Immunogenicity to the bivalent HPV-16/18 vaccine among adolescent African students exposed to helminths and malaria.

INTRODUCTION: Efficacious vaccines that prevent human papillomavirus (HPV) infection, the recognized cause of cervical cancer, are now available. However, in sub-Saharan Africa, immune-modulating infections such as helminths and malaria may affect immunogenicity to the HPV vaccine. This study aimed to evaluate the effect of helminth infections and exposure to malaria on the immune response to the bivalent HPV-16/18 vaccine. METHODOLOGY: AS04-adjuvanted HPV-16/18 vaccinated students between 10 and 16 years of age from western Uganda, at 18 months-post vaccination were followed up for six months. After consent was obtained, demographic data, blood, and stool samples were collected. Multiplex HPV serology technology was used to determine HPV-16/18 antibody levels expressed as median fluorescent intensity (MFI). The malaria antibody immunoassay test was used to detect antibodies to malaria parasites. The Kato-Katz method was used to detect the presence of helminths. HPV-16/18 antibody levels among students exposed to malaria or helminths were compared with those who were not exposed using the Student's t-test. RESULTS: A total of 211 students participated in the study. There was no difference between MFI levels to HPV-16/18 antibodies at 18- and 24-month follow-ups among students who were positive and negative to malaria or helminth exposure. There was an increase in HPV-18 MFI antibody levels at month 24 among the students who were positive for malaria at enrolment (p = 0.05). CONCLUSIONS: Immune-modulating parasites (malaria/helminths) were not associated with reduced immune response to the bivalent HPV-16/18 vaccine. The data may support the use of this vaccine in sub-Saharan Africa.

Association of arsenic with adverse pregnancy outcomes/infant mortality: a systematic review and meta-analysis.

BACKGROUND: Exposure to arsenic is one of the major global health problems, affecting > 300 million people worldwide, but arsenic's effects on human reproduction are uncertain. OBJECTIVES: We conducted a systematic review and meta-analysis to examine the association between arsenic and adverse pregnancy outcomes/infant mortality. METHODS: We searched PubMed and Ovid MEDLINE (from 1946 through July 2013) and EMBASE (from 1988 through July 2013) databases and the reference lists of reviews and relevant articles. Studies satisfying our a priori eligibility criteria were evaluated independently by two authors. RESULTS: Our systematic search yielded 888 articles; of these, 23 were included in the systematic review. Sixteen provided sufficient data for our quantitative analysis. Arsenic in groundwater (≥ 50 µg/L) was associated with increased risk of spontaneous abortion (6 studies: OR = 1.98; 95% CI: 1.27, 3.10), stillbirth (9 studies: OR = 1.77; 95% CI: 1.32, 2.36), moderate risk of neonatal mortality (5 studies: OR = 1.51; 95% CI: 1.28, 1.78), and infant mortality (7 studies: OR = 1.35; 95% CI: 1.12, 1.62). Exposure to environmental arsenic was associated with a significant reduction in birth weight (4 studies: ß = -53.2 g; 95% CI: -94.9, -11.4). There was paucity of evidence for low-to-moderate arsenic dose. CONCLUSIONS: Arsenic is associated with adverse pregnancy outcomes and infant mortality. The interpretation of the causal association is hampered by methodological challenges and limited number of studies on dose response. Exposure to arsenic continues to be a major global health issue, and we therefore advocate for high-quality prospective studies that include individual-level data to quantify the impact of arsenic on adverse pregnancy outcomes/infant mortality.

The levels of anti-HPV16/18 and anti-HPV31/33/35/45/52/58 antibodies among AS04-adjuvanted HPV16/18 vaccinated and non-vaccinated Ugandan girls aged 10-16 years.

