| Conditions: |
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HIV - PCP - Toxoplasmosis |
| Purpose: |
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Background:
- People who are infected with the human immunodeficiency virus (HIV) are at risk of getting
certain diseases. Two of these diseases are a type of pneumonia known as PCP and a brain
infection called toxoplasmosis. Most people with HIV take antiretroviral (ARV) drugs to
treat HIV and lower the risk of infections. However, some ARV drugs may make other drugs
used to treat PCP and toxoplasmosis less effective. Researchers want to test specific ARV
drugs to see if they affect atovaquone, a drug used to treat PCP and toxoplasmosis.
Objectives:
- To see if ARV drugs atazanavir-ritonavir or efavirenz lower the blood levels of
atovaquone.
Eligibility:
- Individuals between 18 and 70 years of age who have HIV.
- Participants must be taking efavirenz or atazanavir-ritonavir, or not taking any ARV
drugs.
Design:
- Participants will be screened with a physical exam and medical history. They will also
have blood and urine tests.
- This study has a screening visit and five study visits. Two of the study visits will
last about 12 hours; the other three visits will last about 1 hour each.
- Participants will receive either a low dose or high dose of atovaquone to take for 14
days. They will record doses and any symptoms on a diary card at home.
- After 14 days, participants will have a 12-hour visit to provide blood samples. There
will be a wash-out period with no doses for up to 6 weeks.
- After the wash-out period, participants will switch dose levels to either the high or
low dose.
- After 14 days, participants will have a 12-hour visit to provide blood samples.
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| Study Summary: |
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The incidence of opportunistic infections such as Pneumocystis jirovecii pneumonia (PCP) and
Toxoplasma gondii have substantially declined in patients with HIV infection due to potent
combination antiretroviral (ARV) therapy and effective prophylaxis. The drug of choice for
prophylaxis and treatment of PCP and toxoplasmosis is trimethoprim-sulfamethoxazole
(TMP-SMX) and sulfadiazine, respectively. In patients who cannot tolerate these first line
therapies, atovaquone is a common alternative. While generally considered safe and
effective, a recent drug interaction study involving a single dose of combination tablet of
atovaquone/proguanil (Malarone(Registered Trademark)) in HIV-infected patients showed that
atovaquone plasma concentrations were significantly lowered (compared to healthy volunteers)
by 75%, 74%, and 46% in patients taking the ARV medications efavirenz (EFV),
lopinavir-ritonavir (LPV/r), and atazanavir-ritonavir (ATV/r), respectively. The mechanism
of this drug interaction is unknown but is presumably due to induction of uridine
diphosphate glucuronsosyltransferase (UGT) enzymes responsible for the metabolism of
atovaquone. The magnitude of this interaction is such that it strongly suggests a clinically
relevant drug interaction between atovaquone and the aforementioned ARVs. The purpose of
this study is to determine whether HIV-infected subjects receiving ATV/r or EFV-containing
ARV regimens, experience reductions in atovaquone exposure under steady state conditions
compared to HIV-infected patients not receiving ARV therapy.
In this open-label study, 30 HIV-infected subjects will participate in 1 of 3 groups of 10
(Groups A, B, and C). Group A will consist of 10 subjects who are already receiving
combination ARV therapy containing ATV/r; Group B will consist of 10 subjects already
receiving combination ARV therapy containing EFV; and Group C will consist of 10 subjects
who are not currently receiving ARV therapy. All subjects in Groups A, B, and C will be
randomly assigned to either receive atovaquone 750 mg twice daily for 14 days (Phase 1)
followed by a 2-6 week washout period, followed by atovaquone 1500 mg twice daily for 14
days (Phase 2), or vice versa. Pharmacokinetic (PK) sampling for atovaquone will occur on
Day 14 of Phase 1 and 2.
