Pharmacokinetics and virologic response of zidovudine/lopinavir/ritonavir initiated during the third trimester of pregnancy
Cressey, Tim Ra,b,c; Jourdain, Gonzaguea,b,c; Rawangban, Boonsongd; Varadisai, Supange; Kongpanichkul, Ruchaf; Sabsanong, Prapang; Yuthavisuthi, Prapaph; Chirayus, Somnuki; Ngo-Giang-Huong, Nicolea,b,c; Voramongkol, Nipunpornj; Pattarakulwanich, Somsakj; Lallemant, Marca,b,c; for the PHPT-5 Team
aProgram for HIV Prevention and Treatment (PHPT), Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand
bDepartment of Immunology & Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, USA
cInstitut de Recherché pour le Développement (IRD), UMI 174-PHPT, Marseille, France
dNopparat Rajathanee Hospital, Bangkok, Thailand
eSamutsakhon Hospital, Samutsakhon, Thailand
fNakhonpathom Hospital, Nakhonpathom, Thailand
gSamutprakarn Hospital, Samutprakarn, Thailand
hPrapokklao Hospital, Chantaburi, Thailand
iVachira Phuket Hospital, Phuket, Thailand
jDepartment of Health, Ministry of Public Health, Nonthaburi, Thailand.
Received 28 April, 2010
Revised 25 May, 2010
Accepted 6 June, 2010
Correspondence to Tim R. Cressey, Program for HIV Prevention and Treatment (PHPT-IRD174), Department of Medical Technology, Faculty of Associated Medical Sciences, 6th Floor, 110 Inthawaroros Road, Muang Chiang Mai 50200, Thailand. Tel: +66 53 894 431; fax: +66 53 894 220; e-mail: email@example.com
Objective: To evaluate the pharmacokinetics and HIV viral load response following initiation during the third trimester of pregnancy of zidovudine plus standard-dose lopinavir boosted with ritonavir (LPV/r), twice daily, until delivery for the prevention of mother-to-child transmission of HIV.
Design: Prospective study nested within a multicenter, three-arm, randomized, phase III prevention of mother-to-child transmission of HIV trial in Thailand (PHPT-5, ClinicalTrials.gov Identifier: NCT00409591).
Methods: Women randomized to receive 300 mg zidovudine and 400/100 mg LPV/r twice daily from 28 weeks' gestation, or as soon as possible thereafter, until delivery had intensive steady-state 12-h blood sampling performed. LPV/r pharmacokinetic parameters were calculated using noncompartmental analysis. Rules were defined a priori for a LPV/r dose escalation based on the proportion of women with an LPV area under the concentration–time curve (AUC) below 52 μg h/ml (10th percentile for LPV AUC in nonpregnant adults). HIV-1 RNA response was assessed during the third trimester.
Results: Thirty-eight women were evaluable; at entry, median (range) gestational age was 29 (28–36) weeks, weight 59.5 (45.0–91.6) kg, CD4 cells count 442 (260–1327) cells/μl and HIV-1 RNA viral load 7818 (<40–402 015) copies/ml. Geometric mean (90% confidence interval) LPV AUC, Cmax and Cmin were 64.6 (59.7–69.8) μg h/ml, 8.1 (7.5–8.7) μg/ml and 2.7 (2.4–3.0) μg/ml, respectively. Thirty-one of 38 (81%) women had an LPV AUC above the AUC target. All women had a HIV-1 viral load less than 400 copies/ml at the time of delivery.
Conclusion: A short course of zidovudine plus standard-dose LPV/r initiated during the third trimester of pregnancy achieved adequate LPV exposure and virologic response.
The WHO's latest recommendations for treating HIV-infected pregnant women and preventing HIV transmission to infants promote triple antiretroviral treatment for all women who need therapy for their own health, that is, CD4 cell count below 350 cells/μl . For women who are not eligible for therapy, the following two options are proposed: zidovudine (ZDV) monotherapy from as early as 14-week gestation plus intrapartum single-dose nevirapine (SD-NVP) or maternal triple antiretroviral prophylaxis. Because of its potency and safety profile, lopinavir boosted with ritonavir (LPV/r) is one of the key antiretroviral components of these prophylactic strategies.
