Antiviral Therapy 2016; 21: (doi: /IMP3001)

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1 Antiviral Therapy ; : (doi:.8/imp) Short communication Contribution of different antiretroviral regimens containing zidovudine, lamivudine and ritonavir boosted lopinavir on HIV viral load reduction during pregnancy Patumrat Sripan,,, Sophie Le Coeur,,, Lily Ingsrisawang *, Tim R Cressey,,, Naïm Bouazza,8, Frantz Foissac,8, Nicole Ngo-Giang-Huong,,, Patrinee Traisathit 9, Ussanee Srirompotong, Orada Patamasingh Na Ayudhaya, Achara Puangsombat, Jantana Jungpipun, Kanokwan Jittayanun, Jean-Marc Tréluyer,8,, Gonzague Jourdain,,, Marc Lallemant, Saïk Urien,8, Department of Statistics, Faculty of Science, Kasetsart University, Bangkok, Thailand Institut de Recherche pour le Développement (IRD) UMI -PHPT, Marseille, France Ecole Doctorale de Santé Publique, Université Paris Saclay, Paris, France Department of Medical Technology, Faculty of Associated Medical Science, Chiang Mai University, Chiang Mai, Thailand Institut d Etudes Démographiques, Paris, France Harvard TH Chan School of Public Health, Boston, MA, USA EAU8 Université Paris Descartes, Sorbonne Paris Cité, Paris, France 8 Unité de Recherche Clinique Necker Cochin, AP-HP, Hôpital Tarnier, Paris, France 9 Department of Statistics, Faculty of Science, Chiang Mai University, Chiang Mai, Thailand Khon Kaen Hospital, Khon Kaen, Thailand Nopparat Rajathanee Hospital, Bangkok, Thailand Samutprakarn Hospital, Samutprakarn, Thailand Fang Hospital, Chiang Mai, Thailand Health Promotion Center Region, Chiang Mai, Thailand CIC9 INSERM, Cochin-Necker, Paris, France *Corresponding author fscilli@ku.ac.th Contributed equally to this work Background: Antiretroviral (ARV) regimens used for the prevention of mother-to-child transmission of HIV have evolved over time. We evaluated the contribution of different ARV regimens on the reduction of the plasma HIV RNA viral load (VL) during pregnancy. Methods: A total of,8 VL measurements from ARVnaive pregnant women participating in perinatal prevention trials in Thailand were included. Women received either zidovudine (ZDV) monotherapy, ZDV plus lopinavir/ritonavir (LPV/r), or ZDV plus lamivudine (TC) plus LPV/r. VL time-course during pregnancy was described as a function of pretreatment VL and treatment duration using an E max non-linear mixed-effect model. VL reduction and median time to achieve a VL< copies/ml were estimated for each regimen. Results: Among women, 9 (%), (%) and (%) received ZDV monotherapy, ZDV+LPV/r and ZDV+TC+LPV/r, respectively. The predicted VL reduction from baseline to delivery after a median of weeks of treatment were.,. and.9 log copies/ml with ZDV monotherapy, ZDV+LPV/r and ZDV+TC+LPV/r, respectively. At delivery, %, % and % of women receiving ZDV monotherapy, ZDV+LPV/r or ZDV+TC+LPV/r had a VL< copies/ml. The addition of TC to ZDV+LPV/r reduced the time to achieve a VL< copies/ml and the higher the pretreatment VL, the larger the effect TC had on reducing the time to VL< copies/ml. Conclusions: The addition of TC to ZDV+LPV/r was associated with a slight further VL reduction but the time to reach a VL< copies/ml was shorter. This beneficial effect of TC is crucial for prevention of motherto-child transmission in women who receive ARVs late and with high pretreatment VL. International Medical Press 9- (print) -8 (online)

2 P Sripan et al. Introduction Antiretroviral (ARV) therapy during pregnancy significantly reduces mother-to-child transmission of HIV (MTCT). It is thought that ARVs reduce perinatal HIV transmission through two complementary mechanisms: reducing RNA viral load (VL) and therefore decreasing fetal/infant exposure to maternal viruses during pregnancy/delivery, and providing pre-/post-exposure prophylaxis to the fetus/infant if the drugs cross the placenta. Zidovudine (ZDV) monotherapy modestly reduces maternal VL [] and may primarily work as pre-/post-exposure prophylaxis as it readily crosses the placenta []. The combination of ZDV with lamivudine (TC), which also crosses the placenta, produces a more rapid and substantial decrease in maternal VL which may explain its higher preventive