Abstract
New Safety Profile Data For Cervical Cancer Vaccine
A
The vaccine is approved for use in the United States in girls and women 9 to 26 years of age for the prevention of cervical, vulvar, and vaginal cancers; precancerous or dysplastic lesions; and genital warts caused by HPV Types 6, 11, 16 and 18. Already, it has been approved in 112 countries, and additional applications are currently under review with regulatory agencies in many more countries around the world.
In August, the FDA issued a summary of Gardasil's vaccine safety monitoring activities and findings. Based on ongoing assessments of vaccine safety information, the FDA and CDC continue to find that Gardasil is a safe and effective vaccine. The CDC's Advisory Committee on Immunization Practices (ACIP) recommends a routine 3-dose vaccination series for girls 11 and 12 years of age. The vaccine is also recommended for girls and women ages 13 through 26 years who have not yet been vaccinated or who have not received all three doses.
VAERS receives reports of many events that occur following immunization. Some of these events may occur coincidentally during the time period following vaccination, while others may actually be caused by vaccination. In the analysis of VAERS data, researchers look for patterns of adverse events that may be plausibly linked to a vaccine. Such patterns of adverse events may require further study.
On August 19, 2009, the FDA and CDC coauthored an article that reviewed the safety data for Gardasil for select adverse events that have been reported to VAERS, from the time period starting from product licensure in June 2006 through December 31, 2008. The article describes 12,424 reports of adverse events following Gardasil vaccination. Of these, 772 were reports of serious events (6.2% of the reports) and the remaining 11,652 (93.8%) were classified as nonserious. During this time period, the manufacturer, Merck and Co., has distributed over 23 million doses of Gardasil in the United States.
In VAERS, a higher proportion of Gardasil reports were of syncope and venous thromboembolic events (VTEs) compared with other vaccines. However, none of the adverse events in the safety review, including syncope and VTEs, were reported at rates (number of adverse events/number of doses distributed) greater than expected in a population of this age and gender and with other known contributing factors to these adverse events. VAERS reports include syncope, pain at the injection site, headache, nausea, and fever. Fainting is common after injections and vaccinations, especially in adolescents.
Thromboembolic disorders have been reported to VAERS in people who have received Gardasil. Most of these individuals had risk factors for blood clots such as use of oral contraceptives which are known to increase the risk of clotting. The article describes 56 cases, 31 of which were confirmed blood clot reports. Twenty-eight reports (90%) had underlying known risk factors such as hormonal birth control, genetic clotting abnormalities, obesity, smoking, and immobility. In the CDC's VSD, blood clots have not been found to occur more often than expected after over 450,000 doses of Gardasil.
Concerns have also been raised about reports of deaths occurring in individuals after receiving Gardasil. As of December 31, 2008, 32 deaths had been reported to VAERS. There was not a common pattern to the deaths that would suggest they were caused by the vaccine. In the majority of cases, the cause of death was explained by factors other than the vaccine.
More details on the FDA's and CDC's safety analysis can be found in the August 19th issue of JAMA, 2009;302(7):750–757.
Advisory Committee Recommends Gardasil® for Boys and Men
The U.S. Food and Drug Administration's (FDA) Vaccines and Related Biological Products Advisory Committee has agreed that efficacy, immunogenicity, and safety data from clinical trials in males support the use of Gardasil® in boys and men 9 through 26 years of age for the prevention of genital warts caused by human papillomavirus (HPV) types 6 and 11.
The committee's recommendation will be considered by the FDA in its review of the supplemental Biologics License Application (sBLA) that Merck submitted for Gardasil in December 2008. Merck expects a decision from the FDA in the fourth quarter of 2009 after the agency has completed its review of the application.
Clinical trials presented to the Advisory Committee evaluated the efficacy, immunogenicity and safety of the vaccine in boys and men 9 to 26 years of age. Vaccine efficacy in males was evaluated in a randomized, double-blind, placebo-controlled trial. A total of 4,055 men were enrolled and received at least one dose of the vaccine or placebo. Of these, 3,457 were heterosexual men aged 16 to 23 years and 598 were men who have sex with men aged 16 to 26 years.