Studies in US pregnant women have shown a significant reduction in LPV plasma exposure with standard dosing [400/100 mg, twice daily (b.i.d.)] during the third trimester  and to a lesser degree during the second trimester . This reduction in LPV exposure during pregnancy has been attributed to the physiological changes associated with pregnancy. Subsequently, higher LPV dosing during the third trimester with 533/100 mg (four soft-gel capsules)  or 600/100 mg (three meltrex 200/50 mg tablets) , b.i.d., have been found to achieve similar LPV exposure to that in nonpregnant adults. However, studies [5,6] in European women using standard LPV/r dosing during the third trimester reported that the majority of women maintained efficacious plasma trough concentrations. To date, no data are available on LPV/r drug exposure during the third trimester of pregnancy in other populations.
Within the context of a phase III, randomized study in Thailand (PHPT-5 trial – ClinicalTrials.gov Identifier NCT00409591), a regimen of ZDV plus LPV/r initiated during the third trimester is one of three different maternal and infant treatment strategies currently under investigation for the prevention of mother-to-child transmission (PMTCT) of HIV-1 in nonimmunocompromised women. The choice of the ZDV plus LPV/r combination, without lamivudine (3TC), a drug active against both HIV and the hepatitis B virus (HBV), was made to avoid the risk of hepatic toxicities after drug discontinuation in a population with a high HBV carriage rate (about 8% of pregnant women are hepatitis BsAg carriers in Thailand). Moreover, the results of the MONotherapy AntiRetroviral Kaletra (MONARK) study have shown the equivalence of LPV/r monotherapy with LPV/r in combination with ZDV and 3TC in suppressing viral replication within the first months of therapy among antiretroviral-naive patients .
Because of the risk of lower lopinavir exposure with standard dosing during the third trimester of pregnancy, we investigated the pharmacokinetics and virologic response in the women randomized to receive ZDV plus standard-dose LPV/r at the start of the PHPT-5 trial.
Patients and methods
The study reported herein was performed at the beginning of the ongoing PHPT-5 clinical trial, a multicenter, phase III, three-arm, randomized, study, investigating the efficacy of three different maternal and infant treatment strategies for the PMTCT of HIV-1 in nonimmunocompromised women in Thailand. In one of the treatment arms, women are randomized to receive 300 mg ZDV, b.i.d., and 400/100 mg LPV/r (Aluvia 100/25 mg tablets, manufacturer Abbott Laboratories (Abbott Park, Illinois, USA), were used as the adult formulation is not registered in Thailand), b.i.d., from 28-week gestation until delivery. All HIV-infected pregnant women provided written informed consent and were enrolled if they were over 18 years of age, antiretroviral treatment-naive based on the women's clinical history except prior exposure to ZDV or SD-NVP prophylaxis for PMTCT of HIV, between 28 and 36-week gestational age, CD4 cell count of at least 250 cells/μl and had the following laboratory values within 14 days of enrollment: hemoglobin above 8.5 g/dl, absolute neutrophil count above 750 cells/μl, platelets above 50 000 cells/μl, serum glutamic pyruvic transaminase (SGPT) five times upper limit of normal or less and serum creatinine 1.5 times upper limit of normal or less. Exclusion criteria included patients who meet the criteria of classes III/IV of the WHO classification of HIV-associated clinical disease, evidence of preexisting fetal anomalies incompatible with life, active tuberculosis and contraindication to the use of LPV/r during pregnancy or at delivery. Among the women enrolled, concomitant drugs included only folic acid, ferrous sulfate, multivitamins, paracetamol, ranitidine and amoxicillin, none of which have reported significant drug interactions with lopinavir/ritonavir.
This study was approved by the Ethics Committees at the Harvard School of Public Health, USA; Ministry of Public Health, Thailand; Faculty of Associated Medical Sciences, Chiang Mai University, Thailand and the local hospital ethics committees.
