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Monoboosted lopinavir/ritonavir as simplified second-line maintenance therapy in virologically suppressed children

Bunupuradah, Torsaka; Kosalaraksa, Popeb; Puthanakit, Thanyaweea,c; Mengthaisong, Tawana; Wongsabut, Jiratchayaa; Lumbiganon, Pagakrongb; Phanuphak, Praphana; Burger, Davidd; Pancharoen, Chitsanuc; Ananworanich, Jintanata,c,eon behalf of the HIV-NAT 077 Study Team

doi: 10.1097/QAD.0b013e32834231f5
Clinical Science

Background: Monoboosted protease inhibitor is being evaluated as a strategy to simplify therapy in virologically suppressed patients who are on complex regimens.

Methods: Children with two consecutive HIV-RNA below 50 copies/ml at least 3 months apart while on double boosted protease inhibitor (dPI) were switched to monoboosted lopinavir/r (mLPV/r). The previous dPI regimen was resumed within 4 weeks in children who experienced virological failure defined as two HIV-RNA at least 500 or three HIV-RNA at least 50 copies/ml. Primary endpoint was the proportion of children still on mLPV/r and having HIV-RNA less than 50 copies/ml at week 48.

Results: Forty children on LPV/r + saquinavir (90%) or LPV/r + indinavir (10%) were enrolled, 50% were female, median [interquartile range (IQR)] age was 11.7 (10.2–13.5) years, and body weight was 29.4 (24.1–40.2 kg). The median (IQR) CD4% was 27 (23.5–29.5%). At 48 weeks, none had died or had HIV disease progression. Thirty-one children were on mLPV/r and 29 (72.5%) had HIV-RNA less than 50 copies/ml. Nine resumed dPI due to mLPV/r failure with four achieving undetectable HIV-RNA. Overall, 31 children (82.5%) had HIV-RNA suppression. Predicting factor for failing mLPV/r was baseline HIV-RNA at least 50 copies/ml. No major protease mutations were found.

Conclusion: By simplifying second-line treatment from dPI to mLPV/r, the majority of children had sustained viral suppression at 48 weeks. Randomized study of simplified mono protease inhibitor therapy in children is warranted.

aThe HIV Netherlands Australia Thailand Research Collaboration (HIV-NAT), Bangkok, Thailand

bKhon Kaen University, Khon Kaen, Thailand

cChulalongkorn University, Bangkok, Thailand

dRadboud University Nijmegen Medical Centre, Nijmegen, the Netherlands

eSouth East Asia Research Collaboration with Hawaii (SEARCH), Bangkok, Thailand.

Received 27 May, 2010

Revised 26 October, 2010

Accepted 1 November, 2010

Correspondence to Torsak Bunupuradah, MD, HIV-NAT, The Thai Red Cross AIDS Research Center, 104 Ratchadamri Road, Pathumwan, Bangkok 10330, Thailand. Tel: +66 2 652 3040; fax: +66 2 252 5779; e-mail:

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The goals of HIV treatment simplification by switching to protease inhibitor monotherapy after virological suppression with HAART are to reduce pill burden, side effects, drug interactions, and medication cost, and to enhance adherence, and preserve future treatment options while maintaining viral suppression. At least 22 studies of boosted protease inhibitor monotherapy have been conducted on HIV-infected adults who have virological suppression with HAART [1]. Lopinavir/ritonavir monotherapy (mLPV/r) has been the most investigated compared to other boosted protease inhibitors because of its co-formulation of lopinavir/ritonavir and its high genetic barrier to resistance [1]. Only six randomized controlled trials of mLPV/r vs. LPV/r-based HAART have been conducted, and from these studies, the risk of virological failure was greater on mLPV/r compared to LPV/r-based HAART; 33.2 vs. 22.9% [pooled odds ratio 1.48 (95% confidence interval 1.02–2.13, P = 0.037]. However, plasma HIV-RNA can be successfully re-suppressed upon reintroducing nucleoside reverse transcriptase inhibitors (NRTIs), as indicated by the comparable risk of therapy failure of 26.9% in the mLPV/r group vs. 22.9% in the LPV/r-based HAART group [1]. The episodes of low-level HIV viremia defined as HIV-RNA 50–500 copies/ml were more common in patients receiving mLPV/r compared to those continuing LPV/r-based HAART, but as noted above, the low-level viremia can be controlled after treatment intensification [1–3]. Factors associated with maintenance of virologic suppression in individuals receiving mLPV/r were high baseline hemoglobin [4], CD4 cell counts [5], and good adherence [4,5].