BACKGROUND: Data on Human Papilloma virus (HPV) vaccine immune response in sub-Saharan Africa is still sparse yet such knowledge is critical for optimal implementation and monitoring of HPV vaccines. Our primary objective was to evaluate levels of anti-HPV-16/18 antibodies and six other 'high risk' HPV (hrHPV) types among the vaccinated and unvaccinated Ugandan girls. METHODS: We conducted a cross sectional study among AS04-adjuvanted HPV-16/18 vaccinated and unvaccinated school girls aged 10-16 years in Western Uganda using purposive sampling. The vaccinated girls were at 18 months post vaccination. After consenting and assenting, data was collected using interviewer administered questionnaires for demographics and sexual history. Blood was drawn from which serum samples were analysed by the multiplex HPV serology technology to determine anti-HPV antibody levels to HPV-16/18 and six other hrHPV types (31, 33, 35, 45, 52 and 58). The antibody levels were expressed as Median Fluorescent Intensity (MFI). A total of 207 vaccinated [mean age 13.1 years (SD 1.5); range 10-16 years] and 197 unvaccinated girls [mean age 13.6 years (SD 1.3); range 10-16 years] participated in the study. Sexual activity was self reported among 14/207 (6.8%) vaccinated and 5/197 (2.5%) unvaccinated girls. The MFI levels for HPV-16 and HPV-18 were 15 and 20 times higher respectively in the vaccinated girls than in the unvaccinated girls. HPV-16 mean MFI level was 4691(SD 1812; 95% CI: 4438-4958) among the vaccinated compared to 218 (SD 685; 95% CI: 190-252) among the unvaccinated girls. For HPV-18 the mean MFI level was 1615 (SD 1326; 95% CI: 1470-1776) among the vaccinated compared to MFI 103 (SD 506; 95% CI: 88 -121) among unvaccinated girls. In addition antibody levels to non vaccine hrHPV types (31, 33, 35, 45, 52 and 58) were all significantly higher in the vaccinated group than in the unvaccinated group (p<0.01). CONCLUSION: The AS04-Adjuvanted HPV-16/18 vaccinated girls showed a higher level of antibodies to HPV-16/18 and other non-vaccine hrHPV types compared to the unvaccinated girls. This may translate into protection against HPV-16/18 and other hrHPV types.

Impact of smoking on the quantity and quality of antibodies induced by human papillomavirus type 16 and 18 AS04-adjuvanted virus-like-particle vaccine - a pilot study.

BACKGROUND: The AS04-adjuvanted bivalent L1 virus-like-particle (VLP) vaccine (Cervarix™) against infection with human papillomavirus (HPV) types 16/18 holds great promise to prevent HPV16/18 infections and associated neoplasias, but it is important to rule out significant co-factors of the neoplasias like smoking. METHODS: We conducted a pilot study to compare the quantity and quality of HPV16/18 antibody response at baseline and 7 months post vaccination in 104 non-smoking and 112 smoking female participants vaccinated at 0, 1 and 6 months with Cervarix™ (55 and 48 study participants) or with Hepatitis A vaccine (HAVRIX™) (48 and 64 participants, respectively). These 216 women were a sub-sample of 4808 baseline 16- to 17-year old Finnish women initially enrolled in the double-blind, randomized controlled phase III PATRICIA trial. Following end-of-study unblinding in 2009 they were randomly chosen out of all the participants of the three major Finnish PATRICIA study sites in the Helsinki metropolitan area (University of Helsinki, N = 535, and Family Federation Finland, N = 432) and Tampere (University of Tampere, N = 428). Following enrolment, serum samples were collected at month 0 and month 7 post 1st vaccination shot, and were analysed for levels and avidity of IgG antibodies to HPV16 and HPV18 using standard and modified (4 M urea elution) VLP ELISAs. RESULTS: We found that at month 7 post vaccination women who smoked (cotinine level > 20 ng/ml) had levels of anti-HPV16/18 antibodies comparable to those of non-smoking women. Low-avidity HPV16/18 IgG antibodies were observed in 16% of the vaccinated women, and active smoking conferred a three-fold increased risk (95% CI 1.0-9.3) of having the low-avidity antibodies. CONCLUSION: Our data suggest that while smoking does not interfere with the quantity of vaccine-induced peak IgG levels, it may affect the avidity of IgG induced by HPV16/18 vaccination.