Pharmacokinetic design and stopping rules
Women randomized to receive ZDV plus LPV/r were scheduled to have intensive 12 h blood sampling after at least 2 weeks of treatment. Drug level analysis was performed ‘real-time’ and women were continually scheduled for LPV/r pharmacokinetic assessment until 25 women had evaluable pharmacokinetic results available. At the pharmacokinetic visit, a predose blood sample was drawn prior to the scheduled LPV/r dose, after which LPV/r was administered with a standard low-fat meal (rice soup with pork), and blood samples were collected at 1, 2, 4, 6, 8 and 12 h after dosing. Antiretroviral drug adherence was assessed by pill counts at each study visit.
Assessment of LPV/r pharmacokinetic data was scheduled a priori to occur after the first 6, 12 and 25 women had evaluable pharmacokinetic data available. The target LPV area under the concentration–time curve (AUC) was at least 52 μg h/ml, the 10th percentile for LPV AUC in nonpregnant adults [8,9]. If three or more of the first six women, or four or more of the first 12 women or six or more of the first 25 women failed to meet the AUC target, one would have 90% confidence that the true rate of pharmacokinetic failure exceeds 10% [i.e., the lower limit of the 90% confidence interval (CI) will exceed 10%]. If any of the stopping criteria were met, the LPV/r dose would be increased to 600/100 mg b.i.d. in all women enrolled and pharmacokinetic sampling would be repeated on an additional 25 women at that dose. The analyses were presented to the PHPT-5 Data and Safety Monitoring Board (DSBM) assisted by a panel of independent pharmacokinetic specialists.
All adverse events were graded using the Division of AIDS Table for Grading the Severity of Adult and Paediatric Adverse Events (version 1.0, dated December 2004).
Antiretroviral drug level measurement and analysis
All blood samples were centrifuged and the plasma frozen at −20°C until analysis. Lopinavir and ritonavir plasma drug concentrations were measured using a validated HPLC assay at the Faculty of Associated Medical Sciences, Chiang Mai University. The average accuracy was 103–112% and precision (interassay and intraassay) was less than 4% of the coefficient of variation. The lower limit of assay quantification was 0.078 μg/ml for lopinavir and 0.048 μg/ml for ritonavir . This laboratory participates in the AIDS Clinical Trial Group, USA, Pharmacology Quality Control (precision testing) program . Data were analyzed with WinNonLin (version 5.2; Pharsight Corporation, Mountain View, California, USA) using noncompartment methods.
Measurement of plasma HIV-1 RNA viral load
Plasma HIV-1 RNA levels were assessed using the Abbott m2000 RealTime HIV-1 assay (Abbott Laboratories) according to the manufacturer's instructions (lower limit of detection, 40 copies/ml).
The first 27 women initiating ZDV plus LPV/r in the PHPT-5 trial had intensive blood sampling during the third trimester of pregnancy to assess LPV/r pharmacokinetics. At study entry, median (range) age was 28 (19–43) years, gestational age 30 (28–36) weeks, weight 59.9 (45.0–91.6) kg, BMI 26 (20–35) kg/m2, CD4 cells count 431 (250–875) cells/μl and HIV-1 RNA viral load 9312 (<40–402 015) copies/ml.
Lopinavir and ritonavir pharmacokinetics
One woman was excluded from the pharmacokinetic analysis due to poor drug adherence. At the time of pharmacokinetic blood sampling, the median gestational age was 33 (30–38) weeks and the duration of LPV/r treatment was 2 (2–4) weeks. Individual lopinavir concentration–time curves are shown in Fig. 1. At the planned interim analyses, two of the first six women and three of the first 12 women had an AUC below the target value of 52 μg h/ml, neither reaching the predefined stopping criteria and enrollment was continued. LPV/r pharmacokinetic parameters are presented in Table 1. Overall, five of 26 (19%; 90% CI 8–36) women had an LPV AUC below the target during the third trimester of pregnancy. The weight and BMI of women with a LPV AUC exposure above or below 52 μg h/ml were not significantly different. One woman (4%) had a LPV Cmin below 1.0 (0.81) μg/ml, the recommended efficacy threshold for protease inhibitor-naive patients.
