The Safety of Tenofovir DF for the Treatment of HIV Infection: The First 4 Years

1. The Safety of Tenofovir DF for the Treatment of HIV Infection: The First 4 Years M Nelson,1 D Cooper,2 R Schooley,3 C Katlama,4 J Montaner,5S Curtis,6 L Hsu,6 B Lu,6 S Smith,6 J Rooney,6 and the Viread Global Expanded Access Program 1Chelsea and Westminster Hospital, London, UK; 2University of New South Wales, Sydney, Australia; 3University of California, San Diego, CA, USA; 4Pitié-Salpêtrière, Paris, France; 5University of British Columbia, Vancouver, Canada;6Gilead Sciences, Inc., Foster City, CA, USA and Cambridge, UK

2. Introduction • Tenofovir disoproxil fumarate (TDF; Viread) is a once daily nucleotide reverse transcriptase inhibitor indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection. TDF was approved in the US in 2001 and in Europe in 2002. Cumulative patient exposure to TDF since first marketing approval is estimated to be 455,392 patient-years of treatment. TDF is administered as a single 300 mg tablet (Viread). • The most common adverse events that occurred in patients receiving TDF with other antiretroviral agents in clinical trials were mild to moderate gastrointestinal events, such as diarrhea, vomiting, and nausea. Laboratory abnormalities observed in these studies occurred with similar frequency in the TDF and placebo treated groups. • The safety of TDF for the treatment of HIV infection in clinical practice has not been fully characterized. Nephrotoxicity, including renal insufficiency and Fanconi’s syndrome, have been reported to occur infrequently but the incidence, risk factors, and time to resolution remain uncertain.

3. Objective • Evaluate the safety profile of TDF for the treatment of HIV infection, as observed in the Viread Global EAP and via spontaneous safety reports submitted to Gilead Drug Safety and Public Health Department through the first 4 years following commercial availability.

4. Methods • Viread EAP: Prior to commercial availability, a global expanded access program (EAP) was initiated in March 2001 for HIV-1 infected patients who failed prior HAART and had limited treatment options. To be eligible to participate, patients must have met the following criteria prior to dosing: age ≥ 18 years, confirmed laboratory diagnosis of HIV-1 infection, unable to construct a viable treatment regimen without Viread, had no hematologic, renal, or hepatic dysfunction, not pregnant or breast feeding and agreed to use effective barrier contraceptive method while receiving Viread. Initial study entry criteria included limitations on CD4 counts or HIV RNA at study entry. These specific criteria (CD4 and HIV RNA) were removed shortly after the start of enrollment in all countries.

5. Methods (cont’d) • At total of 10,343 patients were enrolled in the EAP: 654 (Australia), 348 (Belgium), 1,761 (Canada), 1857 (France), 411 (Germany), 12 (Ireland), 553 (Italy), 256 (Netherlands), 58 (Portugal), 576 (Spain), 819 (United Kingdom), and 3,038 (United States). • Data is available on all patients in the Viread EAP for serious adverse events (SAEs). SAEs were tabulated, and SAEs of clinical importance were characterized. Serum creatinines were collected in over 1,600 patients in the Viread EAP. Risk factors for development of graded creatinine abnormalities were determined using mulitvariate logistic regression models. • Post marketing safety data: Adverse drug reactions (ADRs), both serious and non-serious received through spontaneous reporting up to April 30, 2005 have been collected and analyzed. Reporting rates for individual serious ADRs (SADRs) have been calculated. Based upon an estimated 455,392 patient-years of exposure to TDF (estimated from sales data).

6. Methods (cont’d) • Although reporting rates do not represent the true incidence of SADRs (as post marketing SADRs tend to be underreported and are subject to various reporting biases), the pattern of SADRs reporting in the post-marketing database was compared with the pattern of SAEs reported in the EAP. For patients with renal ADRs the renal events were grouped into relevant categories (renal failure, renal tubulopathy, etc.), and the time to event onset and resolution were calculated. Concomitant risk factors for renal disease were tabulated. For patients with renal ADRs where serum creatinine values were provided, time to onset, median maximal serum creatinine, and time to resolution of serum creatinine were determined.

7. Summary of Demographic and Baseline Disease Characteristics for the Viread EAP

8. Summary of Demographic and Baseline Disease Characteristics for the Viread EAP (cont’d) a. The collection of Baseline HIV RNA and CD4 were no longer required by the protocol shortly after the initiation of the EAP in the US.

9. SAEs from EAPa,b and Most Common SARDs from Post Marketing Safety Databasec(Excluding SAEs listed in Specific SAE Categories of Interest and Serious Renal Adverse Event Categories)

10. SAEs from EAPa,b and Most Common SARDs from Post Marketing Safety Databasec(Excluding SAEs listed in Specific SAE Categories of Interest and Serious Renal Adverse Event Categories) (cont’d) mL g/ h C ( U A • Repeated by  0.1% of patients. • SAEs were reported by 631 patients (6%) in the EAP, and 211 patients (2%) had related SAEs. • 1.3 per 100,000 person years. • Reporting rates do not represent the true incidence of SADRs as PM events tend to be underreported and are subject to various reporting biases.

11. Specific SAE Categories of Interesta ) CL/F (mL/min • Adverse events sometimes associated with ARV use. Each category includes multiple related SAE terms • Incidence of pancreatitis was 0.7% in patients taking didanosine and 0.3% in patients not taking didanoise (p <0.001) • c. See footnote d, SAEs from EAPa,b and Most Common SADRs from Post Marketing Safety Databasec.

