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By Carol A. Kemper, MD, FACP, Clinical Associate Professor of Medicine, Stanford University, Division of Infectious Diseases; Santa Clara Valley Medical Center, Section Editor, Updates; Section Editor, HIV, is Associate Editor for Infectious Disease Alert.
Ketek's Troubled History
Sources: Ross DB. The FDA and the case of Ketek. N Engl J Med 2007; 356, 16:1601-1604. Wall Street Journal, Monday May 1, 2006, page A1.
Nearly one year following an in-depth report in the Wall Street Journal, and a brief synopsis in IDA (see June 2006, C. Kemper), this author, who was involved in the FDA review of telithromycin, provides a closer look at the events leading up to and following the FDA approval of telithromycin in the United States.
As some readers may be aware, serious questions were raised in 2002-2003 regarding the integrity of data from a large outpatient clinical investigation (Study 3014) of telithromycin conducted at more than 400 sites in the United States. Further investigation eventually uncovered serious problems with data collection, fraudulent data, and manufactured patients at 10 sites (all heavy enrollers of study subjects), and criminal proceedings in at least one case eventually resulted in a jail sentence for one of the investigators. However, this same data was presented to an FDA Advisory Committee for drug review and approval in January 2003 without the committee's awareness of these concerns. FDA managers stated they were barred from disclosing concerns because of the active investigation, although the data were nonetheless provided for review. Based on their review of the data, the committee voted 11 to 1 to recommend approval.
In an unexpected move, that makes better sense in retrospect, the FDA chose to ignore the committee's recommendation, indicating additional data was required. Then, in a broad deviation from FDA practice, they approved telithromycin for use in sinusitis, bronchitis and community-acquired pneumonia in April 2004 based on foreign post-marketing data. While the post-marketing data, which was extensive and suggested the drug was safe, was reviewed, there was apparently no attempt to verify its validity. Such data is reliable only in so much as drug sponsors and clinicians elect to submit reports of adverse events, assuming they can identify a complication as an adverse event.
Gradually, information about the problems with Study 3014 and irregularities in the FDA's approval process for telithromycin began to come to light. None of which would have captured much attention except for the emergence of reports of hepatoxicity in patients receiving drug. By the time Congress became interested in May and June 2006, there were 23 cases of acute severe liver injury and 12 cases of liver failure, including 4 deaths, associated with the use of telithromycin. By December 2006, there were 53 suspected cases.
Sixteen months after the first reports of liver failure were submitted to the FDA in 2005 for review, the FDA relabeled Ketek to indicate possible severe hepatotoxicity. Withdrawal of FDA approval for use in acute bacterial sinusitis and acute and chronic bronchitis occurred in February 2007 — one day before a Congressional hearing on Ketek.
Only 3 days earlier, and despite acknowledging the problems with Study 3014, the FDA removed Study 3014 on its website as a citation in support of the initial drug review.
Death in Venice — And Other Parts of the World
Source: MacPherson DW et al. Death and International Travel - The Canadian Experience: 1996-2004. J Trav Med 2007, 14 (2), 77-84.
Data suggest that death during international travel is increasing, in part because of wilderness and adventure travel, but also because more and more people are traveling. Deaths abroad have considerable impact on friends and family, as well as the pocketbook. As part of the Secure Integrated Global Network established in 1993, the Consular Services Bureau, part of the Foreign Affairs Office in Canada, tracks Canadian deaths abroad, including the cause of death, sex and age. Specific data on the purpose of travel, or whether work or pleasure related was not always available.
From 1996-2004, 2,410 Canadians died while traveling abroad. Interestingly, deaths in the United States (297), Germany (240) and China (115) topped the list, far exceeding deaths in Africa (95), generally considered a riskier destination. Two-thirds of the deaths occurred in men, and the average age was just over 60 years (range, 0 to 101). Natural causes of death occurred in 73%, followed by accidental death in 19%, murder in 4% and suicide in 4%. People who died of natural causes averaged age 66 compared with those who died by accident (45 years), murder (43 years), or suicide (41 years). Annual increases in accidental deaths were observed, most likely because of wilderness and adventure travel.
In examining the top 15 destinations for 2004, deaths per 1000 visits were greatest for China (241), Mexico (82), Italy (43), Japan (31), and Spain (30). Obviously the causes and risks for each of these countries vary considerably, but it is of interest that travel to China was associated with such significant risk.
