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IAS 2013: Lower-dose Lopinavir/Ritonavir Reduces Side Effects, Maintains Viral Control in HIV+ Children

Low dose lopinavir/ritonavir (Kaletra or Aluvia) -- 70% of the standard dose -- worked as well as the standard dose in maintaining viral suppression, but with less dyslipidemia, among children with HIV in Thailand, Thanyawee Puthanakit reported on behalf of the HIVNAT 152 PEARL study at the recent 7th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2013) in Kuala Lumpur.

[Produced in collaboration with Aidsmap.com]

This multi-center, randomized, open-label trial was conducted at 11 sites in Thailand, comprising 200 children under 18 years of age, weighing from 25 to 50 kg, with viral suppression (viral load under 50 copies/mL). Findings showed low-dose lopinavir/ritonavir also reduced costs and the potential for long-term complications associated with cardiovascular disease.

In Thailand, children experiencing treatment failure on nucleoside/nucleotide reverse transcriptase inhibitor/non-nucleoside reverse transcriptase inhibitor (NRTI/NNRTI) regimens have limited second-line options. Lopinavir/ritonavir is the most commonly used protease inhibitor (PI) in children and has shown excellent efficacy in antiretroviral-experienced children. The recommended minimal level of lopinavir in the blood is more than 1 mg/dL for PI-naive children.

However, dyslipidemia (increased levels of cholesterol and triglycerides) is associated with lopinavir/ritonavir use, increasing the risk of heart disease with long-term use.

A previous study among Thai adolescents living with HIV, with a median age of 13.5 years, showed that using 70% of the lopinavir/ritonavir standard dose maintained adequate levels of drug in the blood. Low-dose compared to standard-dose administration produced mean concentrations (AUC_0-12h) of 83.1 and 93.8 mg.h/L, respectively.

The researchers hypothesized that viral load suppression would be maintained with adequate drug levels and less dyslipidemia using low-dose lopinavir/ritonavir (70% of the standard dose) as maintenance therapy, compared with the standard dose.

From June to December 2011, children already on a lopinavir/ritonavir-based regimen with viral load under 50 copies/mL were randomly assigned by a minimization scheme (to minimize imbalance) to the U.S. Food and Drug Administration (FDA) recommended standard dose or the lower dose of lopinavir/ritonavir heat stable tablets.

Exclusion criteria included PI resistance, a viral load over 1000 copies/mL after 6 months on a PI-based regimen, being on rifampicin, nevirapine (Viramune), or efavirenz (Sustiva or Stocrin) -- due to drug interactions with lopinavir -- and being on a double boosted PI regimen.

Twice-daily dosages for children weighing between 25 and 35 kg were 300/75 mg for standard-dose and 200/50 mg for low-dose lopinavir/ritonavir; for children weighing 35 to 50 kg, doses were 400/100 mg and 300/75 mg, respectively.

The primary endpoint was the proportion of children with suppressed viral load (under 50 copies/mL) at 48 weeks. Secondary endpoints included lowest concentration of lopinavir in the blood measured after a dose but just before the next dose at 12 hours (Cmin or trough) and dyslipidemia.

Of the 199 children -- with a mean age of 13.4 years and a mean CD4 T-cell count of 786 cells/mm³ -- 98 and 101 were assigned to standard-dose and low-dose arms, respectively. The distribution of children weighing 25-35 kg and 35-50 kg was comparable in both dose groups.

The most commonly used NRTI backbones were zidovudine/lamivudine (47%), zidovudine/didanosine (17%), and tenofovir/lamivudine (16%). The mean time on antiretroviral therapy was 8.8 years, including a mean of 3.5 years on a lopinavir/ritonavir-based regimen.

An intention-to-treat analysis at week 48 showed that the proportion of children with suppressed viral load was 91.8% in the standard-dose arm and 88.1% in the low-dose arm (difference -3.7%; p=0.38). A per-protocol analysis showed the proportions to be 93.7% and 91.8%, respectively (difference -1.9%; p=0.62), respectively. These differences were not statistically significant, indicating that the low dose was non-inferior to the standard dose.

The researchers found that 6 of the 7 children with a viral load above 1000 copies/mL had a lopinavir level lower than the limit of detection, suggesting poor adherence.

Multivariate analysis showed both adherence under 95% (adjusted odds ratio [aOR] 3.3) and weighing between 35 and 50 kg (aOR 3.6) were associated with over a 3-fold increased risk of virological failure.

In the standard-dose and low-dose arms, median lopinavir trough levels were 6.9 and 5.2 mg/dL, respectively, at 48 weeks. Of the 14 children (7.3%) who had a trough level under 1 mg/dL, 4 were in the standard-dose arm and 10 were in the low-dose arm.

A significant proportion of children in the low-dose arm had a greater reduction in both cholesterol and triglyceride levels compared to those in the standard-dose arm.

At week 48, more children in the standard-dose arm had higher cholesterol (over 200 mg/dL) and higher triglycerides (over 150 mg/dL) than those in the low-dose arm, 34.4% compared to 20.6% (p=0.03) and 60.4% compared to 44.3% (p=0.03), respectively.

Findings from this study, Puthanakit noted, could only be generalized to children with controlled, undetectable viral load, not to children with high viral loads just starting antiretroviral therapy. 

Puhanakit agreed with Diana Gibb from the Medical Research Council Clinical Trials Unit in London, who commented that the results "would not apply to the use of liquid lopinavir/ritonavir therapy since this study was done with tablets that have a higher bioavailability."

8/14/13

Reference

T Puthanakit, P Suntarattiwong, P Sangkla, et al. A randomized study comparing low dose versus standard dose lopinavir/ritonavir among HIV-infected children with virological suppression. 7th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention. Kuala Lumpur, June 30-July 3, 2013. Abstract MOAB0101.