In the Thai HIV treatment guideline, two double boosted protease inhibitor (dPI) regimens, LPV/r with indinavir (IDV) or saquinavir (SQV), have been indicated as the alternative second-line HAART option for HIV-infected children with multi NRTI and/or NNRTI resistance [6]. This is due to the limited availability of antiretroviral therapy for second-line HAART such as abacavir due to its high cost, and tenofovir and new drug classes due to their lack of pediatric indication. However, the long-term metabolic side effects and high pill burden from dPI is a concern [7]. Therefore, we investigated the safety and efficacy of mLPV/r stepdown strategy in HIV-infected children after long-term virological suppression on dPI. To our knowledge, there has been no report of boosted protease inhibitor as monotherapy for treatment simplification in HIV-infected children.

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Materials and methods

During October 2007 to September 2008, HIV-infected children were enrolled from two sites in Thailand. We included children who were previously enrolled in the HIV-NAT 017 study [7]. Briefly, these children had failure to first-line NRTI/nonnucleoside reverse transcriptase inhibitor (NRTI/NNRTI) and switched to dPI with lamivudine (only in those who were naive to lamivudine).

After approximately 3 years on dPI (LPV/r + SQV or LPV/r + IDV), 40 of 50 children having two consecutive HIV-RNA below 50 copies/ml at least 3 months apart were enrolled into this simplification study (Fig. 1). Exclusion criteria were active AIDS-defining disease at screening or pregnancy.

Fig. 1

Fig. 1

After enrollment, all children interrupted other antiretroviral drugs and continued only LPV/r at their current standard dosage of 230/57.5 mg/m2 orally twice daily. The formulations of LPV/r were soft gel capsules LPV/r (Kaletra, 133/33 mg) and/or liquid (Kaletra, 80/20 mg/ml). Study participants were not allowed to take oral medication that interferes with the pharmacokinetics of LPV/r, including rifampicin, rifabutin, phenobarbital, phenytoine, carbamazepine, dexamethasone, ketoconazole, and clarithromycin.

The children's weight (kg), height (cm), pill count, CD4%, CD4 cell count, HIV-RNA, and alanine aminotransferase (ALT) were monitored at weeks 0, 4, 8, 12, and every 12 weeks until 48 weeks. The plasma HIV-1 RNA was performed by Roche Amplicor HIV-1 Monitor UltraSensitive assay (Roche, Palo Alto, California, USA). Genotypic resistance tests by an in-house method validated for HIV clade A/E [8] were performed centrally at the HIV-NAT laboratory in Bangkok. The fasting glucose and lipids were monitored at 0, 24, and 48 weeks. Abnormal lipids were defined as total cholesterol more than or equal to 200 mg/dl, triglyceride more than or equal to 150 mg/dl, low-density lipoprotein (LDL) more than or equal to 130 mg/dl, and high-density lipoprotein (HDL) less than 40 mg/dl [9].

Plasma concentrations at premorning dose (minimum concentration or C min) of LPV and ritonavir were measured at any visit when virological failure is suspected. This was done by a validated high performance liquid chromatography method at the HIV-NAT laboratory that participates in the Association for Quality Assessment in Therapeutic Drug Monitoring and Clinical Toxicology (KKGT) program [10]. The lower limit of quantifications of both LPV and ritonavir was 0.01 mg/l. The therapeutic target level for LPV was at least 1 mg/l. As ritonavir was used as a booster, its level is not expected to reach the therapeutic target of at least 2.1 mg/l.

Study nurses performed LPV/r pill counts at every visit. Percentage of adherence was calculated as [(dispensed drug − returned drug)/estimated drug that patient should take in each period] × 100. Poor adherence was defined as LPV/r pill count less than 95% at any visit.

Clinical and laboratory adverse events were graded by the Division of AIDS grading table December 2004 [11]. This protocol (HIV-NAT 077; Clinical identification number NCT00626301) was approved by the ethic committees of King Chulalongkorn Memorial Hospital and Khon Kaen University Hospital and all caregivers signed consent forms.

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Primary endpoint, definitions, and patient management

The primary endpoint was the proportion of children with HIV-RNA less than 50 copies/ml at week 48 while still receiving mLPV/r. For this analysis, we considered noncompleter as failure; therefore, all children who were not able to stay on mLPV/r for any reason were considered as failure. The secondary endpoint was the proportion of all children with HIV-RNA less than 50 copies/ml at week 48 for both children groups who were still receiving mLPV/r and those who resumed their previous dPI regimens.

Treatment failure was defined as children who experienced two consecutive HIV-RNA at least 500 copies/ml or three consecutive HIV-RNA at least 50 copies/ml, each test separated by at least 2 weeks (adapted from the mLPV/r study in adults [12]); in such a case, the previous dPI regimen was resumed within 4 weeks. A viral blip was defined as plasma HIV-RNA at least 50 copies/ml with a subsequent sample with HIV-RNA less than 50 copies/ml without change in therapy.