effect [,]. Finally, protease inhibitors (PIs) generally cross the placenta poorly and probably prevent MTCT by reducing maternal VL [ ]. Very low rates of transmission have been reported in women with VL < copies/ml at delivery [8]. In this analysis, data from pregnant women who received either ZDV monotherapy (with/without singledose nevirapine [sdnvp] at onset of labour), ZDV+ lopinavir/ritonavir (LPV/r), or ZDV+TC+LPV/r (with/ without sdnvp at onset of labour) were used to evaluate the effect of the addition of LPV/r to ZDV, and of TC to ZDV+LPV/r, on the VL reduction during pregnancy. Methods Data were collected from ARV-naive pregnant women who participated in the PHPT- study in Thailand. Pregnant women received either ZDV monotherapy, or ZDV+LPV/r in the first phase of the PHPT- trial (NCT99) [9] or ZDV+TC+LPV/r in the second phase of the PHPT- trial (NCT) []. Plasma HIV RNA levels were assessed at baseline and during pregnancy using the Abbott m RealTime HIV- assay (lower limit of quantification [LLQ], copies/ml; Abbott Molecular, Inc., Des Plaines, IL, USA). VL time courses were analysed through a non-linear mixed-effect modelling approach (MONOLIX software v..) and parameters estimated using the stochastic approximation EM algorithm (SAEM) []. An E max model was applied to determine the effect of each regimen on the VL time course during pregnancy (Equation ). VL = VL E MAX T T + T () T was duration of treatment, VL was pretreatment VL, E max was maximum VL reduction (log copies/ml), T was duration of treatment (days) corresponding to E max / (that is, the shorter the T the faster the time to reach E max ). The effects of adding LPV/r to ZDV, and TC to ZDV+LPV/r, were assessed. CD + T-cell counts and gestational age (GA) at ARV initiation were also tested on model parameters. Population parameters including covariates were expressed as following: VL,POP,COV =VL,POP,REF +b VL, COV COV, E max,pop,cov =E max,pop,ref exp(b Emax,COV COV), T,POP,COV =T,POP,REF exp(b T,COV COV), where COV was the covariate and b the covariate effect on the parameters. Inter-individual variability was modelled with h i being the inter-individual random effect for subject i with mean and variance w. Individual parameters including covariates were expressed as shown in Equations, and : VL,COV,i = VL,POP,REF + β VL,COV COV + η i,vl ; η ~ N (, ω ) i,vl VL E MAX,COV,i = E MAX,POP,REF exp( β EMAX,COV COV) exp( η η ~ N (, ω ) i,emax ); i,emax Emax T,COV,i = T,POP,REF exp( β T,COV COV) exp( η η ~ N (, ω ) i,t ) ; i,t T () () () The distributions of VL<LLQ were estimated using the SAEM extension algorithm []. The effect of a covariate on a structural parameter was retained if it produced acceptable relative standard error (<%) and a decrease in the Bayesian information criterion compared with the covariate-free model []. VL time courses were simulated from the final population model and compared with the observed data to evaluate the predictive performance of the model using visual predictive check []. Simulations were performed to determine the time to reach a VL< copies/ml per regimen. Using the final population model, VL time courses during pregnancy were predicted using different treatment durations and pretreatment VL levels (, replicates of simulation). The PHPT- study received ethical clearance from the Thai Ministry of Public Health, the Harvard School of Public Health, and Chiang Mai University Faculty of Medical Associated Sciences Ethics Committees. All women provided written informed consent for their participation and that of their infants. International Medical Press