Lack of significant effects of Chlamydia trachomatis infection on cervical cancer risk in a nested case-control study in North-East Thailand.

Cervical cancer continues to be an important public health problem in Thailand. While the high risk human papillomavirus (HPV) types have been established as the principle causative agent of both malignancies and the precursor lesions, cervical intraepithelial neoplasia (CIN), other factors may also be involved like other sexually transmitted diseases, as well as smoking. Chlamydia trachomatis is an obligate intracellular Gram-negative bacterium which has a tendency to cause chronic infection featuring inflammation and therefore might be expected to increase the risk of cervical cancer. In the present nested case-control study, 61 cases of cervical cancer and 288 matched controls with original serum samples were identified from the Khon Kaen Cohort, established in the North-East of Thailand, by linkage to the Khon Kaen population based cancer registry. C. trachomatis specific IgG antibodies at recruitment were measured by microimmunofluorescence and assessed for association with cervical cancer using STATA release10. No significant link was noted either with all cancers or after removal of adenocarcinomas. The results suggest no association between Chlamydia infection and cervical cancer development in North-East Thailand, but possible influencing factors must be considered in any future research on this topic.

Changes over time in the Chlamydia trachomatis serotype distribution in Finnish women.

The distribution of Chlamydia trachomatis serotypes in the sexually active population may change over time. Serum from C. trachomatis seropositive women representing the 1980s, 1990s, and 2000s were available from a stratified random sample (11,067) of the Finnish Maternity Cohort for microimmunofluorescence-based classification. The C. trachomatis serotype distributions in the 1980s and 2000s were comparable, with serotypes G, E, and J being the most prevalent. In the 1990s the numbers of women seropositive for ≥ 2 serotypes peaked, and serotypes G/J were replaced by serotypes E/D. The temporary C. trachomatis serotype replacement parallels changes in the sexually active population in the 1990s in Finland.

Order of HPV/Chlamydia infections and cervical high-grade precancer risk: a case-cohort study.

Interactions of carcinogenic human papillomaviruses (most notably HPV types 16/18/31/33/45), and HPV6 or Chlamydia trachomatis are not well understood. We have used seroconversions to study effects the order of these infections has on the risk of high-grade cervical precancer. In a cohort of 94,349 Finnish women with paired sera from consecutive pregnancies within an average of 2.4 years, 490 were diagnosed with cervical CIN3/AIS. Serum antibodies to HPV6/16/18/31/33/45 and C. trachomatis were measured in paired sera of the cases and a subcohort of 2,796 women with a minimum of two pregnancies. HPV16-adjusted rate ratios (RR) and confidence intervals were estimated by stratified Cox model. Compared to dual seropositivity already at the first serum sampling, RRs related to HPV6 seropositivity before and after HPV31 seroconversion were 0.4 (95% CI 0.0, 4.4) and 10 (95% CI 1.8, 57). Furthermore, RR related to seroconversions of both HPV18/45 and C.trachomatis between the consecutive pregnancies was 28 (95% CI 4.3, 190). Virtually concomitant HPV18/45 and C.trachomatis infections are associated with very high CIN3 risk.

Universal routine HPV vaccination for young girls in Uganda: a review of opportunities and potential obstacles.

This article reviews the existing realities in Uganda to identify opportunities and potential obstacles of providing universal routine HPV vaccination to young adolescent girls. Cervical cancer is a public health priority in Uganda where it contributes to about 50-60% of all female malignancies. It is associated with a dismal 5-year relative survival of approximately 20%. With adequate financial resources, primary prevention through vaccination is feasible using existing education and health infrastructure. Cost-effectiveness studies show that at a cost of US$2 per dose, the current vaccines would be cost effective. With optimal (≥70%) coverage of the target population, the lifetime risk of cervical cancer could be reduced by >50%. Uganda fulfils 4 out of the 5 criteria set by the WHO for the introduction of routine HPV vaccination to young adolescent girls. The existing political commitment, community support for immunization and the favorable laws and policy environment all provide an opportunity that should not be missed to introduce this much needed vaccine to the young adolescent girls. However, sustainable financing by the government without external assistances remains a major obstacle. Also, the existing health delivery systems would require strengthening to cope with the delivery of HPV vaccine to a population that is normally not targeted for routine vaccination. Given the high incidence of cervical cancer and in the absence of a national screening program, universal HPV vaccination of Ugandan adolescent girls is critical for cervical cancer prevention.