Amendment to the study: additional enrollment
The LPV/r pharmacokinetic results were reviewed by the members of the PHPT-5 DSMB and pharmacokinetics specialists from the United States and Europe. They concluded at this time that the LPV/r dose should not be modified in the parent study but, because the criteria for increasing the dosing was close to being met, they recommended enrolling 12 additional women to decrease the possible effect of sampling fluctuations. The new stopping criterion calculated to trigger an LPV/r dose escalation to 600/100 mg b.i.d. was 10 or more of 38 women having an AUC below 52 μg h/ml. Twelve additional women randomized to receive ZDV plus LPV/r had pharmacokinetic blood sampling performed during the third trimester. The final baseline characteristics at study entry were: age 27 (19–43) years, gestational age 29 (28–36) weeks, weight 59.6 (45.0–91.6) kg, BMI 25 (20–35) kg/m2, CD4 cell count 441 (250–1327) cells/μl and HIV-1 RNA viral load 8326 (<40–402 015) copies/ml. Thirty-eight women were evaluable and their lopinavir and ritonavir pharmacokinetic parameters are presented in Table 1. In the final analysis, seven of 38 (18%; 90% CI 9–32) women had an LPV AUC below the AUC target and 37 of 38 (97%) women had a LPV Cmin above 1.0 μg/ml. The weight and BMI of women with a LPV AUC exposure above or below 52 μg h/ml were not significantly different.
Virologic response to zidovudine plus lopinavir boosted with ritonavir
HIV-1 RNA viral loads were measured at study entry, at the pharmacokinetic sampling visit and at delivery. At study entry, 22 of 38 women were antiretroviral naive when initiating ZDV–LPV/r, whereas 16 women had initiated ZDV prophylaxis before enrolling into PHPT-5. For these antiretroviral-naive women, the median (range) duration of ZDV–LPV/r treatment at the pharmacokinetic sampling visit and delivery were 2.7 (2.1–7.4) and 10.0 (5.6–12.7) weeks, respectively. The dynamics of the HIV-1 RNA viral load following initiation of ZDV–LPV/r in antiretroviral-naive women during the third trimester until delivery are shown in Fig. 2. One woman stopped LPV/r between the pharmacokinetic visit and delivery (refer to Safety section). All 21 antiretroviral-naive women had a viral load below 400 copies/ml at delivery, and 11 of 21 (53%) achieved below 40 copies/ml. Among the 16 women who initiated ZDV prophylaxis prior to enrolment in PHPT-5, the median duration was 10 days (2–43) before LPV/r was added; all had a viral load below 400 copies/ml and 12 (75%) had a viral load below 40 copies/ml.
Study medications were well tolerated. One grade 4 event was deemed probably treatment related: a woman self-reported convulsions at 30-week gestational age with grade 3 hyperbilirubinemia and grade 2 SGPT (alanine transaminase) elevations. LPV/r was discontinued and the woman's hyperbilirubinemia decreased to grade 1 after 2 months. She delivered uneventfully a live baby. Two stillbirths occurred, one unexplained and one involving an abortion after physical injury, both considered unrelated to antiretroviral treatment. One woman developed a grade 3 and another a grade 2 diarrhea; both resolved within a couple of days. Five women experienced grade 3 hypercholesterolemia, hypertriglyceridemia or both, which resolved after delivery in all but one case. Grade 1 events reported included nausea, vomiting, hyperlipidemia, headaches and anemia.
Standard LPV/r dosing in Thai women during the third trimester provided a LPV exposure similar to that in nonpregnant adults, suggesting that a dose increase is not necessary in this population. Ritonavir pharmacokinetic parameters were similar to those in HIV-infected US pregnant women. All women administered ZDV plus LPV/r during the third trimester had a viral load below 400 copies/ml and 62% below 40 copies/ml at delivery.
