During 48 weeks of follow-up, none of the participants died or had HIV clinical disease progression. No one used medication that might reduce the LPV/r level. Median (IQR) Z-score weight for age and height for age, but not weight for height, were increased significantly (Table 1). Median CD4% and CD4 cell count were not significantly changed. Thirty-one children were still on only mLPV/r at week 48 and 29 (72.5%) had HIV-RNA less than 50 copies/ml. These 29 children did not receive any other antiretroviral drug aside from mLPV/r.
Five children (12.5%) had viral blip during the study. The median time to viral blip was 12 weeks (range 2–36 weeks) and the plasma HIV-RNAs were between 52 and 94 copies/ml. Three of these five children had poor adherence by pill count and all received adherence counseling. Only one of these five children had low LPV C min at week 36 of 0.29 mg/l but had adequate LPV C min at the extra visit a week later of 11.69 mg/l. At week 48, all five children with viral blip had virological suppression below 50 copies/ml while still on mLPV/r treatment.
In Table 2, nine (22.5%) of 40 children resumed their previous dPI regimens due to protocol-defined mLPV/r failure. The majority were older girls. Median (IQR) week of mLPV/r failure was 24 (12–36) weeks. They had similar mean number of NAMs before dPI (3.6) as the children without treatment failure (3.8). Genotyping was performed and only minor protease inhibitor mutations were found. Four children had poor adherence by pill count. The measurements of C min LPV at time of virological failure were done and three had LPV levels below therapeutic target level (<1 mg/l). Two of these three children had poor adherence by pill count.
Median (IQR) duration between mLPV/r failure and dPI intensification was 6.3 (5–11.9) weeks. At week 48, four (44.4%) of nine children who resumed dPI had undetectable HIV-RNA (Table 2). Overall, the proportion of children at week 48 with undetectable HIV-RNA, including children on mLPV/r and those who resumed dPI was 82.5% (33 of 40; Fig. 2). An additional child (patient 1) achieved undetectable HIV-RNA 12 weeks later.
By multivariate logistic regression analysis, the predicting factor for failing mLPV/r was plasma HIV-RNA at least 50 copies/ml at baseline (adjusted hazard ratio 5.9, 95% confidence interval 1.5–24.2, P = 0.01; Table 3).
No serious adverse events were reported during 48 weeks. The most common mild-to-moderate adverse events were upper respiratory tract infection. All events were not related to antiretroviral medication.
The cholesterol, triglyceride, and glucose were similar across 48 weeks except for a decrease in HDL (P = 0.01). In addition, the number of children with abnormal lipids and glucose level at week 48 was not significantly different compared to baseline (Table 1).
At week 48 after simplified second-line treatment from dPI to mLPV/r, 72.5% of children still were virologically controlled with mLPV/r. There were no serious adverse events, progression of HIV diseases, or significant change in immunological response. Virological failure was seen in 22.5%, but no child had major protease inhibitor mutations and 44.4% of these children achieved viral suppression after resuming their previous dPI regimens. However, there were no significant changes in fasting lipid profiles and fasting blood glucose, except for a decrease in HDL that was an unexpected finding.
The majority of children in this study had undetectable plasma HIV-RNA at 48 weeks. There is no publication of mLPV/r or other stepdown regimen in HIV-infected children to compare our data to; however, our data are comparable to results from adult studies. For mLPV/r trials in HIV-infected adults on first-line HAART with undetectable plasma HIV-RNA at the start of monotherapy, the proportion of undetectable plasma HIV-RNA at 48 weeks was 73–85% [2,12]. Viral blip and low viremia (50–500 copies/ml) in our study were not uncommon and were similar to those reported in adults [1,12]. Our results also were comparable or better than those of other pediatric trials with LPV/r-based HAART regimens. For example, the proportion of undetectable plasma HIV-RNA at 48 weeks in 24 Thai children with LPV/r and two NRTIs as their second-line therapy was 50% . In another study of 50 Thai children on LPV/r and SQV after failing NNRTI-based HAART, 64% had undetectable HIV-RNA . Unfortunately, there are limited data of second-line treatment outcomes in Asian HIV-infected children . In 391 sub-Saharan African children treated with protease inhibitor or NNRTI-containing HAART, only 49% had undetectable plasma HIV-RNA at 24 weeks .
Factors associated mLPV/r failure has been reported in HIV-infected adults. Pulido et al.  reported poor adherence, defined as at least two visits with self-reported missed doses in the week prior to the study visit, a lower baseline hemoglobin, and a nadir CD4 cell count less than 100 cells/μl to be associated with loss of virological suppression on mLPV/r at 48 weeks. Campo et al.  reported good adherence, determined by 4-day participant recall, and higher baseline CD4 cell counts as predictors of sustained virological suppression in adult patients on mLPV/r. In our study, CD4 nadir was not associated with mLPV/r failure. Only baseline plasma HIV-RNA at least 50 copies/ml was predictive of mLPV/r failure. This could be seen as estimates of nonadherence, even though the measurement of adherence in our study, that is, pill count was not significantly related to failure. The fact that use of NRTIs or NNRTIs together with the dPI regimen was not a predictive factor for treatment failure of mLPV/r suggests that these drugs were not major contributors to the antiviral activity of the dPI regimen.
