PROF. JAOKO GODFREY W.

To assess correlates of long-acting reversible contraceptive (LARC) use, and explore patterns of LARC use among female sex workers (FSWs) in Kenya.

A recent study of HIV serodiscordant couples found that depot medroxyprogesterone acetate (DMPA) and oral contraceptive pills (OCPs) were associated with increased HIV risk in the presence, but not in the absence, of bacterial vaginosis. We assessed whether bacterial vaginosis is an effect modifier of the association between hormonal contraception and HIV seroconversion in female sex workers (FSWs) in Mombasa, Kenya.

Vaginal washing has been associated with reductions in cultivable and an increased risk of both bacterial vaginosis (BV) and HIV infection. The effect of vaginal washing on the quantity of individual species is not well characterised. This analysis tested the hypothesis that vaginal washing would be associated with a lower likelihood of spp. detected by both culture and quantitative PCR (qPCR).

Some studies suggest that higher body mass index is associated with increased susceptibility to bacterial vaginosis (BV), but results are conflicting.

Varicella-zoster virus (VZV) is under consideration as a promising recombinant viral vector to deliver foreign antigens including HIV. However, new vectors have come under increased scrutiny, since trials with adenovirus serotype 5-vectored (Ad5-vectored) HIV vaccine demonstrated increased HIV risk in individuals with pre-immunity to the vector that was thought to be associated with mucosal immune activation (IA). Therefore, given the prospect of developing an HIV/VZV chimeric vaccine, it is particularly important to define the impact of VZV vaccination on IA.

Varicella-zoster virus (VZV) is under consideration as a promising recombinant viral vector to deliver foreign antigens including HIV. However, new vectors have come under increased scrutiny, since trials with adenovirus serotype 5-vectored (Ad5-vectored) HIV vaccine demonstrated increased HIV risk in individuals with pre-immunity to the vector that was thought to be associated with mucosal immune activation (IA). Therefore, given the prospect of developing an HIV/VZV chimeric vaccine, it is particularly important to define the impact of VZV vaccination on IA.

There is worldwide concern of rapidly increasing antimicrobial resistance (AMR). However, there is paucity of resistance surveillance data and updated antibiograms in Africa in general. This study was undertaken in Kenyatta National Hospital (KNH) -the largest public tertiary referral centre in East & Central Africa-to help bridge existing AMR knowledge and practice gaps.

Attenuated varicella zoster virus (VZV) is a promising vector for recombinant vaccines. Because human immunodeficiencyvirus (HIV) vaccines are believed to require mucosal immunogenicity, we characterized mucosal VZV-specific humoral immunity following VZVOka vaccination.

Little is known about fertility desire in HIV-positive female sex workers. Fertility desire could increase HIV transmission risk if it was associated with condomless sex or lower adherence to antiretroviral therapy.

Nomadic lifestyle has been shown to be a significant factor in low immunization coverage. However, other factors which might aggravate vaccination uptake in nomadic pastoralists are poorly understood. Our study aimed at establishing the relative influence of social demographics, missed opportunities, and geographical mobility on severe under vaccination in children aged less than two years living in a nomadic pastoralist community of Kenya.

Nomadic lifestyle has been shown to be a significant factor in low immunization coverage. However, other factors which might aggravate vaccination uptake in nomadic pastoralists are poorly understood. Our study aimed at establishing the relative influence of social demographics, missed opportunities, and geographical mobility on severe under vaccination in children aged less than two years living in a nomadic pastoralist community of Kenya.

Male circumcision provides men with approximately 60% protection from acquiring HIV infection via heterosexual sex, and has become a key component of HIV prevention efforts in sub-Saharan Africa. Possible mechanisms for this protection include removal of the inflammatory anaerobic sub-preputial environment and the high concentration of Langerhans cells on the inside of the foreskin, both believed to promote local vulnerability to HIV infection. In people who do acquire HIV, viral load is partially determined by infecting partner viral load, potentially mediated by size of infecting inoculum. By removing a portal for virion entry, prior male circumcision could decrease infecting inoculum and thus viral load in men who become HIV-infected, conferring the known associated benefits of slower progression to disease and decreased infectiousness.

Cell surface expression of α4β7, α4β1 and αEβ7 integrins play a key role in T cell distribution. Understanding the contribution of integrins to the density and ratios of CD4+: CD4negT cell at the portals of entry for HIV is of fundamental importance for the advance of more effective HIV prevention strategies. We therefore set out to characterize and compare the expression of α4β7, α4β1 and αEβ7 integrins on systemic, cervical and rectal CD4+ and CD4negT cells isolated from a cohort of healthy Kenyan women at low risk for sexually transmitted infections (STI) (n = 45). Here we show that blood and cervix were enriched in α4+β1+CD4+T cells and α4+β7hiCD4+T cells, whereas the rectum had an equal frequency of α4+β7hiCD4+T cells and αE+β7hiCD4+T cells. Most cervical and rectal αE+β7hiCD4+T cells expressed CCR5 as well as CD69. Interestingly, αEβ7 was the predominant integrin expressed by CD4negT cells in both mucosal sites, outnumbering αE+β7hiCD4+T cells approximately 2-fold in the cervix and 7-fold in the rectum. The majority of αE+β7hiCD4negT cells expressed CD69 at the mucosa. Taken together, our results show unique tissue-specific patterns of integrin expression. These results can help in guiding vaccine design and also the use of therapeutically targeting integrin adhesion as a means to preventing HIV.

