Modeling of In-Utero and Intra-Partum Transmissions to Evaluate the Efficacy of Interventions for the Prevention of Perinatal HIV

Abstract

Background: Antiretroviral treatments decrease HIV mother-to-child transmission through pre/post exposure prophylaxis and reduction of maternal viral load. We modeled in-utero and intra-partum HIV transmissions to investigate the preventive role of various antiretroviral treatments interventions.

Methods: We analysed data from 3,759 women-infant pairs enrolled in 3 randomized clinical trials evaluating (1) zidovudine monotherapy, (2) zidovudine plus perinatal single-dose nevirapine or (3) zidovudine plus lopinavir/ritonavir for the prevention of mother-to-child transmission of HIV in Thailand. All infants were formula-fed. Non-linear mixed effect modeling was used to express the viral load evolution under antiretroviral treatments and the probability of transmission.

Results: Median viral load was 4 log10 copies/mL (Interquartile range: 3.36-4.56) before antiretroviral treatments initiation. An Emax model described the viral load time-course during pregnancy. Half of the maximum effect of zidovudine (28% decrease) and lopinavir/ritonavir (72% decrease) were achieved after 98 and 12 days, respectively. Adjusted on viral load at baseline (Odds ratio = 1.50 [95% confidence interval: 1.34, 1.68] per log10 copies/mL increment), antiretroviral treatments duration (OR = 0.80 [0.75, 0.84] per week increment) but not the nature of antiretroviral treatments were associated with in-utero transmission. Adjusted on gestational age at delivery (<37 weeks, OR = 2.37 [1.37, 4.10]), baseline CD4 (Odds ratio = 0.79 [0.72, 0.88] per 100 cells/mm3 increment) and predicted viral load at delivery (OR = 1.47 [1.25, 1.64] per log10 copies/mL increment), single-dose nevirapine considerably reduced intra-partum transmission (OR = 0.32 [0.2, 0.51]).

Conclusion: These models determined the respective contributions of various antiretroviral strategies on prevention of mother-to-child transmission. This can help predict the efficacy of new antiretroviral treatments and/or prevention of mother-to-child transmission strategies particularly for women with no or late antenatal care who are at high risk of transmitting HIV to their offspring.

Trial registration: This analysis is based on secondary data obtained from three clinical trials. ClinicalTrials.gov. NCT00386230, NCT00398684, NCT00409591.

Conflict of interest statement

Competing Interests: The author BA is employed by Laser ANALYTICA. However, this company does not work on HIV, and did not sponsor this research. This does not alter the authors' adherence to all PLOS ONE policies on sharing data and materials.

Figures

Fig 1. Population disposition.

Fig 2. Diagnostic plots for viral load time-course model.

Top: 2a and 2b: Observed versus model predicted viral load values (expressed as log10 copies) of the population and individual predictions respectively. Solid black circles, measure values; grey symbols, simulation of below the limit of quantification data. Line, identity line. Bottom: Visual predictive check plots. (2c) Women receiving only zidovudine (ZDV); (2d) women receiving zidovudine plus lopinavir/ritonavir (ZDV+LPV/r).The lines denote the median, 5th and 95th percentiles for the observed data. The grey areas stand for the 95% confidence intervals of the median, 5th and 95th model prediction percentiles.

Fig 3. Transmission probabilities according to zidovudine duration, viral load at baseline/delivery, and nevirapine intake.

A. Probability of in-utero HIV transmission as a function of zidovudine duration; B. Probability of in-utero HIV transmission as a function of viral load at baseline. The lines denote the median, 5th and 95thpercentiles of the model predictions. The open circles stand for the observed mean proportion of transmission, the solid vertical segments denote the corresponding 95% confidence intervals (numbers at top of each segment stand for the number of women in each time interval or VL interval). C. Probability of intra-partum HIV mother-to-child transmission as a function of viral load at delivery without single dose nevirapine; D. Probability of intra-partum HIV mother-to-child transmission as a function of viral load at delivery with single dose nevirapine.