Aspects of prophylactic vaccination against cervical cancer and other human papillomavirus-related cancers in developing countries.

Cervical cancer and other human papillomavirus- (HPV-) related cancers are preventable, but preventive measures implemented in developing countries and especially in low-income rural regions have not been effective. Cervical cancer burden derived from sexually transmitted HPV infections is the heaviest in developing countries, and a dramatic increase in the number of cervical cancer cases is predicted, if no intervention is implemented in the near future. HPV vaccines offer an efficient way to prevent related cancers. Recently implemented school-based HPV vaccination demonstration programmes can help tackle the challenges linked with vaccine coverage, and access to vaccination and health services, but prevention strategies need to be modified according to regional characteristics. In urban regions WHO-recommended vaccination strategies might be enough to significantly reduce HPV-related disease burden, but in the rural regions additional vaccination strategies, vaccinating both sexes rather than only females when school attendance is the highest and applying a two-dose regime, need to be considered. From the point of view of both public health and ethics identification of the most effective prevention strategies is pivotal, especially when access to health services is limited. Considering cost-effectiveness versus justice further research on optional vaccination strategies is warranted.

Epidemiology of HPV genotypes in Uganda and the role of the current preventive vaccines: A systematic review.

BACKGROUND: Limited data are available on the distribution of human papillomavirus (HPV) genotypes in the general population and in invasive cervical cancer (ICC) in Uganda. Yet, with the advent of preventive HPV vaccines that target HPV 16 and 18 responsible for causing about 70% of ICC cases in the world, such information is crucial to predict how vaccination and HPV-based screening will influence prevention of ICC. METHODS: To review the distribution of HPV infection and prevalent genotypes, electronic databases (e.g. PubMed/MEDLINE and HINARI) were searched for peer reviewed English articles on HPV infection up to November 30, 2010. Eligible studies were selected according to the following criteria: DNA-confirmed cervical or male genital HPV prevalence and genotypes, HPV incidence estimates and HPV seroprevalence among participants. RESULTS: Twenty studies were included in the review. Among HIV negative adult women, the prevalence of HR-HPV infections ranged from 10.2% -40.0% compared to 37.0% -100.0% among HIV positive women. Among HIV positive young women aged below 25 years, the prevalence of HR-HPV genotypes ranged from 41.6% -75.0% compared to 23.7% -67.1% among HIV negative women. Multiple infections with non vaccine HR-HPV genotypes were frequent in both HIV positive and HIV negative women. The main risk factors for prevalent HPV infections were age, lifetime number of sexual partners and HIV infection. Incident infections with HR-HPV genotypes were more frequent among adult HIV positive than HIV negative women estimated at 17.3 and 7.0 per 100 person-years, respectively. Similarly, incident HR-HPV among young women aged below 25 years were more frequent among HIV positive (40.0 per 100 person-years) than HIV negative women (20.3 per 100 person-years) women. The main risk factor for incident infection was HIV infection. HPV 16 and 18 were the most common genotypes in ICC with HPV 16/18 contributing up to 73.5% of cases with single infections.Among uncircumcised adult HIV positive males, HR-HPV prevalence ranged from 55.3% -76.6% compared to 38.6% -47.6% in HIV negative males. Incident and multiple HR-HPV infections were frequent in HIV positive males. Being uncircumcised was the main risk factor for both prevalent and incident HPV infection. CONCLUSION: Infections with HR-HPV genotypes were very common particularly among HIV positive individuals and young women irrespective of HIV status. Given the high prevalence of HIV infection, HPV-associated conditions represent a major public health burden in Uganda. However, although the most common HPV genotypes in ICC cases in Uganda were those targeted by current preventive vaccines, there were a large number of individuals infected with other HR-HPV genotypes. Technology allowing, these other HR-HPV types should be considered in the development of the next generation of vaccines.

