Patricia J. García

Health professionals for a new century: transforming education to strengthen health systems in an interdependent world

Harvard School of Public Health, Boston, MA, USA (Prof J Frenk MD); China Medical Board, Cambridge, MA, USA (L Chen MD); Aga Khan University, Karachi, Pakistan (Prof Z A Bhutta PhD); George Washington University Medical Center, Washington, DC, USA (Prof J Cohen MD); Independent member of House of Lords, London, UK (N Crisp KCB); James P Grant School of Public Health, Dhaka, Bangladesh (Prof T Evans MD); US Institute of Medicine, Washington, DC, USA (H Fineberg MD, P Kelley MD); School of Public Health Universidad Peruana Cayetano, Heredia, Lima, Peru (Prof P Garcia MD); Peking University Health Science Centre, Beijing, China (Prof Y Ke MD); National Health Laboratory Service, Johannesburg, South Africa (B Kistnasamy MD); School of Nursing, University of Pennsylvania, Philadelphia, PA, USA (Prof A Meleis PhD); University of Toronto, Toronto, ON, Canada (Prof D Naylor MD); The Rockefeller Foundation, New York, NY, USA (A Pablos-Mendez MD); Public Health professionals for a new century: transforming education to strengthen health systems in an interdependent world

Four year efficacy of prophylactic human papillomavirus quadrivalent vaccine against low grade cervical, vulvar, and vaginal intraepithelial neoplasia and anogenital warts: randomised controlled trial.

Objectives To evaluate the prophylactic efficacy of the human papillomavirus (HPV) quadrivalent vaccine in preventing low grade cervical, vulvar, and vaginal intraepithelial neoplasias and anogenital warts (condyloma acuminata). Design Data from two international, double blind, placebo controlled, randomised efficacy trials of quadrivalent HPV vaccine (protocol 013 (FUTURE I) and protocol 015 (FUTURE II)). The trials were to be 4 years in length, and the results reported are from final study data of 42 months’ follow-up. Setting Primary care centres and university or hospital associated health centres in 24 countries and territories around the world. Participants 17 622 women aged 16-26 years enrolled between December 2001 and May 2003. Major exclusion criteria were lifetime number of sexual partners (>4), history of abnormal cervical smear test results, and pregnancy. Intervention Three doses of quadrivalent HPV vaccine (for serotypes 6, 11, 16, and 18) or placebo at day 1, month 2, and month 6. Main outcome measures Vaccine efficacy against cervical, vulvar, and vaginal intraepithelial neoplasia grade I and condyloma in a per protocol susceptible population that included subjects who received all three vaccine doses, tested negative for the relevant vaccine HPV types at day 1 and remained negative through month 7, and had no major protocol violations. Intention to treat, generally HPV naive, and unrestricted susceptible populations were also studied. Results In the per protocol susceptible population, vaccine efficacy against lesions related to the HPV types in the vaccine was 96% for cervical intraepithelial neoplasia grade I (95% confidence interval 91% to 98%), 100% for both vulvar and vaginal intraepithelial neoplasia grade I (95% CIs 74% to 100%, 64% to 100% respectively), and 99% for condyloma (96% to 100%). Vaccine efficacy against any lesion (regardless of HPV type) in the generally naive population was 30% (17% to 41%), 75% (22% to 94%), and 48% (10% to 71%) for cervical, vulvar, and vaginal intraepithelial neoplasia grade I, respectively, and 83% (74% to 89%) for condyloma. Conclusions Quadrivalent HPV vaccine provided sustained protection against low grade lesions attributable to vaccine HPV types (6, 11, 16, and 18) and a substantial reduction in the burden of these diseases through 42 months of follow-up. Trial registrations NCT00092521 and NCT00092534.

A Pooled Analysis of Continued Prophylactic Efficacy of Quadrivalent Human Papillomavirus (Types 6/11/16/18) Vaccine against High-grade Cervical and External Genital Lesions

