Clinical Trials News

In the United States, cervical cancer developed in an estimated 11,150 women and caused death in 3600 women in 2007.

2008-08-25T15:28:00.000-07:00

Image by AJC1 via Flickr

Infection with high-risk "oncogenic" types of human papillomavirus (HPV) is the cause of 100% of cervical cancers, 90% of anal cancers, 40% of vulvar and vaginal cancers, at least 12% of oropharyngeal cancers, and 3% of oral cancers.2 Worldwide, HPV types 16 (HPV-16) and 18 (HPV-18) cause approximately 70% of cases of cervical cancer.3,4

Vaccines against HPV-16 and HPV-18 appear to be highly efficacious in preventing HPV-16 and HPV-18 infections and cervical lesions in girls and women who have not previously been infected with these types.5,6,7,8,9 The vaccine currently licensed in the United States also prevents HPV types 6 and 11 (HPV-6 and HPV-11), which are responsible for most genital warts and juvenile-onset recurrent respiratory papillomatosis.10

There are important questions regarding the appropriate target population for prophylactic vaccination against HPV-16 and HPV-18. Since the vaccine is most efficacious before the onset of sexual activity, most investigators agree that the target population for routine immunization should be adolescents who are approximately 12 years of age.11,12 Recommended temporary catch-up programs to provide vaccine coverage to girls and women 13 years of age and older range from an upper age limit of 18 to 26 years.11,12

The impact of HPV vaccination on the rate of cervical cancer will not be observable for decades; thus, decisions regarding a vaccination policy will inevitably rely on studies reporting intermediate outcomes. Estimating the magnitude of the benefit of vaccination is further complicated when one considers the extensive secondary-prevention program in the United States. This program, which involves the use of cytology-based screening, is recommended annually or biennially, starting 3 years after the first sexual intercourse and no later than 21 years of age.13,14,15 HPV DNA testing is recommended as a triage test for equivocal results of cytologic analysis and in combination with cytologic tests for primary screening in women 30 years of age or older.16

Before long-term data become available, mathematical models used in a decision-analytic framework that synthesize the best available data while ensuring consistency with epidemiologic observations can project outcomes beyond those reported in clinical trials, provide insight into key drivers of cost-effectiveness, and be revised as new information emerges. Extending previous studies of HPV vaccination,17,18,19,20,21,22 we evaluated the cost-effectiveness of vaccinating 12-year-old girls and of temporary catch-up programs. We considered the dynamics of HPV transmission, the duration of vaccine efficacy, the potential benefits of preventing noncervical HPV-related conditions, the anticipated changes in screening practice, and potential disparities in access to care.

Discussion

Vaccination against HPV-16 and HPV-18 is expected to be economically attractive (i.e., <$50,000 per QALY) if high coverage can be achieved in the primary target group of 12-year-old girls and if vaccine-induced immunity is lifelong. Under these conditions, if we are willing to pay $100,000 per QALY, a catch-up program for girls between 13 and 18 years of age appears to be reasonable, especially when we include the benefits of averting genital warts (with the use of the quadrivalent vaccine) or the benefits of cross-protection against other high-risk types of HPV not including HPV-16 and HPV-18 (as reported with the bivalent vaccine). Extending the catch-up program to 21 years of age is less cost-effective, but it also becomes more favorable when the potential benefits of preventing noncervical HPV-16–associated and HPV-18–associated cancers in women are included.

Extending vaccine coverage to women up to 26 years of age generally exceeds $130,000 per QALY. This result is not unexpected, since nearly 90% of women in the United States have had vaginal intercourse by 24 years of age47 and up to 30% of women may be exposed to HPV in the first year of intercourse.54 The cost of extending a catch-up program to women up to 26 years of age is less than $100,000 per QALY only in the context of 100% lifelong efficacy against other outcomes associated with HPV-16, HPV-18, HPV-6, and HPV-11 in women; these outcomes include cervical cancer, warts, other cancers, and juvenile-onset recurrent respiratory papillomatosis. The cost of extending this program is more than $200,000 per QALY when a booster is required to maintain lifelong immunity, when there are disparities in screening and vaccination coverage, and when vaccinated girls undergo frequent screening in adulthood. The benefits of vaccine in most HPV-16 and HPV-18 noncervical cancers and HPV-6 and HPV-11 juvenile-onset recurrent respiratory papillomatosis have not been shown in clinical studies.