Low avidity of human papillomavirus (HPV) type 16 antibodies is associated with increased risk of low-risk but not high-risk HPV type prevalence.

BACKGROUND: Low avidity of antibodies against viral, bacterial and parasitic agents has been used for differential diagnosis of acute versus recent/past infections. The low-avidity antibodies may however, persist for a longer period in some individuals. FINDINGS: We studied the association of human papillomavirus (HPV) type 16 antibody avidity with seroprevalence to HPV types 6/11/18/31/33/45. Antibody avidity was analysed for 365 HPV16 seropositive pregnant Finnish and Ugandan women using a modified ELISA.Low avidity of HPV16 antibodies was found in 15% of Finnish and 26% of Ugandan women. Ugandan women with low-avidity HPV16 antibodies had an increased risk estimate for HPV6/11 (odds ratio, OR 2.9; 95%CI 1.01-8.4) seropositivity but not to high-risk HPV types 18/31/33/45. CONCLUSION: Association of the low avidity HPV16 antibody "phenotype" with possible susceptibility to infections with other HPV types warrants investigation.

Differences in incidence and co-occurrence of vaccine and nonvaccine human papillomavirus types in Finnish population before human papillomavirus mass vaccination suggest competitive advantage for HPV33.

To understand likelihood of type replacement after vaccination against the high-risk human papillomavirus (HPV) types, we evaluated competition of the seven most common genital HPV types in a population sample of unvaccinated, fertile-aged Finnish women. First trimester sera from two consecutive pregnancies were retrieved from 3,183 Finnish women (mean age, 23.1 years) of whom 42.3% had antibodies to at least one HPV type (6/11/16/18/31/33/45) at the baseline. Antibody positivity to more than one HPV types by the second pregnancy was common among the baseline HPV seropositives. However, compared to baseline HPV-seronegative women, significantly increased incidence rate ratios (IRRs), indicating an increased risk to seroconvert for another HPV type, were consistently noted only for HPV33 among baseline HPV16 or HPV18 antibody (ab)-positive women: HPV(16ab only) (→) (16&33ab) IRR 2.9 [95% confidence interval (CI) 1.6-5.4] and HPV(18ab only) (→) (18&33ab) IRR 2.5 (95% CI 1.1-6.0), irrespectively of the presence of antibodies to other HPV types at baseline: HPV(16ab) (→) (16&33ab) IRR 3.2 (95% CI 2.0-5.2) and HPV(18ab) (→) (18&33ab) IRR 3.6 (95% CI 2.1-5.9). Our findings suggest a possible competitive advantage for HPV33 over other genital HPV types in the unvaccinated population. HPV33 should be monitored for type replacement after HPV mass vaccination.