3 Contribution of ARVs on viral load reduction during pregnancy Results Data from HIV-infected pregnant women were included: 9 (%) received ZDV monotherapy, (%) received ZDV+LPV/r and (%) received ZDV+TC+LPV/r during pregnancy. The median (IQR) maternal VL values for the women who received ZDV monotherapy, ZDV+LPV/r and ZDV+TC+LPV/r pretreatment were. (..9),. (..) and.9 (.8.8) log copies/ml, respectively; whereas at delivery were.9 (..), <. (<..) and <. (<..) log copies/ml; baseline CD + T-cell counts were 8 ( ), ( 9) and ( ) cells/mm ; GA at treatment initiation were 9 (8 ), 8 (8 ) and (9 ) weeks; GA at delivery were 9 (8 ), 9 (8 9) and 9 (8 ) weeks, respectively. Finally, the median durations of ZDV monotherapy, ZDV+LPV/r and ZDV+TC+LPV/r were ( 9), ( ) and 9 ( ) days, respectively. A total of,8 VL results from women were available (98% measurements). The E max model described the VL time course during pregnancy well and produced accurate parameter estimates. CD + T-cell count at baseline was associated with pretreatment VL and retained in the model (Table ). Figure shows a good fit between the VL data and model predictions. Using the final model, the predicted VL reductions from baseline to delivery after a median of weeks of treatment were.,. and.9 log copies/ml with ZDV monotherapy, ZDV+LPV/r and Table. Population parameters of HIV time-course model for HIV-infected pregnant women enrolled in PHPT- first and second phase studies Parameters Estimate se RSE, % P-value a Structural model VL, log copies/ml.8.8 b VL,CD -.9. <. T, days. E MAX, ZDV+LPV/r.. E MAX,ZDV.. <. E MAX,ZDV+TC+LPV/r... Statistical model w hvlo.88. w T.. w hemax.. s VL.8. a Likelihood ratio test. E MAX, ZDV+LPV/r, E MAX,ZDV, E MAX,TC+ZDV+LPV/r, maximum treatment effects in log copies/ml; LPV/r, lopinavir/ritonavir; RSE, relative standard error (standard error of estimate/estimate*); T, treatment duration corresponding to half of maximum effect in days; VL, estimated viral load before treatment initiation; ZDV, zidovudine; b VL,CD, effect of CD to parameter VL, VL =.8 (CD/) -.9 ; w hvl, w ht and w hemax, the variability corresponding to interindividual random effect of VL, T and E max (square roots of variances) and s VL, residual (square roots of variances). ZDV+TC+LPV/r, respectively. The percentage of women with a predicted VL< copies/ml at delivery were %, % and % after receiving ZDV monotherapy, ZDV+LPV/r or ZDV+TC+LPV/r, respectively. Simulations showed that women receiving ZDV+LPV/r achieved VL< copies/ml after a median of ( ) weeks and those receiving ZDV+TC+LPV/r achieved VL< copies/ml after a median ( ) weeks (based on the observed pretreatment VL of. log copies/ml). Finally, the model simulation shows that the addition of TC to ZDV+LPV/r reduces the time to achieve VL< copies/ml and that this reduction is proportional to the pretreatment VL, that is, the higher the pretreatment VL, the larger the reduction in time to achieve a VL< copies/ml (Figure ). For example, for women with a pretreatment VL of. log copies/ml, the addition of TC to ZDV+LPV/r would reduce the time to achieve a VL< copies/ml by weeks (that is, from to 9 weeks), while for women with pretreatment VL of. log copies/ml it would only reduce the time to achieve a VL< copies/ml by week. Discussion We modelled the VL reduction and the time to achieve VL< copies/ml for three different ARV regimens during pregnancy. The maximum reduction in VL was modest with ZDV monotherapy but significantly larger with the addition of LPV/r. The addition of TC to ZDV+LPV/r was associated with a significant but slight additional VL reduction. Furthermore, the addition of TC to ZDV+LPV/r reduced the time to achieve a VL< copies/ml. The impact that TC had on reducing the time to a VL< copies/ml was greater when the pretreatment VL was higher. A study limitation is that women s adherence to ARVs was not taken into account. Adherence was measured by pill count at each visit and did not differ according to study treatments [9,]. Also, because women were ARV-naive and ARVs prophylaxis was short (median days for ZDV and ZDV+LPV/r, and 9 days for ZDV+TC+LPV/r), we assumed the absence of resistant mutations. In the PRIMEVA trial comparing LPV/r monotherapy with ZDV+TC+LPV/r for prevention of MTCT, LPV/r monotherapy reduced the VL below copies/ml at delivery in 8% of the women, compared with 9% with ZDV+TC+LPV/r (P=.) []. Using the same VL< copies/ml threshold in our study, % of women who received ZDV+TC+LPV/r had VL< copies/ml at delivery. However, the median pretreatment VL in our study,. log copies/ml, was higher than the. log copies/ml in the PRIMEVA trial. Our results are consistent with those of the MONARK study in Antiviral Therapy.