Our results were sensitive to the duration of vaccine-induced immunity; if immunity lasted 10 years, the vaccination of preadolescent girls exceeded $140,000 per QALY, and all catch-up strategies were less cost-effective than screening alone. Although immunologic data have provided support for a strong initial immune response with antibody levels persisting at a level higher than the level after natural infection,9,55,56 observations in published reports are limited to 5 years after vaccination. With partial natural immunity to type-specific infection, if a vaccinated girl loses vaccine-induced protection and becomes susceptible at a later age when the risk of cancer may be higher, an increased risk of cervical cancer is plausible. There are no empirical data to show whether reinfection or reactivation of a previous infection predominates in older women; as previously described,17 which one of these predominates will influence the implications of waning vaccine protection. There are other important uncertainties. Although HPV infections may be independent from one another,56 our exploratory analysis showed that replacement of the vaccine-targeted types of HPV with other high-risk types could be influential. Vaccination against HPV may also alter sexual behavior in the population or lead to a misperception that screening is no longer necessary. These uncertainties highlight the priorities for surveillance of epidemiologic characteristics and behaviors after vaccination against HPV.

Our results of vaccinating preadolescent girls were consistent with those of other studies.17,18,19,20,21,22,57,58 Elbasha et al.21 reported that the cost of a catch-up program in women up to 24 years of age was less than $5,000 per QALY; none of our strategies had a cost-effectiveness ratio this low, and the cost of a catch-up program in women up to 26 years of age generally exceeded $100,000 per QALY. Differences in assumptions have been summarized in several review articles.59,60,61 Our findings, which were consistent with those of others,20,22 were that high vaccination coverage warranted modification of screening protocols and that the cost-effectiveness of vaccination was enhanced with less frequent screening with more sensitive tests and beginning at later ages.

Our analysis has important limitations. Data on sexual behavior were primarily based on population averages from large surveys, and there were limited data on type-specific HPV transmission according to age and sex. By means of a model-fitting process, we estimated probabilities of transmission that were higher than those of some other analyses62,63; as better data become available, the estimation of these variables may be refined. Other limitations of the data included the incidence, mortality, and quality of life associated with noncervical HPV-related cancers, the long-term efficacy of the vaccine against cervical lesions and warts, and the efficacy of the vaccine against noncervical cancers. As with all model-based analyses, there are trade-offs with regard to the choice of model structure; we used two different modeling techniques to try to best capture the features of HPV infection and cervical carcinogenesis that were most relevant to the key policy questions. The complexities that are introduced with the use of multiple models should be explored further.24

A decision-analytic approach allows for acknowledgment of uncertainty while informing decisions that need to be made now. Accordingly, we emphasized broad qualitative themes that we found to be consistent throughout a range of assumptions. The cost-effectiveness of HPV vaccination in the United States will likely be optimized by achieving universal coverage in young adolescent girls and targeting initial catch-up efforts to girls and women younger than 21 years of age. Optimal synergies between vaccination and screening will involve revisions to current screening practice. Priorities for empirical data collection include surveillance to understand the HPV type-specific epidemiologic factors and screening behavior in vaccinated populations, the duration of vaccine-induced protection, and the long-term impact on other HPV-related conditions.

Supported by grants from the National Cancer Institute (R01 CA93435), the Centers for Disease Control and Prevention, and the American Cancer Society, and by the Bill and Melinda Gates Foundation (30505) for related work in developing countries.

Extended Antiretroviral Prophylaxis to Reduce Breast-Milk HIV-1 Transmission

2008-07-10T05:41:00.000-07:00

In sub-Saharan Africa, where breast-feeding is critical for infant survival, postnatal transmission of human immunodeficiency virus type 1 (HIV-1) occurs in up to 16% of untreated infants when breast-feeding continues into the second year of life.1 Although effective interventions have been identified to reduce in utero and intrapartum transmission of HIV-1 in resource-limited countries,2 breast-feeding attenuates the efficacy of such methods.3,4 Thus, a major concern in developing countries is HIV-1 transmission through breast milk.5 To optimize the survival of infants who are born to mothers with HIV-1 infection, interventions that allow safe breast-feeding during the first 6 months of life or longer are needed.
The aim of our trial, called the Post-Exposure Prophylaxis of Infants (PEPI) trial, was to determine whether extended prophylaxis of infants with nevirapine or with nevirapine plus zidovudine until the age of 14 weeks (when the infant immunization schedule is completed in Malawi) would decrease the rate of HIV-1 infection, as compared with single-dose nevirapine combined with 1 week of zidovudine (control regimen). The control regimen, which was previously shown to be effective in a randomized trial in Malawi, is recommended in resource-limited settings, including Malawi