Atovaquone PK parameters will be determined using non-compartmental methods with the
WinNonlin(Registered Trademark) professional computer program (version 5.2; Pharsight
Corporation, Mountain View, CA). The following PK parameters will be compared among the
groups: area under the concentration vs. time curve (AUC ?), maximum concentration (Cmax),
apparent oral clearance (Cl/F), time to reach maximum concentration (Tmax), and half-life (T
). Data from this investigation will determine whether ATV/r and/or EFV alter the steady
state PK of atovaquone in HIV-infected subjects. This information will assist clinicians in
choosing appropriate alternative therapies for the treatment of PCP and toxoplasmosis in
patients who are not candidates for first line therapies.
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| Criteria: |
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- INCLUSION CRITERIA:
A subject will be considered eligible for this study only if all of the following criteria
are met:
1. Between the ages of 18 and 70 years.
2. HIV-infected patients stabilized (greater than or equal to 90 days) on ARV regimens
containing efavirenz 600 mg daily, or atazanavir/ritonavir 300/100 mg daily or
HIV-infected patients not receiving ARV therapy.
3. CD4 cells greater than or equal to 350 cells/mm3 for HIV-infected patients not
receiving ARV therapy.
4. CD4 cells > 200 cells/mm3 for HIV-infected patients receiving ARV therapy.
5. Virologically suppressed patients receiving ARV therapy (< 200 copies/mL on at least
2 consecutive occasions, within 6 months prior to enrollment).
6. Females of child-bearing potential who are able and willing to prevent pregnancy by
(a) practicing abstinence or (b) using effective methods of birth control, such as
condoms, during the study period and for 1 month after study completion.
7. Subject agrees to storage of specimens for future research.
EXCLUSION CRITERIA:
A subject will be ineligible for this study if 1 or more of the following criteria are
met:
1. Concomitant routine therapy with any prescription, over-the- counter, herbal, or
holistic medications that are known or suspected to alter atovaquone including
rifampin, rifabutin, and metoclopramide for 14 days prior to study participation.
2. Subjects receiving primary or secondary prophylaxis for PCP or toxoplasmosis.
3. ARV regimens containing both EFV and ATV/r.
4. Subjects receiving hormonal contraceptives within 90 days of Study Day 1.
5. Inability to obtain venous access for sample collection.
6. Laboratory and/or physical evidence of any active opportunistic infection.
Diabetes mellitus requiring treatment with insulin, active tuberculosis, cardiac
disease (uncontrolled hypertension and/or heart failure etc.), renal disease (chronic
or acute renal failure or insufficiency resulting in baseline serum creatinine
greater than 1.5 times upper limit of normal [ULN]), untreated/uncontrolled thyroid
disease, untreated/uncontrolled psychiatric disease, active hepatitis (liver failure
resulting in liver function tests greater than 3 times the ULN, ascites, or jaundice
in the absence of ATV), or any other condition that may interfere with the
interpretation of the study results or not be in the best interest of the subject in
the opinion of the Investigator.
7. Positive pregnancy test or breastfeeding female.
8. The presence of persistent diarrhea or malabsorption that could interfere with the
subject's ability to absorb drugs.
9. Drug or alcohol use that may impair safety or adherence.
10. History of intolerance or allergic reaction (rash; hives; swollen lips; difficulty
breathing) to atovaquone.
11. Bleeding disorders (hemophilia, G.I., or intracranial bleeding).
12. Organ transplant recipient.
13. Documented ongoing problems with medication adherence.
14. High likelihood of switching ARV regimen within 12 weeks of the start of the study.
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| NCT ID: |
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NCT01479361 |
| Primary Contact: |
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Principal Investigator
Scott R Penzak, Pharm.D.
National Institutes of Health Clinical Center (CC)
Mopnica M Calderon, Pharm.D.
Phone: (301) 402-7032
Email: calderonmm@mail.nih.gov
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| Backup Contact: |
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Email: spenzak@mail.cc.nih.gov
Scott R Penzak, Pharm.D.
Phone: (301) 496-2997
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| Location Contact: |
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Bethesda, Maryland 20892
United States
For more information at the NIH Clinical Center contact Patient Recruitment and Public Liaison Office (PRPL)
Phone: 800-411-1222
Email: prpl@mail.cc.nih.gov
Site Status: Recruiting |