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Lopinavir Side Effects Differ by Weight in Women, But RNA Response Does Not
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2nd International Workshop on HIV & Women. January 9-10, 2012, Bethesda, Maryland
Mark Mascolini
Obese women enrolled in clinical trials of lopinavir/ritonavir had higher rates of abdominal pain and diarrhea than did lighter women in a 7-study meta-analysis [1]. But neither virologic response nor CD4 response differed by body mass index (BMI) in this study.
BMI can affect drug distribution and therefore efficacy and risk of toxicity. Understanding the impact of BMI on antiretroviral response and side effects takes on added significance when high proportions of HIV-positive women are overweight or obese, as they are in the United States. To assess the impact of BMI on response to lopinavir/ritonavir, researchers from Abbott Laboratories planned this meta-analysis.
The study involved all randomized controlled trials conducted by Abbott in antiretroviral-naive or experienced adults starting a three-drug combination including lopinavir/ritonavir at a licensed once- or twice-daily dose. There were 7 trials that had BMI data plus baseline to week-48 findings on efficacy, safety, and tolerability. The Abbott team grouped women into three clusters: those with normal body mass index (below 25 kg/m2), overweight women (25 to less than 30 kg/m2), and obese women (30 kg/m2 or more).
Of 485 women assessed, 258 (53%) had normal BMI, 130 (27%) were overweight, and 97 (20%) were obese. The "normal" group included 28 women with a BMI below 18.5 kg/m2, which is considered underweight. Age averaged about 39 years in all study groups. The proportion of white women differed significantly by BMI group (53.9% normal, 36.9% overweight, and 25.8% obese, P < 0.05), as did the proportion of Hispanic women (17.4% normal, 33.8% overweight, and 20.6% obese, P < 0.05). The normal-BMI group had a significantly higher proportion of women positive for HCV (17.2% normal, 10.8% overweight, 6.2% obese, P < 0.05).
Average pretreatment viral load was significantly higher in normal-BMI women (4.6 log normal, 4.4 log overweight, 4.3 log obese, P < 0.05), and normal-weight women had the lowest average pretreatment CD4 count (214 normal, 244 overweight, 278 obese, P < 0.05).
Despite these pretreatment differences, 48-week virologic and CD4 responses did not differ significantly between the three groups. A noncompleter-equals-failure analysis determined statistically equivalent 48-week sub-50-copy rates (65.1% normal, 57.7% overweight, 57.7% obese). Average CD4 gains through 48 weeks were 197 in normal-BMI women, 158 in overweight women, and 173 in obese women.
Proportions of women with grade 3 or 4 lab abnormalities and proportions who stopped treatment prematurely for any reason or for adverse events did not differ significantly by BMI. A higher proportion of obese women had moderate or severe treatment-related adverse events, but the difference from lighter women stopped short of statistical significance (29.5% normal, 29.2% overweight, 41.2% obese, P = 0.087).
The 7.2% of obese women who had moderate or severe abdominal pain was significantly higher than the proportion of normal-BMI or overweight women (0.8% and 0%, P < 0.05). A significantly higher proportion of obese women also had diarrhea (9.3% normal, 10.8% overweight, 22.7% obese, P < 0.05). Rates of nausea and vomiting did not differ between the three groups.
The Abbott investigators noted that the higher rates of abdominal pain and diarrhea in obese women seemed surprising at first, because lighter women taking the same dose of a drug would be expected to have more side effects. But the researchers found that higher BMI is also associated with abdominal pain and diarrhea in the general population. They suggested that dietary differences in the three BMI groups could also contribute to the observed differences in abdominal pain and diarrhea. In addition, people with high BMI have a higher incidence of nonalcoholic fatty liver disease, which is associated with liver fibrosis and changes in drug metabolism. The investigators did not have pharmacokinetic data to analyze in this study.
The Abbott team concluded that, "despite differences in baseline demographics, there were no differences in efficacy and few differences in safety across BMI groups."
Reference
1. Hermes A, Fredrick L, Pasley M, Trinh R, Martinez M, Norton M. A meta-analysis of the effect of BMI on efficacy, safety, and tolerability of lopinavir/ritonavir in HIV-infected women in randomized clinical trials. 2nd International Workshop on HIV & Women. January 9-10, 2012, Bethesda, Maryland. Abstract O_15.
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