We assessed the association between recent bacterial vaginosis (BV) and incident Mycoplasma genitalium, a sexually transmitted bacterium associated with adverse female reproductive health outcomes. Female sex workers in Mombasa, Kenya completed a monthly sexual behavior interview and clinical examination. During February 2005-February 2006, vaginal fluid specimens collected from women every other month were tested for M. genitalium by nucleic acid amplification testing. Vaginal microbiota was assessed monthly and categorized by Nugent score (0-3 normal, 4-6 intermediate microbiota, 7-10 BV). A discrete time failure analysis for multiple events using logistic regression was used to estimate the odds of incident M. genitalium infection at follow-up visits in women with BV versus normal microbiota at the preceding visit. Among the 280 women, 54.3% were HIV positive. At baseline, 16.1% had prevalent M. genitalium infections and 40.4% had prevalent BV. There were 59 incident M. genitalium infections among 50 women for an incidence rate of 34.6 per 100 person-years. Following adjustment for age, HIV status, and time, prior BV was associated with a 3.5-fold increase in odds of incident M. genitalium (adjusted odds ratio = 3.49; 95% confidence interval: 1.86, 6.56). This strong association suggests that BV may enhance susceptibility to M. genitalium infection.

Many HIV-positive women now live well beyond menopause. Postmenopausal women are no longer at risk for pregnancy, and some studies suggest that they may use condoms less often than premenopausal women. This study tests the hypothesis that, in HIV-positive women who report trading sex for cash or in-kind payment, unprotected sex is more common at postmenopausal visits compared with premenopausal visits.

HIV-1 superinfection, in which an infected individual acquires a second HIV-1 infection from a different partner, is one of the only settings in which HIV acquisition occurs in the context of a pre-existing immune response to natural HIV infection. There is evidence that initial infection provides some protection from superinfection, particularly after 6months of initial infection, when development of broad immunity occurs. Comparison of the immune response of superinfected individuals at the time of superinfection acquisition to that of individuals who remain singly infected despite continued exposure can shed light on immune correlates of HIV acquisition to inform prophylactic vaccine design. We evaluated a panel of humoral immune responses in the largest published group of superinfected individuals (n=21), compared to a set of 3:1 matched singly infected controls from the same cohort. The immune functions studied included plasma neutralization, plasma and cervical antibody-dependent cellular cytotoxicity, and plasma IgG and IgA binding to a panel of 18 envelope antigens, including correlates of HIV acquisition in the RV144 vaccine trial, IgG binding to V1V2 and IgA binding to gp140. Association between each immune function and HIV superinfection was evaluated using conditional logistic regression. No significant associations were detected between any of the immune functions and superinfection acquisition. This study constitutes the most comprehensive and detailed characterization of multiple immune correlates of superinfection to date. The results suggest that immune responses not commonly measured in current HIV studies may be important in protection from HIV infection, and these or a more robust humoral response than that seen in naturally infected women may be needed for a protective vaccine.

Two cohort studies using data from randomized controlled trials in Africa offer the best evidence to date on the effects of voluntary medical male circumcision (VMMC) on male sexual function and satisfaction, suggesting no significant impairments in sexual function or satisfaction and some improvements in sexual function after male circumcision.

We conducted a prospective cohort study to evaluate intimate partner violence (IPV) as a risk factor for detectable plasma viral load in HIV-positive female sex workers (FSWs) on antiretroviral therapy (ART) in Kenya. IPV in the past year was defined as ≥1 act of physical, sexual, or emotional violence by the index partner (i.e. boyfriend/husband). The primary outcome was detectable viral load (≥180 copies/ml). In-depth interviews and focus groups were included to contextualize results. Analyses included 195 women (570 visits). Unexpectedly, IPV was associated with significantly lower risk of detectable viral load (adjusted relative risk 0.21, 95 % CI 0.05-0.84, p-value = 0.02). Qualitative findings revealed that women valued emotional and financial support from index partners, despite IPV. IPV was not a major barrier to ART adherence. The observed association between IPV and lower risk of detectable viral load in FSWs may be due to unmeasured personal and relationship factors, warranting further research.

Knowledge of the composition of vaginal microbial ecosystem is essential for understanding the etiology, prevention, and treatment of vaginal diseases. A baboon model has been used to provide detailed understanding of reproductive physiology and immunology applicable to women. However, little is known about the composition of its vaginal microbial ecosystem.