Other studies have also suggested that standard LPV dosing during pregnancy was sufficient for antiretroviral treatment-naive patients. In response to the data reported in US women, several studies assessed LPV trough levels following standard 400/100 mg (three soft-gel capsules, b.i.d.) dosing during the third trimester. Lyons et al.  reported that at median gestational age of 33 weeks (range 25–37 weeks), one of 21 women (5%) had an inadequate LPV trough level; three of 26 (14%) women had a plasma HIV RNA viral load above 50 copies/ml after a median of 10 weeks on therapy. In a similarly designed study, four of 26 (15%) women had a subtherapeutic LPV trough level at a median gestational age of 32 weeks. However, inadequate LPV levels were not always associated with a HIV-1 RNA above 50 copies/ml at the time of drug measurement and vice versa . Other studies [12,13] reported similar proportions of women with inadequate LPV trough levels during the third trimester with standard LPV/r dosing, with the majority also achieving viral suppression before delivery.
The comparison of the various published studies is made difficult by the fact that different criteria have been used to assess the adequacy of the LPV/r dosing in pregnant women, that is, achieving drug exposures (AUCs) equivalent to those in nonpregnant adults, or maintaining trough concentrations above those reported to be associated with virological suppression. The results of the original LPV/r dose escalation study, which identified the 400/100 mg dose for further development, were used to define the AUC target for pregnant women [8,9]. It should be noted that, because of the inherent small sample size of such studies, it is not possible to accurately study the relationship between AUC and virological efficacy, thus the adequacy of dosing after the metabolic modifications during pregnancy had to be thought in terms of the ability to reproduce a distribution of AUCs not dissimilar from that observed in nonpregnant adults. The 10th percentile of the distribution of LPV AUCs observed in this adult population (52 μg h/ml) was selected as the value below which LPV exposure would be considered low; and the decision rule for dose increase was designed to ensure 90% confidence that the true percentage of pregnant women with LPV exposures below this target would not exceed 10%. The alternative approach is using plasma LPV trough levels to guide virologic efficacy. A LPV trough concentration above 1.0 μg/ml, approximately 15 times the half maximal inhibitory concentration, has been reported to correlate with a HIV RNA viral load below 400 copies/ml ; however, others have concluded that LPV trough levels do not predict virologic response in naive patients . Clearly, rationale for adopting either target exists. It is reassuring in the presented study that both the LPV exposures and trough concentrations results support the use of standard dosing in this population. More specifically, 31 of 38 (81%) Thai women had an LPV exposure above the AUC target compared with three of 17 (18%) US women , and 97% had an LPV trough concentration above 1.0 μg/ml. Also, all seven women who had an LPV AUC below the 10th percentile for nonpregnant adults achieved a satisfactory HIV-RNA viral suppression at the time of delivery. Thus, for antiretroviral-naive women with no contraindicated concomitant drugs, there seems to be no indication that therapeutic drug monitoring would be necessary in this setting.
Our results confirm that although lopinavir drug exposure is reduced during the third trimester of pregnancy, by 22% in Thai women, this reduction is approximately half that observed in American women. The impact of pregnancy on lopinavir exposure may depend on the characteristics of the population. For example, the median body weight during the third trimester was considerably higher in US women than in Thai women, 90 versus 61 kg. Indeed, an inverse relationship between body weight and lopinavir exposure has been reported in several studies [16–18]. Lopinavir is at least 98% bound to plasma proteins, alpha-1-acid glycoprotein and albumin, and during the third trimester decreased protein binding increases the LPV-free fraction, although this does not compensate for the total reduction in LPV exposure in US women . Plasma protein concentrations were not determined in the presented study but it is possible that differences in plasma proteins binding between populations could contribute toward the higher lopinavir exposure observed in Thai pregnant women. Host genetic polymorphisms could also play a role. LPV is primarily metabolized by the cytochrome P450 enzyme 3A4 (CYP3A4) and is a substrate for the drug efflux transporter P-glycoprotein, coded by the ABCB1 gene. Functional variants of the ABCB1 were not associated with lopinavir plasma concentrations ; however, recent evidence suggests that polymorphisms within the CYP3A and SLCO1B1 [a member of the organic anion transporting polypeptides (OATP) family] genes contribute toward variability in LPV pharmacokinetics [21,22]. Differences between LPV/r formulations should be taken into consideration when comparing studies. The initial assessment of standard LPV/r dosing in US pregnant women used the original soft-gelatin capsule of LPV/r, whereas the new LPV/r tablet formulation was administered in the current study. The LPV/r tablet formulation is bioequivalent to the soft-gelatin capsule after administration with a moderate-fat meal but bioavailability of LPV is approximately 18% higher with tablets compared with capsules . This higher bioavailability may also have contributed toward the somewhat higher LPV exposure observed during the third trimester of pregnancy in Thai women with standard dosing. Finally, sampling fluctuations and attributes such as diet, smoking or herbal intake could explain the differences between studies in lopinavir pharmacokinetic during pregnancy observed.