In the per-protocol efficacy (PPE) analysis, Gardasil was 90.4% efficacious (95% CI: 69.2, 98.1) against HPV 6, 11, 16 and 18-related EGL. Of 34 cases of EGL, 31 were genital warts. All cases of genital warts were positive for HPV 6 and/or 11 (three cases in the vaccine group and 28 in the placebo group). The vaccine was 89.3% efficacious (95% CI: 65.5, 97.9) against HPV 6/11-related external genital warts.
There were three cases of HPV 6/11/16/18-related penile/perianal/perineal intraepithelial neoplasia (PIN) in the PPE analysis and all were in the placebo group. No cases of penile/perianal/perineal cancers were observed in the vaccine or placebo groups during the study. Although vaccine efficacy against HPV 6/11/16/18-related PIN 1 or worse was 100% (95% CI: <0, 100), there was no statistical significance due to the small number of cases seen in the study.
In the full analysis set (FAS) analysis, Gardasil was 65.5% efficacious (95% CI: 45.8, 78.6) against HPV 6, 11, 16 and 18 EGL. Of 104 cases of EGL, 95 were genital warts positive for HPV 6 and/or 11 (24 cases in the vaccine group and 71 in the placebo group). Gardasil was 66.8% efficacious (95% CI: 46.5, 80.0) against HPV 6/11-related external genital warts in this analysis.
In immunogenicity studies, Gardasil generated robust immune responses to HPV types 6, 11, 16 and 18 in 9- to 15-year old boys and 16- to 26-year old men. Immunobridging studies in 9- to 15-year old boys demonstrated that boys had approximately two- to threefold higher HPV type-specific antibody levels at month 7 compared to 16- to 26-year old men. These data established the non-inferiority of the peak immune response as measured at month 7 for all four HPV-types in boys as compared to men.
Resistant TB Strain Caused by Fluoroquinolone Use
Widespread use of fluoroquinolones may be producing a resistant strain of TB. The antibiotic class is considered a first-line therapy for TB that shows signs of drug resistance.
Researchers from Vanderbilt University investigated the causes of the small but growing proportion of fluoroquinolone-resistant TB cases. They performed a retrospective case-control study using data from the Tennessee Department of Health. Records of every newly diagnosed patient with culture-confirmed TB who was also enrolled in Tennessee's Medicaid program, TennCare, between January 2002 and December 2006 were analyzed. Using the TennCare pharmacy database, they were able to obtain information on the patients' use of fluoroquinolone for the 12 months prior to their TB diagnosis. They used M. tuberculosis isolates taken from each patient to test for fluoroquinolone resistance in each case.
After excluding those who were not enrolled in TennCare or whose culture was either unavailable or unusable, the researchers analyzed data for 640 patients. Age, race, and other demographic factors were not significantly associated with resistance. However, the researchers found a linear association between previous fluoroquinolone exposure and resistance.
Overall, patients who had used fluoroquinolones within 12 months of diagnosis were almost five times as likely to have a fluoroquinolone-resistant strain of TB compared to those who had not used the antibiotics. There was a linear association between the length of fluoroquinolone use and fluoroquinolone resistance. Patients undergoing shorter treatment (less than 10 days) had a relatively low rate of resistance of only 1.6%. However, for every additional 10 days of fluoroquinolone use, the research team found that patients had a 50% increase in the likelihood of having resistant TB. Of the 116 people who had taken fluoroquinolones, 13% had fluoroquinolone-resistant TB. Resistance was highest among those who had undergone treatment more than 60 days prior to TB diagnosis.
The study was published in the August 15th issue of the American Journal of Respiratory and Critical Care Medicine, 2009;180(4):365–370.