Effect of single-dose anthelmintic treatment during pregnancy on an infant's response to immunisation and on susceptibility to infectious diseases in infancy: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Helminth infections affect the human immune response. We investigated whether prenatal exposure to and treatment of maternal helminth infections affects development of an infant's immune response to immunisations and unrelated infections. METHODS: In this randomised, double-blind, placebo-controlled trial, we enrolled 2507 women in the second or third trimester of pregnancy who were planning to deliver in Entebbe General Hospital, Entebbe, Uganda. With a computer-generated random number sequence in blocks of 100, we assigned patients to 440 mg albendazole and 40 mg/kg praziquantel (n=628), 440 mg albendazole and a praziquantel-matching placebo (n=625), 40 mg/kg praziquantel and an albendazole-matching placebo (n=626), or an albendazole-matching placebo and praziquantel-matching placebo (n=628). All participants and hospital staff were masked to allocation. Primary outcomes were immune response at age 1 year to BCG, tetanus, and measles immunisation; incidence of infectious diseases during infancy; and vertical HIV transmission. Analysis was by intention-to-treat. This trial is registered, number ISRCTN32849447. FINDINGS: Data were available at delivery for 2356 women, with 2345 livebirths; 2115 (90%) of liveborn infants remained in follow-up at 1 year of age. Neither albendazole nor praziquantel treatments affected infant response to BCG, tetanus, or measles immunisation. However, in infants of mothers with hookworm infection, albendazole treatment reduced interleukin-5 (geometric mean ratio 0·50, 95% CI 0·30-0·81, interaction p=0·02) and interleukin-13 (0·52, 0·34-0·82, 0·0005) response to tetanus toxoid. The rate per 100 person-years of malaria was 40·9 (95% CI 38·3-43·7), of diarrhoea was 134·1 (129·2-139·2), and of pneumonia was 22·3 (20·4-24·4). We noted no effect on infectious disease incidence for albendazole treatment (malaria [hazard ratio 0·95, 95% CI 0·79-1.14], diarrhoea [1·06, 0·96-1·16], pneumonia [1·11, 0·90-1·38]) or praziquantel treatment (malaria [1·00, 0·84-1·20], diarrhoea [1·07, 0·98-1·18], pneumonia [1·00, 0·80-1·24]). In HIV-exposed infants, 39 (18%) were infected at 6 weeks; vertical transmission was not associated with albendazole (odds ratio 0·70, 95% CI 0·35-1·42) or praziquantel (0·60, 0·29-1·23) treatment. INTERPRETATION: These results do not accord with the recently advocated policy of routine antenatal anthelmintic treatment, and the value of such a policy may need to be reviewed. FUNDING: Wellcome Trust.

Effects of maternal and infant co-infections, and of maternal immunisation, on the infant response to BCG and tetanus immunisation.

Some vaccines show poor efficacy in tropical countries. Within a birth cohort in Uganda, we investigated factors that might influence responses to BCG and tetanus immunisation. Whole blood assay responses to crude culture filtrate proteins of Mycobacterium tuberculosis (cCFP)) and tetanus toxoid (TT) were examined among 1506 and 1433 one-year-olds, respectively. Maternal Mansonella perstans infection was associated with higher interleukin (IL)-10 responses to both immunogens but no reduction in gamma interferon (IFN-γ), IL-5 and IL-13 responses; other maternal helminth infections showed little effect. Tetanus immunisation during pregnancy was associated with higher infant responses to TT; maternal BCG scar (from past immunisation) with lower infant IL-5 and IL-13 responses to cCFP. IFN-γ, IL-5 and IL-13 to TT were reduced in HIV-exposed-uninfected infants; infant malaria and HIV were associated with lower IFN-γ, IL-5 and IL-13 responses to both immunogens. We conclude that maternal helminth infections are unlikely to explain poor vaccine efficacy in the tropics. Effects of maternal immunisation on infant responses to vaccines should be explored. Prevention of infant malaria and HIV could contribute to effectiveness of immunisation programmes.

Natural seroconversion to high-risk human papillomaviruses (hrHPVs) is not protective against related HPV genotypes.

The risk of seroconversion for multiple human papillomavirus (HPV) types over time was studied in a cohort of 532 women with cervical HPV infection, prospectively followed-up for >10 y. Of the women who were HPV-antibody positive for at least 1 of the HPV types (6, 11 (low risk, lr), 16, 18, 31, 33, and 45 (high risk, hr)) at baseline, 73-98% seroconverted for 1 or more HPV types over time. Baseline lrHPV-seropositive women had 2.3-fold risk (95% confidence interval (CI) 1.1-4.7) for hrHPV seroconversion, but the opposite was not the case. Cross-protection by the natural HPV16 or HPV18 infection against other types of the HPV species A9 or A7 was not seen. These data suggest that protection against other HPV genotypes (as indicated by the lack of seroconversion) may not be provided by humoral HPV antibodies derived from a natural infection. Instead, these unvaccinated, HPV-antibody-positive women continue to be susceptible to infections by the other HPV genotypes over time.

