Primary Care's 2014 Lessons: The Research Changing Practice

Linda Brookes, MSc


December 18, 2014

In This Article

CV Risks With Testosterone: Europe Has the Last Word, for Now

Testosterone therapy is available worldwide in a range of formulations, including patches, gels, creams, pills, injections, and pellets. It is indicated in hypogonadism, but not to boost testosterone levels in otherwise healthy men. Its use has been linked to increased CV risk, which was addressed this year by both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). A number of studies suggested the possibility of an increased risk for CV events in men treated with testosterone, particularly MI in men with pre-existing heart disease. In November, the EMA announced that its Pharmacovigilance Risk Assessment Committee (PRAC) had concluded that "there is no consistent evidence of an increased risk of heart problems with testosterone medicines in men with hypogonadism," and that this conclusion had been adopted by the European Union's regulatory body.[11,12] Taking all of the data into account, PRAC said, "The signal for an increased cardiovascular risk associated with the use of testosterone remains weak and inconclusive." PRAC also pointed out that testosterone deficiency itself could increase the risk for CV events. However, PRAC recommended updating the product information to include warnings about complications in people who might be at increased risk for heart problems, such as those with severe cardiac, hepatic, or renal insufficiency or ischemic heart disease and in those with pre-existing hypertension.

In September, an FDA advisory panel failed to reach a conclusion that testosterone therapy increased the risk for major adverse CV events or death, but voted in favor of requiring CV safety studies in the age-related hypogonadism population.[13] Earlier in the year, the FDA had called for all testosterone product labels to carry a warning about the potential risk for venous thromboembolism.[14] Both the FDA and the EMA are continuing to monitor reports of CV events and ongoing studies such as the Testosterone Trial (TTrial), which is expected to report soon.[15]

A New Era in HCV: Cure With a Serious Cost

In October the FDA approved the first combination pill to treat chronic hepatitis C virus (HCV) genotype 1 infection, the most common HCV subtype in the United States.[16.17] Harvoni® consists of two oral direct-acting antiviral agents: a nucleotide analog NS5B polymerase inhibitor, sofosbuvir (400 mg), and an NS5A inhibitor, ledipasvir (90 mg). It is the first approved regimen for HCV that does not require coadministration with interferon or ribavirin. Ledipasvir is the third new drug approved to treat chronic HCV infection by the FDA in the past 12 months, following simeprevir and sofosbuvir.

Approval for ledipasvir/sofosbuvir was supported by data from three phase 3 studies: ION-1,[18] ION-2[19] and ION-3.[20] These studies evaluated 8, 12, or 24 weeks of treatment, with or without ribavirin, among nearly 2000 patients with HCV-1 infection. In aggregate, these studies included patients with and without cirrhosis, and treatment-naive patients as well as those who failed prior therapy with an interferon-based regimen, including regimens containing an HCV protease inhibitor. The primary endpoint for each study was sustained virologic response (HCV undetectable) 12 weeks after completing therapy (SVR12), when patients are considered cured. Patients in the three trials who received the ribavirin-free regimens (n = 863) achieved SVR12 rates of 94%-99%. Ribavirin did not increase response rates. Adverse events were minimal and fewer adverse events were observed in the ribavirin-free arms. The most common adverse reactions among patients treated with ledipasvir/sofosbuvir (≥ 5%) were fatigue, headache, nausea, diarrhea, and insomnia.

The prospect of a cure for HCV infection has raised expectations, but the high costs of all the new drugs have also raised concerns about the effects on medical insurance premiums and strains on state Medicaid budgets.[21] Without mentioning costs, new guidelines from the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America (IDSA)[22] recommend prioritizing treatment for patients who are most likely to benefit, such as those with advanced liver diseases or other severe symptoms.


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