Atazanavir/Ritonavir and Zinc Pharmacokinetic Study
Atazanavir/Ritonavir and Zinc Pharmacokinetic Study
The study is being conducted as the most common side effect of the HIV drug atazanavir (taken
 with ritonavir) is hyperbilirubinaemia. Bilirubin is a normal waste product from the body and
 gets broken down in the liver so it can leave the body through the gut. Atazanavir slows the
 breakdown of this chemical, which can cause jaundice (yellowing of the skin) and/or scleral
 icterus (yellowing of the eyes). This is completely harmless; in fact up to 1 in 10 of the UK
 population have an inherited condition that causes the same yellowing. However, some patients
 don't like this side effect and it is the commonest reason for switching off the drug.

 A study in people with Gilberts syndrome (the inherited condition that causes the same
 changes in the chemical bilirubin) showed that a mineral supplement (zinc sulphate) reduced
 the levels of bilirubin in the blood. The aim of this study is to see if using zinc
 supplements can achieve the same effect in patients with high bilirubin due to atazanavir
 use.
Atazanavir is a protease inhibitor (PI) and, like other agents in this class, requires
 pharmacological 'boosting' with the cytochrome p450 inhibitor ritonavir. Ritonavir slows the
 hepatic clearance of PIs, increasing plasma concentration and allowing the us eof lower, and
 less frequent doses. Atazanavir, boosted with ritonavir, is approved for once-daily use, is
 an internationally preferred first-line agent (in combination with a backbone of two
 nucleosides [NRTI]) and the most commonly prescribed PI in the UK. Once-daily
 atazanavir/ritonavir with two NRTI is an effective and well-tolerated therapeutic option for
 people living with HIV infection. The most common adverse event associated with atazanavir
 use is unconjugated hyperbilirubinaemia. This is observed in over 40% of patients and up to
 5% of patients discontinue the drug due jaundice and/or scleral icterus.

 Truvada is a fixed dose combination of two NRTI, tenofovir (245mg) and emtricitabine (200mg),
 administered as one tablet once daily. Truvada is a preferred NRTI backbone in national and
 international guidelines and the first line, therefore most commonly used, NRTI backbone in
 our unit.

 Benefits of atazanavir/ritonavir compared with alternative agents include once daily dosing,
 low pill burden, low rates of gastro-intestinal toxicity and, importantly in a patient
 population already at an elevated risk of cardiovascular disease, a favourable lipid profile.
 If a simple intervention could reduce the incidence of hyperbilirubinaemia this could reduce
 the risk of treatment discontinuation/switch. The aim of this study is to explore the
 benefit, and safety, of adding zinc sulphate in patients on a stable regimen of Truvada,
 atazanavir and ritonavir.
Inclusion Criteria:

 1. The ability to understand and sign a written informed consent form, prior to
 participation in any screening procedure and must be willing to comply with all study
 requirements

 2. Male or non-pregnant, non-lactating females.

 3. Aged between 18 to 65 years, inclusive.

 4. Documented HIV-1 infection

 5. Plasma HIV RNA less than 40 copies/mL (note retesting of screening viral load is
 allowed).

 6. CD4 count > 100 at screening (note retesting of screening CD4 count is allowed).

 7. Receiving an antiretroviral regimen of Truvada and atazanavir/ritonavir for more than
 3 months.

 8. Serum total bilirubin concentration greater than 25 micromol/L

 9. Agrees not to change regimen, outside the study recommendations, from baseline until
 end of the treatment period unless this is medically indicated as decided by their
 treating physician.

 Exclusion Criteria:

 1. Any serious or active medical or psychiatric illness, which, in the opinion of the
 investigator, would interfere with subject treatment, assessment, or compliance with
 the protocol. This would include any active clinically significant renal, cardiac,
 hepatic, pulmonary, vascular, metabolic disorders or malignancy.

 2. Body mass index (BMI) >35 kg/m2

 3. Presence of any current active AIDS defining illness (Category C conditions according
 to the CDC Classification System for HIV Infection 1993) with the following
 exceptions:

 • Stable cutaneous Kaposi's Sarcoma

 4. Clinically relevant alcohol or drug use (positive urine drug screen, with the
 exception of cannabinoids) or history of alcohol or drug use considered by the
 Investigator to be sufficient to hinder compliance with treatment, follow-up
 procedures or evaluation of adverse events.

 5. The use of zinc supplements for 1 month before screening and disallowed concomitant
 therapy (See Concomitant Medication and treatment, section 5.2) or medication that may
 interfere with the study results (as determined by the principal investigator).

 6. Females of childbearing potential who are not using effective non-hormonal birth
 control methods or not willing to continue using these birth control methods for at
 least 14 days after the end of the treatment period.

 7. Previous allergy to any of the constituents of the zinc sulphate tablets administered
 in this trial.

 8. Subjects with laboratory evidence of significantly decreased hepatic or renal function
 (as determined by the principal investigator).

 9. Exposure to any investigational drug or placebo within 4 weeks of first dose of study
 drug