Risk of being seropositive for multiple human papillomavirus types among Finnish and Ugandan women.

Although infections with multiple human papillomavirus (HPV) types have been reported widely, more information is needed on the occurrence of the different types. We determined the distribution of seroprevalences to multiple HPV types in Finland and Uganda to compare the epidemiology of the different HPV types in the 2 populations. Serum samples were obtained from 2784 Finnish and 1964 Ugandan women (mean ages 22 y and 25 y, respectively) of whom 44% and 57%, respectively, had antibodies to at least 1 of the 7 HPV types (6, 11, 16, 18, 31, 33, 45) tested (p < 0.001). Multiple HPV antibody positivity was common. HPV45-seropositive Finns had a higher risk of having antibodies to other high-risk HPV types: HPV18 (odds ratio (OR) = 10.9), HPV31 (OR 6.1), HPV33 (OR 12.2), than their Ugandan counterparts: HPV18 (OR 3.4), HPV31 (OR 2.2), HPV33 (OR 3.3). Increased estimates for being double antibody-positive were also noted among HPV18- and HPV16-seropositive women, but there were no major differences between HPV16-seropositive Finns and Ugandans. In addition to biological and behavioural factors, iatrogenic and societal factors (screening vs no screening) may also result in the different occurrence of infections with the high-risk HPV types in Finland and Uganda.

Risk factors for helminth, malaria, and HIV infection in pregnancy in Entebbe, Uganda.

BACKGROUND: Infections during pregnancy may have serious consequences for both mother and baby. Assessment of risk factors for infections informs planning of interventions and analysis of the impact of infections on health outcomes. OBJECTIVES: To describe risk factors for helminths, malaria and HIV in pregnant Ugandan women before intervention in a trial of de-worming in pregnancy. METHODS: The trial recruited 2,507 pregnant women between April 2003 and November 2005. Participants were interviewed and blood and stool samples obtained; location of residence at enrolment was mapped. Demographic, socioeconomic, behavioral and other risk factors were modelled using logistic regression. RESULTS: There was a high prevalence of helminth, malaria and HIV infection, as previously reported. All helminths and malaria parasitemia were more common in younger women, and education was protective against every infection. Place of birth and/or tribe affected all helminths in a pattern consistent with the geographical distribution of helminth infections in Uganda. Four different geohelminths (hookworm, Trichuris, Ascaris and Trichostrongylus) showed a downwards trend in prevalence during the enrolment period. There was a negative association between hookworm and HIV, and between hookworm and low CD4 count among HIV-positive women. Locally, high prevalence of schistosomiasis and HIV occurred in lakeshore communities. CONCLUSIONS: Interventions for helminths, malaria and HIV need to target young women both in and out of school. Antenatal interventions for malaria and HIV infection must continue to be promoted. Women originating from a high risk area for a helminth infection remain at high risk after migration to a lower-risk area, and vice versa, but overall, geohelminths seem to be becoming less common in this population. High risk populations, such as fishing communities, require directed effort against schistosomiasis and HIV infection.

The impact of helminths on the response to immunization and on the incidence of infection and disease in childhood in Uganda: design of a randomized, double-blind, placebo-controlled, factorial trial of deworming interventions delivered in pregnancy and early childhood [ISRCTN32849447].