Several countries scaling-up adult medical male circumcision (MMC) for HIV prevention intend to introduce early infant male circumcision (EIMC). To assess preference for EIMC in a community with a mature adult MMC program, we conducted a cross-sectional survey of a representative sample of mothers (n = 613) and fathers (n = 430) of baby boys ("index son") at 16 health facilities in western Kenya. Most (59 %) were for EIMC, generally. Just 29 % were for circumcising the index son. Pain and protection from HIV were the most frequently cited barrier and facilitator to EIMC, respectively. In multivariable logistic regression, ever talking with the partner about EIMC and positive serostatus were associated with preference for EIMC for the index son. Attitudes towards EIMC are favorable. Willingness to circumcise an infant son is modest. To facilitate EIMC uptake, education about EIMC pain management and encouraging discussion between parents about EIMC during pregnancy should be integrated into programs.

We conducted a prospective cohort study to test the hypothesis that intimate partner violence (IPV) is associated with unprotected sex in HIV-positive female sex workers in Mombasa, Kenya. Women completed monthly visits and quarterly examinations. Any IPV in the past year was defined as ≥1 act of physical, sexual, or emotional violence by the current or most recent emotional partner ('index partner'). Unprotected sex with any partner was measured by self-report and prostate specific antigen (PSA) test. Recent IPV was associated with significantly higher risk of unprotected sex (adjusted relative risk [aRR] 1.91, 95 % CI 1.32, 2.78, p = 0.001) and PSA (aRR 1.54, 95 % CI 1.17, 2.04, p = 0.002) after adjusting for age, alcohol use, and sexual violence by someone besides the index partner. Addressing IPV in comprehensive HIV programs for HIV-positive women in this key population is important to improve wellbeing and reduce risk of sexual transmission of HIV.

Depot medroxyprogesterone acetate (DMPA) is associated with HIV acquisition. We studied changes in vaginal microbiota and inflammatory milieu after DMPA initiation.

Schistosomes and soil-transmitted helminths (STH) (hookworm, Trichuris trichiura and Ascaris lumbricoides) are widely distributed in developing countries where they infect over 230 million and 1.5 billion people, respectively. The parasites are frequently co-endemic and many individuals are co-infected with two or more of the species, but information on how the parasites interact in co-infected individuals is scarce. The present study assessed Schistosoma haematobium and STH infection and morbidity patterns among school children in a hyper-endemic focus in the Tana River delta of coastal Kenya.

To date, there is no research on voluntary medical male circumcision (VMMC) catchment areas or the relationship between distance to a VMMC facility and attendance at a post-operative follow-up visit. We analyzed data from a randomly selected subset of males self-seeking circumcision at one of 16 participating facilities in Nyanza Province, Kenya between 2008 and 2010. Among 1437 participants, 46.7 % attended follow-up. The median distance from residence to utilized facility was 2.98 km (IQR 1.31-5.38). Nearly all participants (98.8 %) lived within 5 km from a facility, however, 26.3 % visited a facility more than 5 km away. Stratified results demonstrated that among those utilizing fixed facilities, greater distance was associated with higher odds of follow-up non-attendance (OR5.01-10km vs. 0-1km = 1.71, 95 % CI 1.08, 2.70, p = 0.02; OR>10km vs. 0-1 km = 2.80, 95 % CI 1.26, 6.21, p = 0.01), adjusting for age and district of residence. We found 5 km marked the threshold distance beyond which follow-up attendance significantly dropped. These results demonstrate distance is an important predictor of attending follow-up, and this relationship appears to be modified by facility type.

SummaryWe evaluated the prevalence and correlates of intimate partner violence in the past year by a regular male partner in HIV-positive female sex workers in Mombasa, Kenya. This cross-sectional study included HIV-positive women ≥18 years old who reported engagement in transactional sex at the time of enrolment in the parent cohort. We asked 13 questions adapted from the World Health Organization survey on violence against women about physical, sexual, or emotional violence in the past year by the current or most recent emotional partner (index partner). We used standardised instruments to assess socio-demographic and behavioural characteristics as possible correlates of intimate partner violence. Associations between intimate partner violence and these correlates were evaluated using univariate and multivariate logistic regression. Overall, 286/357 women (80.4%) had an index partner, and 52/357 (14.6%, 95% confidence interval 10.9%-18.2%) reported intimate partner violence by that partner in the past year. In multivariate analysis, women with severe alcohol problems (adjusted odds ratio 4.39, 1.16-16.61) and those experiencing controlling behaviours by the index partner (adjusted odds ratio 4.98, 2.31-10.74) were significantly more likely to report recent intimate partner violence. Recent intimate partner violence was common in HIV-positive female sex workers. Interventions targeting risk factors for intimate partner violence, including alcohol problems and partner controlling behaviours, could help to reduce recurrent violence and negative health outcomes in this key population.

To test the hypothesis that increasing community antiretroviral therapy (ART) coverage would be associated with lower HIV incidence in female sex workers (FSWs) in Mombasa District, Kenya.

Clinical features are unreliable for distinguishing ocular surface squamous neoplasia (OSSN) from benign conjunctival lesions.