HIV Genome Structure Decoded
University of North Carolina at Chapel Hill researchers have decoded the structure of an entire HIV genome. The accomplishment paves the way for additional research and the development of new antiretroviral therapies. Before this attempt, only small regions of the HIV RNA genome had been modeled.
The researchers analyzed the architecture of HIV genomes isolated from infectious cultures containing trillions of viral particles that were grown by researchers at the National Cancer Institute (NCI). RNA structures were found to influence multiple steps in the HIV infectivity cycle. The study provides further information to unlock additional roles of RNA genomes in the life cycle of HIV. Researchers will be able to change RNA sequences to determine if HIV notices the change. Retarded growth after such mutations indicates that something important has been disrupted. The decoding of the HIV genome structure will also help researchers understand how HIV escapes detection by the human host.
More details can be found in the August 6th cover story of Nature 2009;400:711–716.
New Strain of HIV Discovered
A new strain of HIV has been found in a woman from Cameroon in Africa. The strain is different from the three currently identified strains of HIV related to the simian virus that occurs in chimpanzees. Researchers have found that the new strain is closely related to a variant of simian virus recently discovered in wild gorillas.
According to researchers from the University of Rouen, France, gorilla-to-human transmission is likely responsible for the new strain. However, it is possible that the new strain started in chimpanzees and moved into gorillas and then humans or moved directly from chimpanzees to both gorillas and humans.
The 62-year-old patient tested positive for HIV in 2004, shortly after she moved from Cameroon to Paris. While a resident in Cameroon, she lived near Yaounde, the capital. During interviews, the patient denied having any contact with apes or bush meat, a name often given to meat from wild animals in tropical countries. At the moment, she shows no signs of AIDS and remains untreated.
Researchers do not know how widespread the strain is. It may be circulating unnoticed in Cameroon or elsewhere. The strain replicates rapidly. This indicates that it has adapted to human cells.
The findings were published in the August 2nd issue of Nature Medicine 2009;15:871–872.
HIV Risk Continues after Herpes Sores Heal
People with genital herpes remain at increased risk of HIV infection even after the herpes sores have healed and the skin appears normal. Even after lesions appear to have cleared, immune-cell activity is still present that can promote the transmission of HIV.
Researchers at the Fred Hutchinson Cancer Research Center tested the skin of herpes patients for several weeks after their sores had healed. Compared with other genital skin, from 2 to 37 times more immune cells remained at the locations where the sores were once present. HIV was found to reproduce three to five times faster in tissue from the healed sites compared to tissue from other areas.
The study was published in the August 2nd issue of Nature Medicine 2009;15:886–892.
Similar Efficacy Found for Three Interferon Therapies for HCV
Results from the IDEAL trial demonstrate that three common interferon treatments for hepatitis C virus (HCV) are equally effective and have similar rates of side effects. A total of 14 institutions participated in the Individualized Dosing Efficacy Versus Flat Dosing to Assess Optimal Pegylated Interferon Therapy (IDEAL) study, which took place over 2 years.
The IDEAL trial, conducted between March 2004 and June 2006, included 3,070 patients with the most common and difficult to treat form of HCV infection. Participants, who had not received prior treatment, were assigned randomly to groups that received one of the three treatments. The first two groups received a standard and a low dose of peginterferon alfa-2b, respectively. The third group received peginteferon alfa-2a. All three groups received their interferon with ribavirin.
Participants received 48 weeks of treatment and then were followed for 6 months to see if HCV cleared from blood samples. Each group achieved about 40% clearance of the virus. Side effects included extreme flu-like symptoms such as fever, chills, fatigue, depression, muscle aches, chest pain, difficulty breathing, nausea, vomiting, and weight and hair loss. No differences in side effects among the three groups were noted. There was little difference overall in treatment results. However, women achieved higher rates of virus clearance with the standard dose of peginterferon alfa-2b.
Results of the two-year study were published in the August 6th issue of the New England Journal of Medicine 2009;361(6):580–593.