Quadrivalent human papillomavirus (HPV) vaccine has been shown to provide protection from HPV 6/11/16/18–related cervical, vaginal, and vulvar disease through 3 years. We provide an update on the efficacy of the quadrivalent HPV vaccine against high-grade cervical, vaginal, and vulvar lesions based on end-of-study data from three clinical trials. Additionally, we stratify vaccine efficacy by several baseline characteristics, including age, smoking status, and Papanicolaou (Pap) test results. A total of 18,174 females ages 16 to 26 years were randomized and allocated into one of three clinical trials (protocols 007, 013, and 015). Vaccine or placebo was given at baseline, month 2, and month 6. Pap testing was conducted at regular intervals. Cervical and anogenital swabs were collected for HPV DNA testing. Examination for the presence of vulvar and vaginal lesions was also done. Endpoints included high-grade cervical, vulvar, or vaginal lesions (CIN 2/3, VIN 2/3, or VaIN 2/3). Mean follow-up time was 42 months post dose 1. Vaccine efficacy against HPV 6/11/16/18–related high-grade cervical lesions in the per-protocol and intention-to-treat populations was 98.2% [95% confidence interval (95% CI), 93.3-99.8] and 51.5% (95% CI, 40.6-60.6), respectively. Vaccine efficacy against HPV 6/11/16/18–related high-grade vulvar and vaginal lesions in the per-protocol and intention-to-treat populations was 100.0% (95% CI, 82.6-100.0) and 79.0% (95% CI, 56.4-91.0), respectively. Efficacy in the intention-to-treat population tended to be lower in older women, women with more partners, and women with abnormal Pap test results. The efficacy of quadrivalent HPV vaccine against high-grade cervical and external anogenital neoplasia remains high through 42 months post vaccination.

HPV antibody levels and clinical efficacy following administration of a prophylactic quadrivalent HPV vaccine

The efficacy of the quadrivalent Human Papillomavirus (HPV) vaccine is thought to be mediated by humoral immunity. We evaluated the correlation between quadrivalent HPV vaccine-induced serum anti-HPV responses and efficacy. 17,622 women were vaccinated at day 1, and months 2 and 6. At day 1 and at 6-12 months intervals for up to 48 months, subjects underwent Papanicolaou and genital HPV testing. No immune correlate of protection could be found due to low number of cases. Although 40% of vaccine subjects were anti-HPV 18 seronegative at end-of-study, efficacy against HPV 18-related disease remained high (98.4%; 95% CI: 90.5-100.0) despite high attack rates in the placebo group. These results suggest vaccine-induced protection via immune memory, or lower than detectable HPV 18 antibody titers.

Evaluation of quadrivalent HPV 6/11/16/18 vaccine efficacy against cervical and anogenital disease in subjects with serological evidence of prior vaccine type HPV infection

Objective In the quadrivalent (types 6/11/16/18) HPV vaccine (GARDASIL®/SILGARD®) clinical program, 73% of women aged 16-26 were naïve to all vaccine HPV types. In these women, prophylactic administration of the vaccine was highly effective in preventing HPV 6/11/16/18-related cervical disease. Of the remaining women, 15% of had evidence of past infection with one or more vaccine HPV types (seropositive and DNA negative) at the time of enrollment. Here we present an analysis in this group of women to determine the efficacy of the HPV 6/11/16/18 vaccine against new cervical and external anogenital disease related to the same vaccine HPV type which had previously been cleared. Vaccine tolerability in this previously infected population was also assessed. Methods 18,174 women were enrolled into 3 clinical studies. The data presented comprise a subset of these subjects (n = 2,617) who were HPV seropositive and DNA negative at enrollment (for ≥1 vaccine type). In each study, subjects were randomized in a 1:1 ratio to receive HPV 6/11/16/18 vaccine or placebo at day 1, month 2 and month 6 (without knowledge of baseline HPV status). Procedures performed for efficacy data evaluation included detailed genital examination, Pap testing, and collection of cervicovaginal and external genital specimens. Analyses of efficacy were carried out in a population stratified by HPV serology and HPV DNA status at enrollment. Results Subjects were followed for an average of 40 months. Seven subjects in the placebo group developed cervical disease, and eight subjects developed external genital disease related to a vaccine HPV type they had previously encountered. No subject receiving HPV 6/11/16/18 vaccine developed disease to a vaccine HPV type to which they were seropositive and DNA negative at enrolment. Conclusions These results suggest that natural HPV infection-elicited antibodies may not provide complete protection over time, however the immune response to the HPV 6/11/16/18 vaccine appears to prevent reinfection or reactivation of disease with vaccine HPV types. Vaccine-related adverse experiences were higher among subjects receiving vaccine, mostly due to increased injection site adverse experiences.

Health-system reform and universal health coverage in Latin America

Starting in the late 1980s, many Latin American countries began social sector reforms to alleviate poverty, reduce socioeconomic inequalities, improve health outcomes, and provide financial risk protection. In particular, starting in the 1990s, reforms aimed at strengthening health systems to reduce inequalities in health access and outcomes focused on expansion of universal health coverage, especially for poor citizens. In Latin America, health-system reforms have produced a distinct approach to universal health coverage, underpinned by the principles of equity, solidarity, and collective action to overcome social inequalities. In most of the countries studied, government financing enabled the introduction of supply-side interventions to expand insurance coverage for uninsured citizens--with defined and enlarged benefits packages--and to scale up delivery of health services. Countries such as Brazil and Cuba introduced tax-financed universal health systems. These changes were combined with demand-side interventions aimed at alleviating poverty (targeting many social determinants of health) and improving access of the most disadvantaged populations. Hence, the distinguishing features of health-system strengthening for universal health coverage and lessons from the Latin American experience are relevant for countries advancing universal health coverage.

