophylaxis
is applied to a range of ARV interventions that were included in the recommendations at that time. This included settings in which breast feeding was the dominant infant feeding practice and also settings where replacement feeding (formula feeds) were the default recommendation. It also includes settings where single dose nevirapine may or may not have been given to infants in the immediate postnatal period (within 72 h). While not included in WHO recommendations at that time,7
this practice was reported in some studies.
Any breast feeding includes exclusive, predominant and partial breast feeding (mixed breast feeding=predominant and partial breast feeding). No attempt to further disaggregate was made given limitations in the data.
Estimating HIV transmission probabilities
The median peripartum and postnatal transmission probability and ranges for each ARV regimen and CD4 count were determined from reported data. Exceptions to this approach are separately presented and justified. In some instances, the median value was overruled based on other considerations and in these situations the rationale is outlined. The transmission probabilities were not weighted by the size of the study as each study had its own limitations.
When reports presented transmission probabilities separately for mothers with CD4 counts 350–500 cells/ml and >500 cells /ml, these probabilities were averaged and included as the transmission probability for women with CD4 counts >350 cells/ml. This concept was applied similarly in some instances for other grouped ranges of CD4 counts (see online supplementary table 1).
For the purposes of Spectrum it was not necessary to calculate the transmission probabilities for different CD4 distributions for single dose nevirapine (sdNVP) and WHO 2006 dual ARV regimens as these interventions will only be applied to historical populations without reference to CD4 counts when disaggregated data by CD4 distributions were not generally available. Options A and B were only recommended for women with CD4 counts of 350 or higher and thus probabilities for those scenarios were estimated. Although not recommended by WHO for women with CD4 counts below 350 cells/ml, a transmission probability is included for Option A in this population because (i) those data were available from some reports and (ii) some countries were providing Option A to this population before revisions of national guidelines (ie, criteria for ART from a CD4 count of <200 to <350) and (iii) in settings where CD4 testing is not routinely available, some women with lower CD4 counts may only receive this intervention.
Monthly postnatal transmission probabilities were not estimated for a population where CD4 count is ‘not specified’ (as presented in the first column of for Peripartum transmission). For modelling postnatal transmission in populations where data on maternal CD4 counts are not known, such as historical cohorts, then assumptions can be made on the distribution of CD4 counts in these populations and an average transmission probability is secondarily estimated and attributed. Since 2011 Spectrum assumes a CD4 distribution among pregnant women to determine which transmission probability will be applied during breast feeding.
Summary of transmission probabilities by antiretroviral regimen and maternal CD4 count
Separate monthly postnatal transmission probabilities were not estimated for populations receiving sdNVP or WHO 2006 dual prophylaxis as it was assumed that, although both regimens provide an ARV to infants postnatally, neither is considered to have substantial impact on postnatal transmission through breast feeding.