Genetic polymorphisms of the Fc gamma receptors (FcγR) IIa and IIIa have been implicated in the rate of HIV-1 disease progression, but results are inconsistent. We aimed to determine the association between these polymorphisms and disease progression in a cohort of HIV-1 seroconverters from Mombasa, Kenya. Neither FcγRIIa nor FcγRIIIa genotypes were predictive of set point viral load, viral load increase, CD4 decline, or HIV-1 disease progression (time to CD4 count <200 cells/mm(3), death, or treatment initiation). Our results suggest that FcγR polymorphisms might not be an important indicator of viral control and disease progression in this population.

Cells from women who are epidemiologically deemed resistant to HIV infection exhibit a 40-60% reduction in endogenous IRF-1 (interferon regulatory factor-1), an essential regulator of host antiviral immunity and the early HIV replication. This study examined the functional consequences of reducing endogenous IRF-1 on HIV-1 replication and immune response to HIV in natural HIV target cells. IRF-1 knockdown was achieved in ex vivo CD4(+) T cells and monocytes with siRNA. IRF-1 level was assessed using flow cytometry, prior to infection with HIV-Bal, HIV-IIIB, or HIV-VSV-G. Transactivation of HIV long terminal repeats was assessed by p24 secretion (ELISA) and Gag expression (reverse transcription-polymerase chain reaction (RT-PCR)). The expression of IRF-1-regulated antiviral genes was quantitated with RT-PCR. A modest 20-40% reduction in endogenous IRF-1 was achieved in >87% of ex vivo-derived peripheral CD4(+) T cells and monocytes, resulted in >90% reduction in the transactivation of the HIV-1 genes (Gag, p24) and, hence, HIV replication. Curiously, these HIV-resistant women demonstrated normal immune responses, nor an increased susceptibility to other infection. Similarly, modest IRF-1 knockdown had limited impact on the magnitude of HIV-1-elicited activation of IRF-1-regulated host immunologic genes but resulted in lessened duration of these responses. These data suggest that early expression of HIV-1 genes requires a higher IRF-1 level, compared to the host antiviral genes. Together, these provide one key mechanism underlying the natural resistance against HIV infection and further suggest that modest IRF-1 reduction could effectively limit productive HIV infection yet remain sufficient to activate a robust but transient immune response.

HIV-1-related inflammation is associated with increased levels of biomarkers of vascular adhesion and endothelial activation, and may increase production of the inflammatory protein angiopoietin-2 (ANG-2), an adverse prognostic biomarker in severe systemic infection. We hypothesized that antiretroviral therapy (ART) initiation would decrease endothelial activation, reducing plasma levels of ANG-2. METHODS: Antiretroviral-naive Kenyan women with advanced HIV infection were followed prospectively. Endothelial activation biomarkers including soluble intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1), and E-selectin, and plasma ANG-2 and angiopoietin-1 (ANG-1) were tested in stored plasma samples from 0, 6, and 12 months after ART initiation. We used Wilcoxon matched-pairs signed rank tests to compare endothelial activation biomarkers across time-points, generalized estimating equations to analyze associations with change in log10-transformed biomarkers after ART initiation, and Cox proportional-hazards regression to analyze associations with mortality. RESULTS: The 102 HIV-1-seropositive women studied had advanced infection (median CD4 count, 124 cells/muL). Soluble ICAM-1 and plasma ANG-2 levels decreased at both time-points after ART initiation, with concomitant increases in the beneficial protein ANG-1. Higher ANG-2 levels after ART initiation were associated with higher plasma HIV-1 RNA, oral contraceptive pill use, pregnancy, severe malnutrition, and tuberculosis. Baseline ANG-2 levels were higher among five women who died after ART initiation than among women who did not (median 2.85 ng/mL [inter-quartile range (IQR) 2.47--5.74 ng/mL] versus median 1.32 ng/mL [IQR 0.35--2.18 ng/mL], p = 0.01). Both soluble ICAM-1 and plasma ANG-2 levels predicted mortality after ART initiation. CONCLUSIONS: Biomarkers of endothelial activation decreased after ART initiation in women with advanced HIV-1 infection. Changes in plasma ANG-2 were associated with HIV-1 RNA levels over 12 months of follow-up. Soluble ICAM-1 and plasma ANG-2 levels represent potential biomarkers for adverse outcomes in advanced HIV-1 infection.