Pregnant women who presented for either antenatal or delivery services at Queen Elizabeth Central Hospital or at one of five other health centers in Blantyre, Malawi, were offered HIV-1 counseling and testing. All women with HIV-1 infection, except those whose HIV-1 infection was not identified until after they gave birth (late presenters), received intrapartum single-dose nevirapine. Women could be enrolled in the trial if they had HIV-1 infection, were at least 18 years of age (although women <18 years of age could be enrolled if they consented and a guardian gave permission), were pregnant or had given birth within the previous 24 hours at one of the study clinics, were a resident of the study area, were willing to return for postnatal follow-up visits for up to 2 years, and intended to breast-feed. Infants with life-threatening conditions requiring immediate care were excluded. All eligible women provided written informed consent at enrollment.

The protocol and study consent forms were approved by institutional review boards at the University of Malawi, Johns Hopkins University, and the Centers for Disease Control and Prevention. Enrollment began on April 20, 2004. The current analysis includes data on women and their infants who were enrolled in the study through August 7, 2007. All authors vouch for the completeness and accuracy of the data presented.
HIV-1 Infection

Of the 3016 infants, 255 were found to have HIV-1 infection by August 7, 2007. Of these cases, 242 were confirmed and 13 were presumptive; the frequency of HIV infections that were classified as presumptive was similar in the three study groups (P=0.22 for all comparisons). Both confirmed and presumptive HIV-1 infections were included in the primary analysis, although limiting the analysis to only confirmed HIV-1 infections produced similar results (data not shown). The rates of HIV-1 positivity on DNA analysis at birth were 6.5% in the control group and 7.1% in both extended-prophylaxis groups (P=0.85 for all comparisons). Before the primary end point at 9 months, the numbers of infants who were lost to follow-up without a positive HIV-1 test were 136 in the control group, 131 in the extended-nevirapine group, and 109 in the extended-dual-prophylaxis group.

Among infants who were not infected at birth (i.e., excluding infants with positive DNA PCR tests for HIV), between the ages of 6 weeks and 18 months, the control group had consistently higher rates of HIV-1 infection, as compared with both extended-prophylaxis groups (Figure 2A). Among 9-month-old infants, the rate of HIV-1 infection, as estimated from Kaplan–Meier curves for which data were censored at the time of loss to follow-up, was 10.6% (95% confidence interval [CI], 8.7 to 12.8) in the control group, 5.2% (95% CI, 3.9 to 7.0) in the extended-nevirapine group (P<0.001 for the comparison with the control group), and 6.4% (95% CI, 4.9 to 8.3) in the extended-dual-prophylaxis group (P=0.002 for the comparison with the control group). The total numbers of infants with positive results on HIV-1 DNA PCR at 9 months were 98 in the control group, 51 in the extended-nevirapine group, and 61 in the extended-dual-prophylaxis group. The estimated protective efficacy10 of the extended-nevirapine regimen was 67% (95% CI, 43 to 81) at 6 weeks, 67% (95% CI, 49 to 79) at 14 weeks, 60% (95% CI, 42 to 73) at 6 months, and 51% (95% CI, 30 to 66) at 9 months. The estimated protective efficacy of the extended-dual-prophylaxis regimen was 69% (95% CI, 45 to 83) at 6 weeks, 66% (95% CI, 48 to 78) at 14 weeks, 49% (95% CI, 27 to 64) at 6 months, and 40% (95% CI, 16 to 57) at 9 months. There were no significant differences between the two extended-prophylaxis groups at any time point.

Discussion

We evaluated two different extended 14-week post-exposure regimens to reduce postnatal HIV-1 transmission in a large, randomized clinical trial. Our study demonstrated that both extended-prophylaxis regimens significantly reduced the risk of postnatal transmission at 14 weeks with a protective efficacy of more than 60%. The cumulative risk of postnatal infection between birth and 14 weeks was 8.4% in the control group, as compared with approximately 2.8% in the extended-prophylaxis groups. This net difference of approximately 5% between the extended-prophylaxis groups and the control group continued at 24 months.

Although there were no significant differences in overall mortality, the control group had consistently higher mortality after the age of 6 months than did either of the extended-prophylaxis groups, a difference that appeared to be largely due to a higher rate of HIV-1 infection in the control group. There were significant increases in HIV-1–free survival for the infants in both extended-prophylaxis groups at the age of 9 months and for those in the extended-nevirapine group up to the age of 15 months.

