The largest safety analysis so far of tenofovir disoproxil fumarate (Viread) has shown low rates of serious adverse events (SAEs) and demonstrated a “favourable safety profile” for the drug. Serious adverse events were observed in 6% of the Expanded Access Program (EAP) patients and considered related to tenofovir in 2%; kidney-related SAEs were seen in 0.5%. The report, by a multinational study team, was published in the June edition of AIDS.
Tenofovir disoproxil fumarate, a nucleotide analogue, was approved for marketing in the United States in 2001 and in the United Kingdom and Europe in 2002. Reports from clinical trials have included side-effects ranging from mild to moderate gastrointestinal upset to more severe adverse events. Reports of elevated serum levels of creatinine (a sign of impaired kidney function) and rare incidents of Fanconi’s syndrome (a life-threatening kidney dysfunction) led to concern over tenofovir’s potential kidney toxicity. Ongoing studies have tended to confirm tenofovir-related kidney toxicity as occurring less frequently than originally feared, and generally in people with additional risk factors.
The new report, based on data from the tenofovir Expanded Access Program plus four years of post-marketing safety data, represents the largest safety analysis of tenofovir to date. The EAP enrolled 10,343 patients in twelve countries between March 2001 and March 2004 (after which point tenofovir was approved in most countries). Importantly, the researchers note that the EAP included only people without pre-existing elevations in serum creatinine (≥ 1.5 mg/dl), and that many clinical trials have also excluded people with a history of renal (kidney) disease – thereby eliminating many patients at particular risk for additional toxicity.
The analysis was also limited to serious adverse events – those which “result in hospitalisation or prolongation of hospitalization, death, disability, or require medical intervention to prevent permanent impairment.” Adverse events of lesser severity were not described.
Expanded Access Program data
Of the 10,343 EAP participants, 84% were male, the median age was 42, and the median baseline CD4 cell count (in the 7,791 for whom this data were available) was 215 cells/mm3. All had been on prior antiretroviral therapy. The cumulative EAP data represent approximately 3,700 person years of exposure; however, the median time on drug was only 16.1 weeks for individual participants.
Serious adverse events were reported in 631 participants (6%) and were deemed related to tenofovir in 211 (2%). Not a single SAE was reported in more than 0.6% of the EAP patients. Only three distinct SAEs were reported in 0.5% or more of the patients: pneumonia (0.6%), pancreatitis (0.5%) and kidney-related SAEs of any kind (0.5%). Of the 56 reported renal SAEs, 32 (0.3%) were acute or chronic renal failure and 10 (
Serum creatinine levels were more extensively analysed in a subgroup of 1,704 EAP recipients in France, Germany and Italy. In this group, creatinine levels were elevated to grade 1 levels or above (≥0.5 mg/dl from baseline) in 37 (2.2%), and grade 2 or above (≥2.0 mg/dL) in 11 (0.6%). Overall median changes through month thirteen were “small and nonprogressive.” By multivariate analysis, the risk factors for increased creatinine (grade 1 or higher) were additional kidney-toxic medications, increased age, lower CD4 cell count and lower body weight. The only predictors of grade 2 or greater elevations were baseline creatinine levels (odds ratio [OR] = 17.4, 95% confidence interval [CI] 1.64 – 184.1, p = 0.018) and body weight (in kg, OR=0.88, 95% CI 0.82 – 0.95, p = 0.001).
Post-marketing safety data
Analysis was also done on data from post-marketing safety reports (a voluntary system through which healthcare providers can report adverse events) provided up to April 2005. The longer-term post-marketing data represented an additional estimated 455,392 person years of drug exposure. As the researchers note, however, post-marketing systems are underutilised and can be expected to significantly under-report adverse events. In terms of reports per person year, post-marketing data did in fact report vastly lower apparent incidences of SAEs. However, the relative reported frequencies of individual AEs followed a very similar pattern to those seen in the EAP, tending to validate the EAP reports.
The researchers report that their findings “confirm and extend the findings from controlled clinical trials and indicated a favourable safety profile for tenofovir DF in the treatment of adults with HIV infection.”
While the larger safety analysis identified virtually no new or unexpected SAEs, a letter describing case reports of tenofovir-associated skin rashes was published in the same journal issue. Clinicians at Oklahoma Health Sciences Center reported nine cases of itchy skin rash in people who had started tenofovir – a reaction noted in preliminary studies of tenofovir but not in most subsequent reports. In most cases the rash involved the face; it began a mean of 15 days after beginning tenofovir and recurred in most of the people who discontinued but then restarted the drug.
In related news, two reports at the recent Third International Workshop on HIV and Hepatitis Coinfection indicated that tenofovir appears effective and relatively safe for people coinfected with HIV and hepatitis B virus (HBV). Tenofovir is not currently licensed for treatment of HBV. However, studies presented at this conference showed favourable, sustained HBV viral load responses in two small groups of HIV/HBV coinfected people who had been treated with tenofovir for four to five years. Tenofovir-related adverse events (kidney problems and osteoporosis) caused treatment to be discontinued in four of 39 patients in one study; none of the 12 in the other study discontinued the drug.
Reference
Nelson MR et al. The safety of tenofovir disoproxil fumarate for the treatment of HIV infection in adults: the first 4 years. AIDS 21: 1277 –1281, 2007
Lockhart SM et al. Cutaneous reactions with tenofovir disoproxil fumarate: a report of nine cases. AIDS 21: 1370–1373, 2007.
Mauss S et al. Long term suppression of HBV by tenofovir in HIV/HBV-coinfected patients. Third International Workshop on HIV and Hepatitis Coinfection, abstract 38, Paris, 2007.
Tan L et al. Long term treatment with tenofovir in an open label study of individuals co-infected with HIV and hepatitis B. Third International Workshop on HIV and Hepatitis Coinfection, abstract 41, Paris, 2007.