HIV-resistant mutations can reduce patients' future treatment options. Data from a study revealed that five (6%) of 83 adults developed major protease inhibitor resistance-associated mutations (i.e., L10F, M46I, L76V, and V82A) within 96 weeks of mLPV/r  and four of these patients developed it after the first year of mLPV/r. We did not find major protease inhibitor mutations in the patients who had genotyping done. As most children who failed subsequently achieved viral suppression after resuming their previous dPI regimen, it is unlikely that major protease inhibitor mutation developed in those patients.
The long-term metabolic adverse event of antiretroviral therapy is a major concern in HIV-infected children. We expected to see the protective effect on lipids by using fewer drugs in the current monotherapy regimen, but unfortunately, no significant change was found. An adult randomized trial of mLPV/r vs. LPV/r-based HAART also did not see improved lipids with mLPV/r . Apparently, LPV/r was mainly responsible for the negative effect on lipids in the LPV/r-containing regimens. In our study, the mean HDL was significantly decreased, but it was still in the normal range. It is possible that the increase in HIV viremia after mLPV/r contributed to low HDL as our subanalysis shows a correlation at week 24 between the proportion of children with low HDL (<40 mg/dl) and the presence of HIV viremia (P = 0.022). Low HDL and increased systemic inflammatory responses have been shown in adults after treatment interruption .
Our study is unique and has several strengths. First, this is the first report of mLPv/r as maintenance therapy in HIV-infected children. Although there are several reports in adults, children have different HIV-RNA and CD4 cell dynamics, and HIV disease progression rates than adults making the adult studies less relevant to the pediatric population. Second, our study population is unique as these are children who had shown successful viral suppression and good adherence during a 144-week dPI study. It is interesting to see whether by stepping down to one PI in their regimen, viral suppression can be maintained. We believe that this piece of information will be useful for future research on monoboosted protease inhibitor therapy in HIV-infected children.
Our study also has some limitations. First, this was a single arm study, without any comparative arm. Second, the children were on dPI before switching to mLPV/r; therefore, the results may not be applicable to children treated with other types of regimens. Finally, this is a short-term report of mLPV/r at week 48 and there is a need for long-term follow-up to assess the durability of mLPV/r.
Further randomized controlled trials of potent monoboosted protease inhibitor in the pediatric population are needed. Fortunately, the Pediatric European Network for Treatment of AIDS (PENTA) will conduct a randomized trial, PENTA 17 (EudraCT number 2010–020682–24) to explore the efficacy and durability of mLPV/r compared to LPV/r-based HAART in HIV-infected children (http://www.penta.org). Furthermore, a randomized study in adults showed that darunavir/ritonavir monotherapy was noninferior in its ability to suppress HIV-RNA when compared to HAART . Boosted darunavir is an attractive option for monotherapy protease inhibitor in children due to its high potency; however, the requirement for ritonavir is an obstacle for treatment simplification in children.
In conclusion, at 48 weeks of simplification from dPI to mLPV/r in children who previously failed NRTI/NNRTI first-line treatment, 72.5% were still on mLPV/r with undetectable HIV-RNA. Overall, 82.5% of children, including both the children who were still receiving mLPV/r and those who resumed dPI had undetectable plasma HIV-RNA. The children who had a single viral blip could be re-suppressed with additional adherence support without modifications in the mLPV/r regimen. No major protease inhibitor mutations were found. Our data support further evaluation of long-term efficacy and safety of boosted protease inhibitor monotherapy as a treatment simplification strategy in children.
We thank the Aligning Care and Prevention of HIV/AIDS with Government Decentralization to Achieve Coverage and Impact: ACHIEVED Project (Global fund Thailand) for lopinavir/ritonavir supply, CD4, and HIV-RNA reagents; the Thai National Health Security Office (NHSO) for lamivudine, indinavir; Roche for saquinavir supply; HIV-NAT for personnel cost. We are grateful to the HIV-NAT 077 children and their families for participating in this study.
HIV-NAT 077 study team.
HIV-NAT: Chayapa Phasomsap, Walaiporn Wongngam, Jintana Intasan, Primwichaya Intakan, Stephen Kerr, Tanakorn Apornpong, Chulalak Sriheara, Sasiwimol Ubolyam, and team.
Khon Kaen University: Chanasda Sopharak, Thanitta udompanit, and team
Roles of each of the co-authors are described in the table at the top of this page.
T.B. and P.K. have received educational grants, travel grants, and/or speakers' honoraria from Roche and Abbott. J.A. has received educational grants, travel grants, and/or speakers' honoraria from Roche, Gilead, and Abbott. Other authors declare no conflict of interest and that members of their immediate families do not have a financial interest in or arrangement with any commercial organization that may have a direct interest in the subject matter of this article.
The 24 weeks preliminary analysis of this study was presented as an oral presentation (abstract O_12) at the 1st International Workshop on HIV Pediatrics, Cape Town, South Africa, 17–18 July 2009 and a poster presentation (MOPEB062) at the 5th IAS Conference on HIV Pathogenesis Treatment and Prevention, Cape Town, South Africa, 19–22 July 2009 as the abstract entitled: Simplifying antiretroviral treatment in virally suppressed children by switching from double boosted protease inhibitors to lopinavir/ritonavir monotherapy.
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Keywords:© 2011 Lippincott Williams & Wilkins, Inc.
children; HIV; lopinavir monotherapy; protease inhibitor; treatment simplification