The frequency of breast-feeding was high during the first 6 months (approximately 90%). Although most infants were weaned between the ages of 6 and 9 months, more than 20% were still breast-feeding at that time. After discontinuation of extended prophylaxis, the rate of postnatal HIV-1 infection occurring in infants between the ages of 14 weeks and 9 months was similar in the three study groups, with a rate of additional HIV-1 infections of 2.2% in the control group, 2.4% in the extended-nevirapine group, and 3.5% in the extended-dual-prophylaxis group.

The choice of providing daily prophylaxis up to 14 weeks was based on the recommended infant immunization schedule in Malawi, which is completed at 14 weeks. Most infants do not return to the clinic until the age of 9 months to receive measles immunization. Therefore, from a public health point of view, an approach to HIV-1 prophylaxis that is integrated into the typical infant immunization schedule would facilitate implementation in resource-constrained settings. There were no significant differences in efficacy between the two extended-prophylaxis groups. However, serious adverse events (primarily neutropenia) that were possibly related to a study drug were more frequent in the extended-dual-prophylaxis group. Whether the two-drug regimen would reduce the risk of resistance to nevirapine among infants who become infected with HIV-1 despite extended prophylaxis is being investigated.

Another approach to the prevention of postnatal transmission of HIV-1 is the treatment of mothers with HIV-1 infection with highly active antiretroviral therapy (HAART). Although maternal HAART is clearly warranted in women who require therapy for their own health, the benefits and safety of HAART used solely for prevention of postnatal transmission in healthy women with HIV infection have not yet been demonstrated in clinical trials, although several observational studies suggest it may be effective.12,13,14 Data from two observational studies in Tanzania have suggested that infant antiretroviral prophylaxis (the MITRA study14) and maternal HAART prophylaxis (the MITRA-Plus study15) may result in similar postnatal transmission rates. Since HAART that is used solely for prophylaxis is stopped after the infant is weaned, the mother may receive 9 months or more of HAART (if therapy is started before birth), followed by an interruption. The effect of interruption of long-term HAART on maternal health is unknown. Some studies have demonstrated an increased risk of disease progression and death among HIV-1–infected adults with high CD4 counts who interrupted treatment, as compared with that associated with continuous therapy.16,17,18 Antiretroviral treatment of the mother may also expose infants to potential toxic effects or drug resistance if the infant becomes infected because of a potential elevation in the plasma concentration of these drugs in the infant.19,20,21,22 Thus, further evaluation of maternal HAART that is used solely for prophylaxis is needed to determine efficacy and long-term safety for both mothers and infants.

On the basis of data from our trial, the 14-week extended nevirapine regimen appears to be safe, with the rate of adverse events similar to that in the control group. This infant-only antiretroviral prophylaxis is practical and effective in reducing HIV-1 transmission and in improving HIV-1–free survival in settings in which breast-feeding is common. The question of whether infants who are born to HIV-1–infected mothers should receive antiretroviral prophylaxis for the entire duration of breast-feeding needs to be assessed, including analysis of safety, added efficacy, and cost-effectiveness.

Watson Files FDA Application for Generic LYBREL(R)

2008-03-15T03:41:00.000-07:00

Watson Pharmaceuticals, Inc. (NYSE:WPI) , a leading specialty pharmaceutical company, today confirmed that it has filed an Abbreviated New Drug Application (ANDA) with the U.S. Food and Drug Administration (FDA) seeking approval to market its Levonorgestrel and Ethinyl Estradiol tablets, USP (0.09 mg/0.02 mg) extended-cycle oral contraceptive product prior to the expiration of patents owned by Wyeth. Watson's Levonorgestrel and Ethinyl Estradiol product is a generic version of Wyeth's LYBREL(R) (levonorgestrel and ethinyl estradiol) tablets which is indicated for the prevention of pregnancy.

Wyeth filed suit against Watson on March 12, 2008 in the U.S. District Court, District of Delaware, seeking to prevent Watson from commercializing its product prior to the expiration of U.S. patent number 6,500,814. Wyeth's suit was filed under the provisions of the Hatch Waxman Act, resulting in a stay of final FDA approval of Watson's ANDA for up to 30 months or until final resolution of the matter before the court, whichever occurs sooner. Based on available information, Watson believes it may be the first applicant to file an ANDA for LYBREL(R) and, should its product be approved, may be entitled to 180 days of generic market exclusivity.