For patient management, if the HIV-RNA was at least 50 copies/ml at any visit, the child was asked to return within 4 weeks for HIV-RNA, LPV and ritonavir plasma C min, adherence counseling, and pill count. Genotyping of HIV-1 protease was performed for samples with HIV-RNA at least 1000 copies/ml. Mutations were defined according to the International AIDS Society-USA Drug Resistance Mutations Group [13].

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Statistical analysis

Variable distributions were described as median, interquartile range (IQR), or proportions as appropriate. The Wilcoxon rank-sum test was used for comparison of continuous covariates and the χ 2 test was used for comparison of categorical covariates. In time to mLPV/r failure analyses, univariate screening of variables was done by the Kaplan–Meier method and the log-rank test was used for statistical significance testing. Thereafter, we used Cox proportional hazards modeling to calculate hazard ratios for the risk of mLPV/r treatment failure. All significance tests were two-sided with significance at the 0.05 level. All analyses were undertaken using STATA 10.0 (StataCorp. 2007. Stata Statistical Software: Release 10; StataCorp LP, College Station, Texas, USA).

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Forty children, 19 from the Bangkok site and 21 children from the Khon Kaen site were enrolled. Fifty percent were female. The median (IQR) age was 11.7 (10.2–13.5) years (Table 1). At baseline, the dPIs were LPV/r+ SQV in 36 children (90%) and LPV/r+ IDV in four children (10%) with 11 children taking lamivudine (27.5%). Six children needed additional drugs in addition to dPI, due to HIV-RNA rise while on dPI, including four (10%) who were on zidovudine and two (5%) who were on efavirenz. The median (IQR) duration of using dPI before switching to mLPV/r was 3.6 (3.0–4.2) years. The median (IQR) CD4% was 27 (23.5–29.5)%. The twice daily median (IQR) dose of LPV was 236 (167–296) mg/m2 and for ritonavir, it was 59 (42–74) mg/m2. The median (IQR) C min of LPV and ritonavir at baseline were 5.36 (3.36–8) mg/l and 0.23 (0.14–0.38) mg/l, respectively. Although all children had HIV-RNA below 50 copies/ml at screening, four (10%) had HIV-RNA at least 50 copies/ml at the baseline visit (Table 2). Regarding reverse transcriptase mutations at time of failing NRTI/NNRTI and prior to switching to dPI, 51% of these children had at least four nucleoside-associated mutations (NAMs). The three commonest NAMs were D67N (64%), M41L (49%), T215F, and K70R (41%). M184V was found in 67%. Thirty-four percent had NNRTI mutations. The three commonest NNRTI mutations were G190A (59%), K103N, Y188L (24%), and Y181C (18%) [14].

Table 1

Table 1

Table 2

Table 2

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.

Fig. 2

Fig. 2

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).

Table 3

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).

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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% [15]. In another study of 50 Thai children on LPV/r and SQV after failing NNRTI-based HAART, 64% had undetectable HIV-RNA [14]. Unfortunately, there are limited data of second-line treatment outcomes in Asian HIV-infected children [16]. In 391 sub-Saharan African children treated with protease inhibitor or NNRTI-containing HAART, only 49% had undetectable plasma HIV-RNA at 24 weeks [17].

Factors associated mLPV/r failure has been reported in HIV-infected adults. Pulido et al. [4] 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. [5] 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 [18] 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 [3]. 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 [19].

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 ( Furthermore, a randomized study in adults showed that darunavir/ritonavir monotherapy was noninferior in its ability to suppress HIV-RNA when compared to HAART [20]. 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.

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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.

