Fanconi Syndrome Due to ARVs in HIV-Infected Persons

This is a cross-sectional cohort study of HIV+ subjects with protocol-defined Fanconi syndrome (confirmed CrCl decline and evidence of proximal tubulopathy), who are referred from multiple sites in the U.S. and Canada.

45 TDF Fanconi cases and 90 matched controls are planned for enrollment in this study. The number of non-TDF Fanconi cases is not pre-defined.

This study will evaluate risk factors for Fanconi Syndrome in HIV-infected persons receiving ARVs and consists of 3 substudies:

Substudy A - All Fanconi Cases

Describe the clinical characteristics of HIV-infected subjects who develop protocol-defined Fanconi syndrome irrespective of their antiretroviral (ARV) regimen.

Substudy B - Case Control Study of Tenofovir DF (TDF) Cases

Using a matched control cohort, explore risk factors for the development of Fanconi syndrome in subjects from Substudy A who are receiving TDF and have known baseline renal function. Each TDF case will be compared to two controls who are receiving TDF but who show no evidence of protocol defined Fanconi syndrome.

Substudy C - Prospective Follow-up of TDF Cases

In subjects from Substudy B who have protocol defined Fanconi syndrome, determine time to TDF discontinuation after diagnosis of Fanconi syndrome, and time to confirmed resolution will be determined.

Substudy A - All Fanconi Cases

Subjects with confirmed CrCl decline and evidence of proximal tubulopathy

Substudy B - Case Control Study of TDF Cases

For subjects from Substudy A who are receiving TDF and who have protocol-defined Fanconi syndrome (confirmed CrCl decline and evidence of proximal tubulopathy), their clinical characteristics will be characterized and compared to control subjects.

For each identified TDF case, two HIV-infected subjects (controls) from the same clinic, in a similar age category, and with no evidence of protocol-defined Fanconi syndrome while receiving TDF for a similar or longer duration, will be identified.

Substudy C - Prospective Follow-up of TDF Cases

Subjects from Substudy B who have Fanconi syndrome will be included in this substudy. Those subjects who continue on a TDF containing regimen will be followed for a maximum of 12 weeks, or until resolution of Fanconi syndrome, whichever occurs earlier. Subjects, who discontinue TDF prior to Week 12, will be followed for 48 weeks from date of discontinuation, or until resolution, whichever occurs earlier.

Resolution is defined as a confirmed return of CrCl to within 10% of the CrCl at the start of TDF as a component of the current ARV regimen. Confirmatory laboratory testing will be done within 14 days.

• HIV Infections
• Fanconi Syndrome
• Kidney Disease
• Renal Impairment

Inclusion Criteria - Fanconi Cases

Subjects must meet all of the following inclusion criteria to be eligible for participation in this study.

• Adult (greater than or equal to 18 years) HIV-1 infected subjects regardless of race or ethnicity.
• Subjects must be on a stable ARV regimen for greater than or equal to 1 month prior to study entry.
• Evidence of protocol-defined Fanconi syndrome
• TDF subjects must be on TDF-containing regimen at the time of onset of Fanconi syndrome.
• Negative serum pregnancy test (females of child-bearing potential only).
• Less than two years post-menopausal women of child-bearing potential (TDF subjects only) agree to follow an adequate birth control barrier method or agree to abstain from heterosexual intercourse while participating in the study.
• The ability to understand and sign a written informed consent form, which must be obtained prior to initiation of any study procedures.

Exclusion Criteria - Fanconi Cases

Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.

• Non TDF subjects who have received any TDF within the prior 6 months, or those who have received greater than 2 weeks cumulative treatment.
• TDF subjects who have previously served as a TDF control for this protocol.
• History of current alcohol or substance abuse judged by the investigator to potentially interfere with laboratory results.

Inclusion Criteria - Controls

Subjects must meet all of the following inclusion criteria to be eligible for participation in this study.

• Adult (greater than or equal to 18 years) HIV-1 infected subjects regardless of race or ethnicity.
• No evidence of protocol-defined Fanconi syndrome
• On a TDF-containing regimen matched to a Fanconi case by clinic location, duration on TDF and age.
• Negative serum pregnancy test (females of child-bearing potential only).
• The ability to understand and sign a written informed consent form, which must be obtained prior to initiation of any study procedures.

Exclusion Criteria - Controls

Subjects who meet the following exclusion criteria are not to be enrolled in this study.

• History of current alcohol or substance abuse judged by the investigator to potentially interfere with laboratory results.