Kaletra Sex/Gender Pharmacokinetics (PK) Study: A Switch From Twice Daily to Once Daily Lopinavir/Ritonavir

The association between patient sex and the tolerability of antiretroviral drugs (ARVs) is
increasingly being recognized. Several lines of evidence suggest that women are more likely
than men to develop side effects to ARVs. On the other hand, it has been generally accepted
that the efficacies of the ARVs are similar in both sexes. However, recent studies suggest
that this may not always be the case. In addition to these observed sex-related differences
in the effects of ARVs, there is growing evidence that the pharmacokinetic profile of some
of these drugs may be different among male and female HIV infected patients.

The fact that female sex is a risk factor for enhanced antiretroviral effects (including
toxicities) has an important implication, particularly from a global health perspective as
women now represent the fastest growing segment of the HIV/AIDS epidemic. Therefore, an
understanding of the magnitude, clinical significance, and the mechanisms underlying this
phenomenon deserves further study. Knowledge acquired from such studies will likely
contribute to improved survival among female HIV-infected patients, through optimization of
antiretroviral therapeutic regimens in manners that minimize serious adverse effects and
improve adherence.

Similarly, the influence of race on the pharmacological effects of ARVs deserves further
investigation. Although, there is no reason to believe based on available evidence that
racial differences exist in the pharmacological effects of ARVs, the need however exists to
explore the influence of race on ARVs pharmacokinetics and treatment outcomes. This is so
because data on race related differences on ARV effects is limited, and in addition, people
of ethnic minority have been disproportionately under represented in clinical trials
involving these drugs in spite of the fact that they bear a larger burden of the HIV
epidemic.

Our study will examine the influence of race and sex on the 24-hr pharmacokinetics of
lopinavir/ritonavir (an antiretroviral agent commonly used in naïve patients) following a
switch from LPV/r 400/100 mg BID to 800/200 mg QD dosing. Tolerability (measured by toxicity
grade of diarrhea) and change in quality of life following switch from BID to QD dosing will
also be assessed using appropriate validated measurement tools.

Inclusion Criteria:

- Age greater or equal to 18 years

- Diagnosis of HIV infection as previously established by HIV Enzyme-Linked
Immunosorbent Assay (ELISA) test and confirmed by Western blot analysis.

- Must have been taking LPV/r as part of an antiretroviral regimen at a dose of 400/100
mg orally twice per day for at least 3 months.

- Recent (within last 90 days) HIV-RNA copies must be less than 400 copies/ml

Exclusion Criteria:

- Hepatic abnormality: alanine-aminotransferase (ALT), aspartate-aminotransferase (AST)
or total bilirubin (TBR) ≥ 3 x upper limit of normal

- Renal insufficiency: serum creatinine ≥ 2 mg/dl

- Co-infection with hepatitis B and/or C viruses

- Pregnant or breastfeeding

- Use of concurrent medications known to affect lopinavir or ritonavir concentrations
significantly.