While voluntary medical male circumcision (VMMC) has been shown to be protective against HIV-acquisition, the procedure may place men and their partners at risk of HIV infection in the period following circumcision if sex is resumed before the wound is healed. This prospective cohort study evaluates post-circumcision wound healing to determine whether the 42-day post-circumcision abstinence period, recommended by the World Health Organization and adopted by VMMC programs, is optimal. Methods and Findings Men were circumcised by forceps-guided method and their post-circumcision wounds examined weekly for seven weeks and at 12 weeks. Time to complete healing was recorded in completed weeks since circumcision, and its associations with baseline covariates were assessed by Kaplan-Meier methods and Cox Proportional Hazard Models. A total of 215 HIV-negative and 108 HIV-positive men aged 18–35 years (median 26, IQR 23–30) were enrolled. 97.1% of scheduled follow-up visits were completed. At week 4, 59.3% of HIV-positive men and 70.4% of age-matched HIV-negative men were healed. At week 6, these percentages rose to 93.4% in HIV-positive men and 92.6% in age-matched HIV-negative men. There was no difference in the hazard of healing between 108 HIV-positive and 108 age-matched HIV-negative men (HR 0.91 95% CI 0.70–1.20). Early post-operative infection was associated with delayed healing in both HIV-positive and HIV-negative men (HR 0.48 95% CI 0.23–1.00). Conclusions Our results indicate that the WHO recommendation for 42-days post-circumcision sexual abstinence should be maintained for both HIV-positive and HIV-negative men. It is important to stress condom use upon resumption of sex in all men undergoing circumcision.

A case-control study was performed to determine the effects of HIV-1-specific cellular immune responses on the odds of acquiring a second HIV-1 infection (superinfection). Changes in the frequency of cytokine-producing or cytolytic CD8+ or CD4+ T cells were not associated with significant alterations in the odds of superinfection, suggesting that HIV-1 specific cellular immune responses at the level induced by chronic infection do not appear to significantly contribute to protection from HIV-1 superinfection.

Ongoing antiretroviral therapy (ART) adherence and secondary HIV transmission-risk reduction (positive prevention) support are needed in resourcelimited settings.We evaluated a nurse-delivered counseling intervention in Kenya. We trained 90 nurses on a brief counseling algorithm that comprised ART and sexual-risk assessment, risk-reduction messages, and health-promotion planning. Self-reported measures were assessed before, immediately after, and 2 months post-training. Consistent ART adherence assessment was reported by 29% of nurses at baseline and 66% at 2 months post-training (p , .001). Assessment of patient sexual behaviors was 25% at baseline and 60% at 2 months post-training (p , .001). Nurse practice behaviors recommended in the counseling algorithm improved significantly at 2 months posttraining compared with baseline, odds ratios 4.30– 10.50. We found that training nurses in clinical counseling for ARTadherence and positive prevention is feasible. Future studies should test impact of nurse counseling on patient outcomes in resource-limited settings.

We previously demonstrated a decrease in bacterial vaginosis (BV) and an increase in Lactobacillus colonization among randomized controlled trial (RCT) participants who received monthly oral periodic presumptive treatment (PPT) [2g metronidazole + 150mg fluconazole]. Post-trial data were analyzed to test the hypothesis that the treatment effect would persist following completion of one year of PPT. Methods Data were obtained from women who completed all 12 RCT visits and attended ≥1 post-trial visit within 120 days following completion of the RCT. We used Andersen-Gill proportional hazards models to estimate the post-trial effect of the intervention on the incidence of BV by Gram stain and detection of Lactobacillus species by culture. Results The analysis included 165 subjects (83 active and 82 placebo). The post-trial incidence of BV was 260 per 100 person-years in the intervention arm versus 358 per 100 person-years in the placebo arm (hazard ratio [HR]=0.76; 95% confidence interval [CI]: 0.51–1.12). The post-trial incidence of Lactobacillus colonization was 180 per 100 person-years in the intervention arm versus 127 per 100 person-years in the placebo arm (HR=1.42; 95% CI: 0.85–2.71). Conclusions Despite a decrease in BV and an increase in Lactobacillus colonization during the RCT, the effect of PPT was not sustained at the same level following cessation of the intervention. New interventions that reduce BV recurrence and promote Lactobacillus colonization without the need for ongoing treatment are needed.

Understanding the prevalence and correlates of genital warts will help to determine whether coverage for the wart-inducing subtypes 6 and 11 in a human papillomavirus vaccine is an important consideration in resource-limited countries

Trichomonas vaginalis has been associated with increased vaginal HIV-1 RNA shedding in antiretroviral therapy (ART)-naïve women. The effect of trichomoniasis on vaginal HIV-1 shedding in ART-treated women has not been characterized. We tested the hypothesis that T. vaginalis infection would increase vaginal HIV-1 RNA shedding in women on ART, and that successful treatment would reduce vaginal HIV-1 RNA level

With the persistent challenges towards controlling the HIV epidemic, there is an ongoing need for research into HIV vaccines and drugs. Sub-Saharan African countries - worst affected by the HIV pandemic - have participated in the conduct of clinical trials for HIV vaccines. In Kenya, the Kenya AIDS Vaccine Initiative (KAVI) at the University of Nairobi has conducted HIV vaccine clinical trials since 2001

Studies of human immunodeficiency virus (HIV)–exposed seronegative individuals are crucial to informvaccine design. In the present study we demonstrated that HIV-exposed seronegative commercial sex workers produce lower levels of proinflammatory cytokines at baseline than HIV-negative control subjects. We also showed that CD4+ T cells of HIV-exposed seronegative commercial sex workers have a characteristically lower level of gene expression that can be seen in differentially expressed genes and systems crucial for HIV replication, such as the T cell receptor pathway and previously identified HIV dependency factors. This apparent lowered activation results in a phenomenon we term “immune quiescence,” which may contribute to host resistance to HIV.

