Standard LPV/r dosing in Thai women during the third trimester provided a LPV exposure similar to that in non-pregnant 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 naïve patients. In response to the data reported in US women, several studies assessed LPV trough levels following standard 400/100 mg (3 soft gel capsules, twice daily) dosing during the third trimester. Lyons et al,
reported that at median gestational age of 33 weeks (range 25–37), 1 of 21 women (5%) had an inadequate LPV trough level; 3 of 26 (14%) women had a plasma HIV RNA viral load above 50 copies/mL after a median of 10 weeks on therapy [5
]. In a similarly designed study, 4 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 >50 copies/mL at the time of drug measurement; and vice versa [6
]. Other studies 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 [12
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, i.e. achieving drug exposures (AUCs) equivalent to those in non-pregnant 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
]. 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 non pregnant adults. The 10th
percentile of the distribution of LPV AUCs observed in this adult population (52 mcg.hr/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 mcg/mL, approximately 15 times the IC50
, has been reported to correlate with a HIV RNA viral load <400 copies/mL [14
]; however, others have concluded that LPV trough levels do not predict virologic response in naïve patients [15
]. 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 to 3 of 17 (18%) US women [2
], and 97% had an LPV trough concentration above 1.0 mcg/mL. Also, all 7 women who had an LPV AUC below the 10th
percentile for non-pregnant adults achieved a satisfactory HIV-RNA viral suppression at the time of delivery. Thus, for antiretroviral naïve 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 kg versus 61 kg. Indeed, an inverse relationship between body weight and lopinavir exposure has been reported in several studies [16
]. Lopinavir is ≥98% bound to plasma proteins, alpha-1-acid glycoprotein (AAG) 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 [19
]. Plasma proteins concentrations were not determined in the presented study but it is possible that differences in plasma proteins binding between populations could contribute towards 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 [20
]; however, recent evidence suggests that polymorphisms within the CYP3A
(a member of the organic anion transporting polypeptides (OATP) family) genes contribute towards variability in LPV pharmacokinetics [21
]. 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 while the new LPV/r tablet formulation was administered in the present 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 to capsules [23
]. This higher bioavailability may also have contributed towards 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 PK during pregnancy observed.
Since discontinuation of 3TC after three months of treatment in a population with a high rate of hepatitis B virus (HBV) co-infection (~8% of pregnant women are Hepatitis BsAg carriers in Thailand) can trigger HBV rebound and hepatic flare [24
], 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 <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 where, 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% less than 50 copies/mL. The efficacy of the ZDV/LPV/r regimen for the prevention of mother-to-child transmission 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 [26
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.