Table 1

Table 1

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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1. Bierman WF, van Agtmael MA, Nijhuis M, Danner SA, Boucher CA. HIV monotherapy with ritonavir-boosted protease inhibitors: a systematic review. AIDS (London, England) 2009; 23:279–291.
2. Pulido F, Arribas JR, Delgado R, Cabrero E, Gonzalez-Garcia J, Perez-Elias MJ, et al. Lopinavir-ritonavir monotherapy versus lopinavir-ritonavir and two nucleosides for maintenance therapy of HIV. AIDS (London, England) 2008; 22:F1–F9.
3. Arribas JR, Delgado R, Arranz A, Munoz R, Portilla J, Pasquau J, et al. Lopinavir-ritonavir monotherapy versus lopinavir-ritonavir and 2 nucleosides for maintenance therapy of HIV: 96-week analysis. J Acquir Immune Defic Syndr (1999) 2009; 51:147–152.
4. Pulido F, Perez-Valero I, Delgado R, Arranz A, Pasquau J, Portilla J, et al. Risk factors for loss of virological suppression in patients receiving lopinavir/ritonavir monotherapy for maintenance of HIV suppression. Antivir Ther 2009; 14:195–201.
5. Campo RE, Da Silva BA, Cotte L, Gathe JC, Gazzard B, Hicks CB, et al. Predictors of loss of virologic response in subjects who simplified to lopinavir/ritonavir monotherapy from lopinavir/ritonavir plus zidovudine/lamivudine. AIDS Res Hum Retroviruses 2009; 25:269–275.
6. Sungkanuparph S, Anekthananon T, Hiransuthikul N, Bowonwatanuwong C, Supparatpinyo K, Mootsikapun P, et al. Guidelines for antiretroviral therapy in HIV-1 infected adults and adolescents: the recommendations of the Thai AIDS Society (TAS) 2008. J Med Assoc Thai 2008; 91:1925–1935.
7. Bunupuradah T, van der Lugt J, Kosalaraksa P, Engchanil C, Boonrak P, Puthanakit T, et al. Safety and efficacy of a double-boosted protease inhibitor combination, saquinavir and lopinavir/ritonavir, in pretreated children at 96 weeks. Antivir Ther 2009; 14:241–248.
8. Sirivichayakul S, Ruxrungtham K, Ungsedhapand C, Techasathit W, Ubolyam S, Chuenyam T, et al. Nucleoside analogue mutations and Q151M in HIV-1 subtype A/E infection treated with nucleoside reverse transcriptase inhibitors. AIDS (London, England) 2003; 17:1889–1896.
9. Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, et al. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation 2005; 112:2735–2752.
10. Droste JA, Verweij-Van Wissen CP, Burger DM. Simultaneous determination of the HIV drugs indinavir, amprenavir, saquinavir, ritonavir, lopinavir, nelfinavir, the nelfinavir hydroxymetabolite M8, and nevirapine in human plasma by reversed-phase high-performance liquid chromatography. Ther Drug Monitor 2003; 25:393–399.
11. National Institute of Allergy and Infectious Disease. Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events.;2004.
12. Arribas F R, Pulido F, Delgado R, Lorenzo A, Miralles P, Arranz A, et al. Lopinavir/ritonavir as single-drug therapy for maintenance of HIV-1 viral suppression: 48-week results of a randomized, controlled, open-label, proof-of-concept pilot clinical trial (OK Study). J Acquir Immune Defic Syndr (1999) 2005; 40:280–287.
13. Johnson VA, Brun-Vezinet F, Clotet B, Gunthard HF, Kuritzkes DR, Pillay D, et al. Update of the drug resistance mutations in HIV-1: Spring 2008. Top HIV Med 2008; 16:62–68.
14. Kosalaraksa P, Bunupuradah T, Engchanil C, Boonrak P, Intasan J, Lumbiganon P, et al. Double boosted protease inhibitors, saquinavir, and lopinavir/ritonavir, in nucleoside pretreated children at 48 weeks. Pediatr Infect Dis J 2008; 27:623–628.
15. Puthanakit T, van der Lugt J, Bunupuradah T, Ananworanich J, Gorowara M, Phasomsap C, et al. Pharmacokinetics and 48 week efficacy of low-dose lopinavir/ritonavir in HIV-infected children. J Antimicrob Chemother 2009; 64:1080–1086.
16. Bunupuradah T, Aurpibul L, Ananworanich J, Puthanakit T. The effectiveness of highly active antiretroviral therapy among HIV-infected children in Asian countries. Asian Biomed 2009; 3:89–100.
17. Jaspan HB, Berrisford AE, Boulle AM. Two-year outcomes of children on nonnucleoside reverse transcriptase inhibitor and protease inhibitor regimens in a South African pediatric antiretroviral program. Pediatr Infect Dis J 2008; 27:993–998.
18. Delaugerre C, Flandre P, Chaix ML, Ghosn J, Raffi F, Dellamonica P, et al. Protease inhibitor resistance analysis in the MONARK trial comparing first-line lopinavir-ritonavir monotherapy to lopinavir-ritonavir plus zidovudine and lamivudine triple therapy. Antimicrob Agents Chemother 2009; 53:2934–2939.
19. Tebas P, Henry WK, Matining R, Weng-Cherng D, Schmitz J, Valdez H, et al. Metabolic and immune activation effects of treatment interruption in chronic HIV-1 infection: implications for cardiovascular risk. PloS One 2008; 3:e2021.
20. Arribas JR, Horban A, Gerstoft J, Fatkenheuer G, Nelson M, Clumeck N, et al. The MONET trial: darunavir/ritonavir with or without nucleoside analogues, for patients with HIV RNA below 50 copies/ml. AIDS (London, England) 2010; 24:223–230.

children; HIV; lopinavir monotherapy; protease inhibitor; treatment simplification

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