To determine the prevalence, clinical features, risk factors and outcomes associated with cryptococcal meningitis (CM) in human immunodeficiency virus (HIV) positive patients at two referral hospitals in Nairobi, Kenya Kenyatta National Hospital (KNH) and Mbagathi District Hospital (MDH), Nairobi, There is a high prevalence of CM and CM-associated mortality in HIV patients at KNH and MDH despite treatment with antifungal and anti-retroviral drugs. This study demonstrates the need to address the existing inadequacies of CM patient outcomes in Kenya

The objective of this study was to test the hypothesis that sexual risk behaviour would increase following initiation of antiretroviral therapy (ART) in Kenyan female sex workers (FSWs). Design—Prospective cohort study. Setting—FSW cohort in Mombasa, Kenya, 1993-2008. Subjects—898 women contributed HIV-1-seropositive follow-up visits, of whom 129 initiated ART. Intervention—Beginning in March 2004, ART was provided to women qualifying for treatment according to Kenyan National Guidelines. Participants received sexual risk reduction education and free condoms at every visit. Main Outcome Measures—Main outcome measures included unprotected intercourse, abstinence, 100% condom use, number of sexual partners, and frequency of sex. Outcomes were evaluated at monthly follow-up visits using a one week recall interval. Results—Compared to non-ART-exposed follow-up, visits following ART initiation were not associated with an increase in unprotected sex (adjusted odds ratio [AOR] 0.86, 95% confidence interval [CI] 0.62-1.19, P=0.4). There was a non-significant decrease in abstinence (AOR 0.81, 95% CI 0.65-1.01, P=0.07), which was offset by a substantial increase in 100% condom use (AOR 1.54, 95% CI 1.07-2.20, P=0.02). Numbers of sex partners and frequency of sex were similar before versus after starting ART. A trend for decreased sexually transmitted infections following ART initiation provides additional support for the validity of the self-reported behavioural outcomes (AOR 0.67, 95% CI 0.44-1.02, P=0.06). Conclusions—In the setting of ongoing risk reduction education and provision of free condoms, initiation of ART was not associated with increased sexual risk behaviour in this cohort of Kenyan FSWs.

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Ninety seven patients were examined for dental caries using two standard methods: (a) clinical examination based on WHO Basic Methods Oral Health surveys and (b) radiographic examination. Clinical examination method under records caries by upto 40%. Such under recording may give an impression of a decreasing caries prevalence in epidemiological studies.

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Ninety seven patients were examined for dental caries using two standard methods: (a) clinical examination based on WHO Basic Methods Oral Health surveys and (b) radiographic examination. Clinical examination method under records caries by upto 40%. Such under recording may give an impression of a decreasing caries prevalence in epidemiological studies.

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Ninety seven patients were examined for dental caries using two standard methods: (a) clinical examination based on WHO Basic Methods Oral Health surveys and (b) radiographic examination. Clinical examination method under records caries by upto 40%. Such under recording may give an impression of a decreasing caries prevalence in epidemiological studies.

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Ninety seven patients were examined for dental caries using two standard methods: (a) clinical examination based on WHO Basic Methods Oral Health surveys and (b) radiographic examination. Clinical examination method under records caries by upto 40%. Such under recording may give an impression of a decreasing caries prevalence in epidemiological studies.

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Ninety seven patients were examined for dental caries using two standard methods: (a) clinical examination based on WHO Basic Methods Oral Health surveys and (b) radiographic examination. Clinical examination method under records caries by upto 40%. Such under recording may give an impression of a decreasing caries prevalence in epidemiological studies.

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Ninety seven patients were examined for dental caries using two standard methods: (a) clinical examination based on WHO Basic Methods Oral Health surveys and (b) radiographic examination. Clinical examination method under records caries by upto 40%. Such under recording may give an impression of a decreasing caries prevalence in epidemiological studies.

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Ninety seven patients were examined for dental caries using two standard methods: (a) clinical examination based on WHO Basic Methods Oral Health surveys and (b) radiographic examination. Clinical examination method under records caries by upto 40%. Such under recording may give an impression of a decreasing caries prevalence in epidemiological studies.

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Ninety seven patients were examined for dental caries using two standard methods: (a) clinical examination based on WHO Basic Methods Oral Health surveys and (b) radiographic examination. Clinical examination method under records caries by upto 40%. Such under recording may give an impression of a decreasing caries prevalence in epidemiological studies.

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Ninety seven patients were examined for dental caries using two standard methods: (a) clinical examination based on WHO Basic Methods Oral Health surveys and (b) radiographic examination. Clinical examination method under records caries by upto 40%. Such under recording may give an impression of a decreasing caries prevalence in epidemiological studies.

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Ninety seven patients were examined for dental caries using two standard methods: (a) clinical examination based on WHO Basic Methods Oral Health surveys and (b) radiographic examination. Clinical examination method under records caries by upto 40%. Such under recording may give an impression of a decreasing caries prevalence in epidemiological studies.