BACKGROUND: Helminths have profound effects on the immune response, allowing long-term survival of parasites with minimal damage to the host. Some of these effects "spill-over", altering responses to non-helminth antigens or allergens. It is suggested that this may lead to impaired responses to immunizations and infections, while conferring benefits against inflammatory responses in allergic and autoimmune disease. These effects might develop in utero, through exposure to maternal helminth infections, or through direct exposure in later life. PURPOSE: To determine the effects of helminths and their treatment in pregnancy and in young children on immunological and disease outcomes in childhood. METHODS: The trial has three randomized, double-blind, placebo-controlled interventions at two times, in two people: a pregnant woman and her child. Pregnant women are randomized to albendazole or placebo and praziquantel or placebo. At age 15 months their children are randomized to three-monthly albendazole or placebo, to continue to age five years. The proposed designation for this sequence of interventions is a 2 x 2(x2) factorial design. Children are immunized with BCG and against polio, Diphtheria, tetanus, Pertussis, Haemophilus, hepatitis B and measles. Primary immunological outcomes are responses to BCG antigens and tetanus toxoid in whole blood cytokine assays and antibody assays at one, three and five years of age. Primary disease outcomes are incidence of malaria, pneumonia, diarrhoea, tuberculosis, measles, vertical HIV transmission, and atopic disease episodes, measured at clinic visits and twice-monthly home visits. Effects on anaemia, growth and intellectual development are also assessed. CONCLUSION: This trial, with a novel design comprising related interventions in pregnant women and their offspring, is the first to examine effects of helminths and their treatment in pregnancy and early childhood on immunological, infectious disease and allergic disease outcomes. The results will enhance understanding of both detrimental and beneficial effects of helminth infection and inform policy.

A randomised controlled trial of the effects of albendazole in pregnancy on maternal responses to mycobacterial antigens and infant responses to Bacille Calmette-Guérin (BCG) immunisation [ISRCTN32849447].

BACKGROUND: Maternal schistosomiasis and filariasis have been shown to influence infant responses to neonatal bacille Calmette-Guérin (BCG) immunisation but the effects of maternal hookworm, and of de-worming in pregnancy, are unknown. METHODS: In Entebbe, Uganda, we conducted a randomised, double-blind, placebo-controlled trial of a single dose of 400 mg of albendazole in the second trimester of pregnancy. Neonates received BCG. Interferon-gamma (IFN-gamma) and interleukin (IL)-5 responses to a mycobacterial antigen (crude culture filtrate proteins (CFP) of Mycobacterium tuberculosis) were measured in a whole blood assay. We analysed results for binary variables using chi2 tests and logistic regression. We analysed continuous variables using Wilcoxon's tests. RESULTS: Maternal hookworm was associated with reduced maternal IFN-gamma responses to CFP (adjusted odds ratio for IFN-gamma > median response: 0.14 (95% confidence interval 0.02-0.83, p = 0.021). Conversely, maternal hookworm was associated with subsequent increased IFN-gamma responses in their one-year-old infants (adjusted OR 17.65 (1.20-258.66; p = 0.013)). Maternal albendazole tended to reduce these effects. CONCLUSION: Untreated hookworm infection in pregnancy was associated with reduced maternal IFN-gamma responses to mycobacterial antigens, but increased responses in their infants one year after BCG immunisation. The mechanisms of these effects, and their implications for protective immunity remain, to be determined.

HIV risk perception and prevalence in a program for prevention of mother-to-child HIV transmission: comparison of women who accept voluntary counseling and testing and those tested anonymously.

OBJECTIVE: To determine whether data from voluntary counseling and testing (VCT)/prevention of mother-to-child transmission (PMTCT) programs can be used for HIV surveillance. METHODS: Women attending an antenatal clinic at the district hospital in Entebbe, Uganda, from May 2002 to April 2003 were offered counseling and HIV testing with same-day results (VCT) and nevirapine for PMTCT was provided for HIV-positive women and their babies. Those who declined VCT were tested for HIV anonymously. RESULTS: Overall, 2635 women accepted VCT; 883 were tested anonymously. HIV prevalence was higher in VCT than in anonymously tested women in the first month of the program (20% vs. 11%, P=0.05) and in months with <70% VCT uptake (17% vs. 8%, P<0.001) but was similar in months with high uptake. Uptake of VCT was higher in women who had risk factors for HIV, especially those who believed themselves to have been exposed (84% vs. 73%, P<0.001). CONCLUSION: There was a bias to accepting VCT in women with HIV, or risk factors for HIV infection, the former most apparent when there was low coverage. Data from VCT/PMTCT programs cannot replace anonymous surveillance for monitoring of HIV epidemic trends where coverage is incomplete within clinics or communities.