As discontinuation of 3TC after 3 months of treatment in a population with a high rate of HBV coinfection (∼8% of pregnant women are hepatitis BsAg carriers in Thailand) can trigger HBV rebound and hepatic flare [24,25], the regimen tested in the PHPT-5 trial did not include 3TC. Nevertheless, the HIV-1 RNA virological response after ZDV–LPV/r initiation during the third trimester was rapid. After a median duration of LPV/r treatment of 10 weeks, all women had a viral load below 400 copies/ml at delivery, with 62% achieving less than 40 copies/ml. This virologic response is consistent with that reported in the MONARK trial in which, using either ZDV/3TC/LPV/r or LPV/r monotherapy, approximately 60, 80 and 90% of patients achieved a viral load below 400 copies/ml at 4, 8 and 12 weeks, respectively, and 20, 50 and 60% of patients achieved less than 50 copies/ml. The efficacy of the ZDV–LPV/r regimen for the PMTCT of HIV is still under investigation in the parent trial. However, the risk of transmission with a viral load less than 400 copies/ml has been shown to be extremely low .
The reduction of LPV drug exposure associated with pregnancy was less pronounced in Thai women than in US women. Standard LPV dosing appeared sufficient and the ZDV plus LPV/r regimen initiated during the third trimester of pregnancy achieved adequate virological response at delivery. These results are likely applicable for women in the many clinical settings around the world who have similarly low body weights during the third trimester of pregnancy; however, concomitant drug use, diet and available drug formulations should also be taken into consideration.
We would like to thank all the women who participated in the PHPT-5 trial and the study staff conducting the protocol at the sites. This study was supported by the National Institute of Child Health and Human Development, National Institutes of Health (NIH), USA (grant #R01 HD056953). Pharmaceutical support for the PHPT-5 trial is provided from GlaxoSmithKline and Boehringer Ingelheim. Lopinavir and ritonavir for the antiretroviral drug assay were obtained through the NIH AIDS Research and Reference Program, Division of AIDS, National Institute of Allergy and Infectious Diseases, NIH, USA.
PHPT-5 DSBM: Professor Scott Hammer, Professor René Ecochard, Professor Suwachai Intaraprasert, Associate Professor Rudiwilai Samakoses and Dr Wiput Phoolcharoen. Pharmacology consultants: Edmund Capparelli, Alice Stek, Mark Mirochnick and Jean-Marc Treluyer.