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Ninety seven patients were examined for dental caries using two standard methods: (a) clinical examination based on WHO Basic Methods Oral Health surveys and (b) radiographic examination. Clinical examination method under records caries by upto 40%. Such under recording may give an impression of a decreasing caries prevalence in epidemiological studies.

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Ninety seven patients were examined for dental caries using two standard methods: (a) clinical examination based on WHO Basic Methods Oral Health surveys and (b) radiographic examination. Clinical examination method under records caries by upto 40%. Such under recording may give an impression of a decreasing caries prevalence in epidemiological studies.

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Ninety seven patients were examined for dental caries using two standard methods: (a) clinical examination based on WHO Basic Methods Oral Health surveys and (b) radiographic examination. Clinical examination method under records caries by upto 40%. Such under recording may give an impression of a decreasing caries prevalence in epidemiological studies.

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Ninety seven patients were examined for dental caries using two standard methods: (a) clinical examination based on WHO Basic Methods Oral Health surveys and (b) radiographic examination. Clinical examination method under records caries by upto 40%. Such under recording may give an impression of a decreasing caries prevalence in epidemiological studies.

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Ninety seven patients were examined for dental caries using two standard methods: (a) clinical examination based on WHO Basic Methods Oral Health surveys and (b) radiographic examination. Clinical examination method under records caries by upto 40%. Such under recording may give an impression of a decreasing caries prevalence in epidemiological studies.

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Ninety seven patients were examined for dental caries using two standard methods: (a) clinical examination based on WHO Basic Methods Oral Health surveys and (b) radiographic examination. Clinical examination method under records caries by upto 40%. Such under recording may give an impression of a decreasing caries prevalence in epidemiological studies.

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Ninety seven patients were examined for dental caries using two standard methods: (a) clinical examination based on WHO Basic Methods Oral Health surveys and (b) radiographic examination. Clinical examination method under records caries by upto 40%. Such under recording may give an impression of a decreasing caries prevalence in epidemiological studies.

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Ninety seven patients were examined for dental caries using two standard methods: (a) clinical examination based on WHO Basic Methods Oral Health surveys and (b) radiographic examination. Clinical examination method under records caries by upto 40%. Such under recording may give an impression of a decreasing caries prevalence in epidemiological studies.

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Ninety seven patients were examined for dental caries using two standard methods: (a) clinical examination based on WHO Basic Methods Oral Health surveys and (b) radiographic examination. Clinical examination method under records caries by upto 40%. Such under recording may give an impression of a decreasing caries prevalence in epidemiological studies.

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Ninety seven patients were examined for dental caries using two standard methods: (a) clinical examination based on WHO Basic Methods Oral Health surveys and (b) radiographic examination. Clinical examination method under records caries by upto 40%. Such under recording may give an impression of a decreasing caries prevalence in epidemiological studies.

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Ninety seven patients were examined for dental caries using two standard methods: (a) clinical examination based on WHO Basic Methods Oral Health surveys and (b) radiographic examination. Clinical examination method under records caries by upto 40%. Such under recording may give an impression of a decreasing caries prevalence in epidemiological studies.

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Ninety seven patients were examined for dental caries using two standard methods: (a) clinical examination based on WHO Basic Methods Oral Health surveys and (b) radiographic examination. Clinical examination method under records caries by upto 40%. Such under recording may give an impression of a decreasing caries prevalence in epidemiological studies.

Ninety seven patients were examined for dental caries using two standard methods: (a) clinical examination based on WHO Basic Methods Oral Health surveys and (b) radiographic examination. Clinical examination method under records caries by upto 40%. Such under recording may give an impression of a decreasing caries prevalence in epidemiological studies.

The safety and immunogenicity of plasmid pTHr DNA, modified vaccinia virus Ankara (MVA) human immunodeficiency virus type 1 (HIV-1) vaccine candidates were evaluated in four Phase I clinical trials in Kenya and Uganda. Both vaccines, expressing HIV-1 subtype A gag p24/p17 and a string of CD8 T-cell epitopes (HIVA), were generally safe and well-tolerated. At the dosage levels and intervals tested, the percentage of vaccine recipients with HIV-1-specific cell-mediated immune responses, assessed by a validated ex vivo interferon gamma (IFN-gamma) ELISPOT assay and Cytokine Flow Cytometry (CFC), did not significantly differ from placebo recipients. These trials demonstrated the feasibility of conducting high-quality Phase 1 trials in Africa.