12. Serious Renal Adverse Event Categoriesa • Each category includes multiple related SAE terms. • Patients can have > 1 event. • Reporting rate for non-serious renal events was 61.5 events per 100,000 person years. • See footnote d, SAEs from EAPa,b and Most Common SADRs from Post Marketing Safety Databasec.

13. Viread EAP: Abnormalities in Serum Creatininea • Patients in Viread EAP with available serum creatinine data.

14. Viread EAP: Risk Factors for Unconfirmed ≥ Grade 1 Serum Creatinine Increase – Multivariant Analysis • All patients with a baseline and followup serum creatinine, and relevant information on risk factors available (n = 911). • Other risk factors evaluated in the model but did not reach significance were: – Abacavir taken at baseline, didanosine taken at baseline, LPV/r taken at baseline, lamivudine taken at baseline, stavudine taken at baseline, baseline creatinine, baseline HIV RNA - ordinal categories, CDC classification, coinfection with HBV, days since HIV diagnosis, diabetes at baseline, gender, hypertension at baseline, ACE inhibitors at baseline, and nephrotoxic antibiotics at baseline.

15. Viread EAP: Risk Factors for Unconfirmed ≥ Grade 2 Serum Creatinine Increase – Multivariant Analysis • All patients with a baseline and followup serum creatinine, and relevant information on risk factors available (n = 911). • Other risk factors evaluated in the model but did not reach significance were: • Abacavir taken at baseline, didanosine taken at baseline, LPV/r taken at baseline, lamivudine taken at baseline, stavudine taken at baseline, age, baseline CD4-ordinal categories, baseline HIV RNA ordinal categories, CDC classification, coinfection with HBV, days since HIV diagnosis, diabetes at baseline, gender, hypertension at baseline, nephrotoxic medications taken at baseline, ACE inhibitors at baseline, and nephrotoxic antibiotics at baseline.

16. Post Marketing Safety Database: • For all post marketing renal events with creatinine data, the median maximum serum creatinine was 2.3 mg/dL (IQR 4.1). • For post marketing serious renal events with creatinine data, the median maximum serum creatinine was 2.7 mg/dL (IQR 4.4).

17. Post Marketing Serious Renal Events – Time to Onseta All serious renal events with TDF start date and event onset data available. Reporting rate 29.2 events per 100,000 person-years. Median time to onset for all post marketing serious renal adverse events was 282 days (IQR 443 days).

18. Post Marketing Renal Events: Median Time to Resolution of Serum Creatininea KM analysis of renal spontaneous reports with serum creatinine data available, time to resolution from TDF stop data. Includes maximum grades 1, 2, 3, and 4. Includes maximum grades, 2, 3, and 4. Includes maximum grades 3 and 4.

19. Possible Concomitant Risk Factors for Renal/Urinary Events Reported Between 1 November 2004 and 30 April 2005a Spontaneous and serious, related clinical trial adverse event reports. Each case may involve more than one alternative cause. Reporting rate of 86 per 100,000 person years. Restricted to drugs well known for causing renal toxicity. Rhabdomyolysis, drug / alcohol abuse, liver disease, chemotherapy, hx low phosphate.

20. Conclusions • The most common SAEs reported in the Viread EAP were pneumonia (0.6%), pancreatitis (0.5%), fever (0.4%), bacterial infection (0.3%), and lymphoma (0.3%). No individual SAE was reported in > 1% of patients. • The incidence of all serious renal SAEs was 0.5% amongst 10,343 patients in the Viread EAP. • The most common SADR categories reported in post-marketing safety surveillance were renal, pancreatitis, lactic acidosis, and fever. The pattern of renal events is similar in the post-marketing safety database and the Viread EAP database. • Possible risk factors for renal events reported in the postmarketing safety database include concomitant nephrotoxic medications, late stage HIV, past history of renal disease, and sepsis. • For all post marketing renal events with creatinine data, the median maximal serum creatinine was 2.3 mg/dL, and the median time to resolution to ≤ Grade 2 serum creatinine was 29 days.

21. Conclusions (cont’d) • In multivariate analysis of data from Viread EAP, risk factors forincrease in serum creatinine included low CD4 cell count, older age, low baseline weight, higher baseline serum creatinine, and concomitant nephrotoxic medications, but coadministration of Kaletra was not a risk factor. • Bone fractures, neuropathy, and mitochondrial toxicity were reported infrequently in both the Viread EAP (≤ 0.1%) and in the postmarketing safety database. • The safety profile of tenofovir DF observed in the Viread EAP confirms and extends the safety profile observed in the tenofovir DF clinical trials program. No new major unexpected toxicities have been observed in the post marketing safety surveillance program through 4 years observation.

22. Acknowledgments Gilead Sciences , Inc., would like to thank the large number of patients, physicians, and their research personnel who have participated in the Viread EAP and the CROs that assisted in the conduct of these studies: Parexel International; Ingenix Pharmaceutical Services, Inc.; and Charles River Labaratories. Additional members of the Viread Global Expanded Access Program include B Gazzard (UK), H Gallais (France), A Lazzarin (Italy), A Adam (Germany), B Clotet (Spain), R Colebunders (Belgium), J Lange (The Netherlands), MJ Aguas (Portugal), F Mulcahy (Ireland), S Follansbee (USA), J Elder (Charles River Laboratories), M Wulfsohn, L Metzler, A Cheng, and N Bischofberger (Gilead Sciences).