It would be useful if pre-travel medicine could address but the authors found that most pre-travel advice, vaccines, anti-malarials and diarrhea management would not have prevented most of these fatalities. Violent deaths from vehicular accidents remain a significant problem; traffic fatalities and injuries affect 1.2 million and 50 million persons annually around the world, and are expected to increase 65% during the next 2 decades. Murder was generally associated with robbery, assault, or sexual violence, and aside from garden variety advice to use common sense, there is little that travel practitioners can offer. Little is known whether suicides, an unexpected cause of death in 4% of international Canadian travelers, were pre-planned, occurred in persons with mental illness, or as the result of some travel-related event.
Two items that travel practitioners should include in their list for discussion are verification of insurance coverage during illness abroad (for example, some travel insurance provides only limited coverage or coverage solely for "emergencies" with a cap); as well as providing advanced directive, power of attorney and directions on handling remains. For example, shipping a whole body is hugely expensive whereas cremation is cheap.
Lactic Acidosis in Africans Receiving HAART
Source: Bolhaar MG and Karstaedt AS. A high incidence of lactic acidosis and symptomatic hyperlactatemia in women receiving highly active antiretroviral therapy in Soweto, South Africa. Clin Infect Dis 2007; 45:254-260.
Nucleoside reverse transcriptase use in persons with HIV infection has been associated with elevated lactic acid levels and lactic acidosis, presumably related to mitochondrial toxicity. Although first described in 1990 in persons receiving didanosine, symptomatic hyperlactatemia and lactic acidosis is more commonly associated with the use of stavudine, especially when combined with didanosine. Mortality of 30%-100% has been reported in persons developing lactic acidosis from antiretroviral use.
In a retrospective cohort analysis, these authors identified the incidence and risk factors for symptomatic hyperlactatemia and lactic acidosis in 1735 HIV+ adults receiving highly active antiretroviral therapy (HAART) in Soweto, South Africa in 2004-2006. (Drugs such as abacavir and tenofovir were not available at that time). Most of the patients were treatment naïve. Only patients with confirmed elevations > 4.5 mmol/L were included in the analysis. Lactate levels were not routinely performed but only at the discretion of the treating clinician when symptoms suggested possible toxicity.
The overall incidence of symptomatic hyperlactatemia and lactic acidosis was 30.8 cases per 1000 patients years of HAART therapy. One of the 2 syndromes was found in 1 of every 18 women (5%) and 1 of every 80 men (1.2%). With 23-months of observation, 23 patients experienced lactic acidosis, including 22 women (1 pregnant) and 1 man. The mortality rate was 30.4%, despite supportive care and discontinuation of HIV treatment (at the lower end of that described in published reports). Presenting symptoms included nausea, vomiting, abdominal pain (87%), weight loss (74%), and dyspnea (56%). Twenty-two of the patients were receiving stavudine (at the standard dose), including one who received stavudine and didanosine in combination.
Forty-four persons, including 37 women, developed symptomatic hyperlactatemia; thus, 1of every 30 women and 1 of every 92 men developed symptomatic hyperlactatemia during HAART therapy. All 44 patients were receiving stavudine, including 3 who took it with didanosine. The most common symptoms were weight loss (75%) and anorexia (61%). None of these patients died.
Therapy was interrupted in all of the patients identified. In most cases, therapy was reinitiated, switching to zidovudine, none of whom relapsed.
In addition to the use of stavudine with or without didanosine, 2 risk factors for lactic acidosis and symptoms hyperlactatemia were identified. A longer duration of use was associated with a greater risk of toxicity. The mean duration of stavudine use before developing lactic acidosis was 34 weeks (range 17 to 76 weeks). In addition, a BMI ≥ 30 at baseline appeared to be a significant risk factor, and was found in 24% of patients initiating HAART. BMI data, available for 19 of the 23 patients who developed lactic acidosis, indicated that 8 (35%) of these patients were considered obese with a BMI ≥ 30, and 5 (22%) were overweight with a BMI of 25-30. None were underweight. Similar findings were observed for patients who developed symptomatic hyperlactatemia.
This study summarizes the risk of lactic acidosis in South Africans initiating HAART, especially in women (16.1 cases per 1000 patient years), all but one of whom received stavudine. The lack of consistent definition of lactic acidosis in the literature causes some confusion, and renders it difficult to directly compare this with other data. In addition, because lactic acid levels were not prospectively collected on a routine basis in these patients, the incidence of hyperlactatemia or lactic acidosis may be underestimated. It would be useful to better understand the risk of progression from asymptomatic elevations of lactic acid to the development of symptomatic or fatal complications.