Point-of-Care Tests to Strengthen Health Systems and Save Newborn Lives: The Case of Syphilis

Rosanna Peeling and colleagues describe their experience of introducing point-of-care testing to screen for syphilis in pregnant women living in low- and middle-income countries.

Risk factors for human papillomavirus exposure and co-factors for cervical cancer in Latin America and the Caribbean.

The incidence of cervical cancer in Latin America and the Caribbean (LAC) is among the highest in the world. Because there are major demographic shifts happening in LAC countries (population growth, urbanization and ageing) cervical cancer incidence and mortality will likely continue to be a significant public health problem. Overall human papillomavirus (HPV) prevalence in the LAC general population has been found to be 2-fold higher than the average worldwide prevalence. The large HPV and cancer burden may be explained by the highly prevalent HPV variants of HPV types -16 and 18, which have an increased oncogenic potential. Given the major mode of transmission of genital HPV is sexual, certain, patterns of sexual behaviour (early age at first sexual intercourse, number of sexual partners and sexual behaviour of the partner) are associated with an increased risk of HPV genital acquisition. Although HPV infection is necessary for carcinogenesis, certain co-factors (high parity, long term use of oral contraceptives, smoking and co-infection with the human immunodeficiency virus (HIV)) help in the progression from infection to cancer. Many studies that have contributed to this evidence have been carried out in LAC and are reviewed and summarised in this article. Since HPV vaccines will likely take years to implement, and many more years to show impact on disease, cervical cancer screening programmes remain as the key intervention to control disease in LAC in the years to come.

Bartonellosis (Carrión's Disease) in the Modern Era

Bartonellosis remains a major problem in Peru, but many contemporary aspects of this disease have not been adequately described. We examined the cases of 145 symptomatic patients in Lima, Peru, in whom bartonellosis was diagnosed from 1969 through 1992, including 68 patients in the acute (hematic) phase and 77 patients in the eruptive (verruga) phase. In modern Peru, symptomatic patients who have acute-phase bartonellosis typically present with a febrile illness and systemic symptoms caused by profound anemia; most patients respond successfully to treatment with chloramphenicol. Patients who have eruptive-phase bartonellosis most often present with cutaneous verrugas but may have less specific symptoms, such as fever and arthralgias; diagnosis can be confirmed in such patients by Western immunoblotting, and most patients appear to respond to treatment with rifampin.

Nontuberculous mycobacterial infections in hematopoietic stem cell transplant recipients: Characteristics of respiratory and catheter-related infections

Over a 20-year period, 40 nontuberculous mycobacteria (NTM) were isolated from 6259 hematopoietic stem cell transplant (HSCT) recipients (0.64%), of which 28 were considered to have probable or definite infection (0.44%). Only 3 of 15 lower respiratory isolates obtained by bronchoalveolar lavage (BAL) and/or biopsy; (Mycobacterium avium complex [n = 2] and M. gordonae [n = 1]) caused definite or probable lower respiratory tract disease, whereas 12 of 15 were considered to cause possible lower respiratory tract disease according to Centers for Disease Control and Prevention definitions. The median time to diagnosis was 251 days following HSCT. All 3 patients with definite NTM disease were successfully treated with 3 antimicrobials for several months. Twenty-three patients had catheter-related infections, including exit site infection (n = 5), tunnel infection (n = 7), and catheter-related bacteremia (n = 11). All were caused by rapidly growing mycobacteria. The median time to diagnosis was 61 days following HSCT. All patients with catheter-related infections were successfully treated with an average of 2 antibiotics for a median of 3 weeks for exit site infection and 6 weeks for tunnel infection and catheter-related bacteremia. Soft tissue debridement was performed in all cases with tunnel infection. The catheter was removed in 21 of 23 patients with catheter-related infections. Two additional patients were diagnosed, one with lymphadenitis and one with skin lesion, due to NTM. In conclusion, NTM infections are infrequent in HSCT recipients and carry a good clinical prognosis. In the majority of lower NTM respiratory isolates obtained by BAL, a pathogenic role could not be established. However, lower respiratory tract disease can occur late after HSCT and should be considered if patients fail to respond to the treatment of concomitant infections or if evidence of tissue infection or concomitant bacteremia is present. Therapy should be performed with 2 to 3 antimicrobials, guided by antimicrobial susceptibilities, with additional surgical debridement in patients with tunnel infection.