Members of the PHPT-5 team (pharmacokinetic study) – Phayao Provincial Hospital: Jittapol Hemvuttiphan, Ruethai Wongchai, Borwornluck Changlor, Ampai Maneekaew, Kunlaya Jansook, and Saowakhon Bunchaisun. Chiang Rai Prachanukroh Hospital: Jullapong Achalapong, Subenya Jinasa, Purivis Chart, Kannikar Saisawat, Pollawat Thongsuk and Supaporn Utsaha. Mae Chan Hospital: Sudanee Buranabanjasatean, Natjaree Thuenyeanyong, Phithak Kaeha, Thanutra Taiyaithieng and Benjaporn Juntapoon. Prapokklao Hospital: Prapap Yuthavisuthi, Renoo Wongsrisai, Ubon Chanasit, Nuttupassasorn Tungtongcha and Pisut Greetanukroh. Banglamung Hospital: Kamol Boonrod, Suchada Thongsuwan, Prateep Kanjanavikai, Watcharin Kaewsaweat and Sarocha Sawatmarn. Chonburi Hospital: Nantasak Chotivanich, Tiwacha Thimakam, Nusara Krapunpongsakul, Chanida Asarath, Raewadee Wanno, Prakit Yothipitak, Suluck Soontaros and Kessarin Chaisiri. Rayong Hospital: Weerapong Suwankornsakul, Phatcharin Thuraset, Arthit Cheawchan and Sukonta Phasuk. Nakornping Hospital: Aram Limtrakul, Janjira Thonglo, Benjawan Thomyota, Autcharaporn Nakrit and Pusdee Lymthavorn. Nopparat Rajathanee Hospital: Boonsong Rawangban, Patcharaporn Krueduangkam, Thamon Wijitwong, Kantinan Leepaiboon and Pranom Poolpat. Bhumibol Adulyadej Hospital: Sinart Prommas, Marina Thitathan, Santi Winaitham and Boonruen Pengmark. Pranangklao Hospital: Surachai Pipatnakulchai, Jiradsadaporn Khanmali, Kesorn Jitmaleerat and Kingtong Wongsirikul. Hat Yai Hospital: Tapnarong Jarupanich, Namthip Kruenual, Usa Sukhaphan and Raruay Jitsakulchaidej. Nong Khai Hospital: Noossara Puarattana.aroonkorn, Waropart Pongchaisit, Sinnapa Pothinukka, Nunthiya Phomcheam and Supattra Kaengklang. Samutsakhon Hospital: Supang Varadisai, Jantra Chalasin, Yaowalak Sookbumrung and Wilai Raiva. Nakhonpathom Hospital: Rucha Kongpanichkul, Chutima Seema, Parawan Bunditwong and Panita Kapol. Samutprakarn Hospital: Prapan Sabsanong, Boonyavee Ratchanee, Kedsara Bunluesak, Arun Yaisiri and Noupporn Jenpoomjai. Lampang Hospital: Prateung Lianpongsabuddhi, Sirirat Thammajitsagul, Tiemjan Keowkarnkah, Sasipun Supong, Sunee Hanyutthapong and Wanpen Leelaporn. Vachira Phuket Hospital: Somnuk Chirayus, Sompong Wannun, Sudtida Eawsakul, Iriyaporn Kongthap and Nuttharee Pinkaew. Pathumthani Hospital: Boonrak Wiriyachoke, Chisakan Thanadechworasate, Punjamaporn Satjeanphong and Ratchadaporn Katekaraj. Panasnikom Hospital: Manoch Chakorngowit, Somsong Niamlamul, Samapond Saithong and Parinee Suebchart. Ministry of Public Health: Siripon Kanshana. Mahidol University: Suporn Koetsawang. PHPT-IRD174 Clinical Trial Unit, Chiang Mai: Sophie Le Coeur, Ken McIntosh, Pra-ornsuda Sukrakanchana, Suwalai Chalermpantmetagul, Kanchana Than-in-at, Yardpiron Taworn, Pimpinun Punyati, Angkana Thongkum, Paporn Mongkolwat, Ampika Kaewbundit, Panida Pongpunyayuen, Luc Decker, Aksorn Lueanyod, Suriyan Tanasri, Sanupong Chailert, Kanjana Yoddee, Rungruangrong Seubmongkolchai, Dujrudee Chinwong, Pongpreeda Saenchitta and Chalermpong Sanjoom.
T.R.C. designed the pharmacokinetic study, developed the pharmacokinetic case report forms, oversaw the lopinavir/ritonavir drug level measurement, performed the data analysis and wrote the first draft of the manuscript. G.J. assisted with the pharmacokinetic study design and statistical analysis, cowrote the PHPT-5 study and contributed to the writing of the manuscript. B.R., S.V., R.K., P.S., P.Y. and S.C. assisted with the study design, enrolled and monitored patients and edited the manuscript. N.N. assisted with the pharmacokinetic study design, oversaw the virological testing, cowrote the PHPT-5 study and edited the manuscript. N.V. and S.P. assisted with the study design and implementation and edited the manuscript. M.L. assisted with the pharmacokinetic study design and implementation, cowrote the PHPT-5 study and contributed to the analysis and writing of the manuscript.
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