4 P Sripan et al. Figure. Visual predictive check plots ZDV ZDV + LPV/r ZDV + TC + LPV/r Viral load, log copies/ml Duration of treatment, days The solid lines denote the median, th and 9 th percentiles of the observed data. The grey areas represent the 9% CIs of the median, th and 9 th percentiles of the model prediction. LPV/r, lopinavir/ritonavir; ZDV, zidovudine; TC, lamivudine. which % of treatment-naive adult patients receiving ZDV+TC+LPV/r had VL< copies/ml after weeks of treatment []. For ZDV+LPV/r, our model predicts that % of women would have VL< copies/ml at delivery, consistent with the results from the PHPT- pharmacokinetic substudy []. In the ANRS- study [] initiating ZDV at weeks and adding TC at weeks of gestation, VL reduction at delivery was. log copies/ml. In our study, adding TC at the same time as initiating ZDV+LPV/r for a -week treatment duration, produced a modest but significant VL reduction (.9 log copies/ml versus. without TC). In a study by Read et al. [8] investigating the optimum timing of short-term combination ARV (carv) in pregnancy, the estimated duration to achieve VL< copies/ml appeared longer than in our study; however, the study analysed various databases, with women receiving different ARV regimens (including NNRT-based) during pregnancy, a quarter of them having previously received carv, and/or having baseline resistance mutations. Given the time needed to reach VL< copies/ml, our results also support early initiation of carv during pregnancy [9]. However, early initiation of PIbased regimens for MTCT has been associated with preterm birth [] therefore the risks/benefits of early prevention of MTCT have to be considered. Although VL reduction is not the only mechanism involved in prevention of MTCT, our results support the use of carv including PIs plus two NRTIs in pregnant women with high pretreatment VL. The addition of TC to ZDV+LPV/r associated with a slight further VL reduction but shortened the time to reach a VL< copies/ml; thus, the beneficial effect of TC may be critical for prevention of MTCT in women with high pretreatment VL and/or who start ARVs late during pregnancy. Acknowledgements The data used in this analysis were obtained from clinical trials funded by Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD: R HD and R HD9, USA) and Institut de Recherche pour le Développement (IRD), France. We would like to thank all members of the hospital teams, and the women and children who participated in PHPT- First Phase and PHPT- Second Phase studies. ZDV plus TC was provided by GlaxoSmithKline. We are also grateful to Nicolas Salvadori, Nontiya Homkham, 8 International Medical Press

5 Contribution of ARVs on viral load reduction during pregnancy Figure. Median treatment durations a to achieve viral load < copies/ml according to different viral load at baseline with, replicates of simulations Treatment duration to viral load < copies/ml, weeks ZDV+LPV/r ZDV+LPV/r+TC.... Viral load at baseline, log copies/ml a Weeks. LPV/r, lopinavir/ritonavir; VL, viral load; ZDV, zidovudine; TC, lamivudine. Rapeepan Suaysod and Prakit Riyaten for statistical advices, PHPT laboratory team who performed the VL measurements and Kanchaya Yoddee who did the data management. For her PhD, Patumrat Sripan received a scholarship from the French Embassy in Thailand and a Science Achievement Scholarship of Thailand. The results of this study were partially presented as a poster (number 8) at the nd Conference on Retroviruses and Opportunistic Infections, February, Seattle, WA, USA. Disclosure statement The authors declare no competing interests. References. Sperling RS, Shapiro DE, Coombs RW, et al. Maternal viral load, zidovudine treatment, and the risk of transmission of human immunodeficiency virus type from mother to infant. N Engl J Med 99; : 9.. Moodley J, Moodley D, Pillay K, et al. Pharmacokinetics and antiretroviral activity of lamivudine alone or when coadministered with zidovudine in human immunodeficiency virus type -infected pregnant women and their offspring. J Infect Dis 998; 8:.. Clarke JR, Braganza R, Mirza A, et al. Rapid development of genotypic resistance to lamivudine when combined with zidovudine in pregnancy. J Med Virol 999; 9: 8.. Mandelbrot L, Landreau-Mascaro A, Rekacewicz C, et al. Lamivudine-zidovudine combination for prevention of maternal-infant transmission of HIV-. JAMA ; 8:8 9.. Gingelmaier A, Kurowski M, Kästner R, et al. Placental transfer and pharmacokinetics of lopinavir and other protease inhibitors in combination with nevirapine at delivery. AIDS ; :.. Ivanovic J, Nicastri E, Anceschi MM, et al. Transplacental transfer of antiretroviral drugs and newborn birth weight in HIV-infected pregnant women. Curr HIV Res 9; :.. Else LJ, Taylor S, Back DJ, Khoo SH. Pharmacokinetics of antiretroviral drugs in anatomical sanctuary sites: the male and female genital tract. Antivir Ther ; :9. 8. Townsend CL, Cortina-Borja M, Peckham CS, de Ruiter A, Lyall H, Tookey PA. Low rates of mother-to-child transmission of HIV following effective pregnancy interventions in the United Kingdom and Ireland, -. AIDS 8; :9 98. Antiviral Therapy. 9

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