BACKGROUND: Bacterial vaginosis (BV) is common and has been associated with increased HIV-1 susceptibility. The objective of this study was to identify risk factors for BV in African women at high risk for acquiring HIV-1. METHODS: We conducted a prospective study among 151 HIV-1-seronegative Kenyan female sex workers. Nonpregnant women were eligible if they did not have symptoms of abnormal vaginal itching or discharge at the time of enrollment. At monthly follow-up, a vaginal examination and laboratory testing for genital tract infections were performed. Multivariate Andersen-Gill proportional hazards analysis was used to identify correlates of BV. RESULTS: Participants completed a median of 378 (interquartile range 350-412) days of follow-up. Compared with women reporting no vaginal washing, those who reported vaginal washing 1 to 14 [adjusted hazard ratio (aHR) 1.29, 95% confidence interval (CI) 0.88-1.89], 15 to 28 (aHR 1.60, 95% CI 0.98-2.61), and >28 times/wk (aHR 2.39, 95% CI 1.35-4.23) were at increased risk of BV. Higher BV incidence was also associated with the use of cloth for intravaginal cleansing (aHR 1.48, 95% CI 1.06-2.08) and with recent unprotected intercourse (aHR 1.75, 95% CI 1.47-2.08). Women using depot medroxyprogesterone acetate contraception were at lower risk for BV (aHR 0.59, 95% CI 0.48-0.73). CONCLUSIONS: Vaginal washing and unprotected intercourse were associated with increased risk of BV. These findings could help to inform the development of novel vaginal health approaches for HIV-1 risk reduction in women.

OBJECTIVES: Toll-like receptors (TLR) are important in pathogen recognition and may play a role in HIV disease. We evaluated the effect of chronic untreated and treated HIV-1 infection on systemic TLR expression and TLR signalling. METHODS: Two hundred HIV-infected and uninfected women from a Kenya cohort participated in the studies. TLR1 to TLR10 messenger RNA expression was determined by quantitative reverse transcriptase polymerase chain reaction in peripheral blood mononuclear cells (PBMC). TLR ligand responsiveness was determined in or using ex-vivo PBMC by cytokine production in culture supernatants. RESULTS: Chronic, untreated HIV-1 infection was significantly associated with increased mRNA expression of TLR6, TLR7, and TLR8 and when analysis was limited to those with advanced disease (CD4 cell count < 200 cells/ml) TLR2, TLR3, and TLR4 were additionally elevated. TLR expression correlated with the plasma HIV-RNA load, which was significant for TLR6 and TLR7. In vitro HIV single-stranded RNA alone could enhance TLR mRNA expression. PBMC of HIV-infected subjects also demonstrated profoundly increased proinflammatory responsiveness to TLR ligands, suggesting sensitization of TLR signalling in HIV. Finally, viral suppression by HAART was associated with a normalization of TLR levels. CONCLUSION: Together, these data indicate that chronic viraemic HIV-1 is associated with increased TLR expression and responsiveness, which may perpetuate innate immune dysfunction and activation that underlies HIV pathogenesis, and thus reveal potential new targets for therapy.

BACKGROUND: Vaginal infections are common and have been associated with increased risk for acquisition of human immunodeficiency virus type 1 (HIV-1). METHODS: We conducted a randomized trial of directly observed oral treatment administered monthly to reduce vaginal infections among Kenyan women at risk for HIV-1 acquisition. A trial intervention of 2 g of metronidazole plus 150 mg of fluconazole was compared with metronidazole placebo plus fluconazole placebo. The primary end points were bacterial vaginosis (BV), vaginal candidiasis, trichomoniasis vaginalis (hereafter, "trichomoniasis"), and colonization with Lactobacillus organisms. RESULTS: Of 310 HIV-1-seronegative female sex workers enrolled (155 per arm), 303 were included in the primary end points analysis. A median of 12 follow-up visits per subject were recorded in both study arms (P = .8). Compared with control subjects, women receiving the intervention had fewer episodes of BV (hazard ratio [HR], 0.55; 95% confidence interval [CI], 0.49-0.63) and more frequent vaginal colonization with any Lactobacillus species (HR, 1.47; 95% CI, 1.19-1.80) and H(2)O(2)-producing Lactobacillus species (HR, 1.63; 95% CI, 1.16-2.27). The incidences of vaginal candidiasis (HR, 0.84; 95% CI, 0.67-1.04) and trichomoniasis (HR, 0.55; 95% CI, 0.27-1.12) among treated women were less than those among control subjects, but the differences were not statistically significant. CONCLUSIONS: Periodic presumptive treatment reduced the incidence of BV and promoted colonization with normal vaginal flora. Vaginal health interventions have the potential to provide simple, female-controlled approaches for reducing the risk of HIV-1 acquisition.

BACKGROUND: Bacterial vaginosis (BV) is common and has been associated with increased HIV-1 susceptibility. The objective of this study was to identify risk factors for BV in African women at high risk for acquiring HIV-1. METHODS: We conducted a prospective study among 151 HIV-1-seronegative Kenyan female sex workers. Nonpregnant women were eligible if they did not have symptoms of abnormal vaginal itching or discharge at the time of enrollment. At monthly follow-up, a vaginal examination and laboratory testing for genital tract infections were performed. Multivariate Andersen-Gill proportional hazards analysis was used to identify correlates of BV. RESULTS: Participants completed a median of 378 (interquartile range 350-412) days of follow-up. Compared with women reporting no vaginal washing, those who reported vaginal washing 1 to 14 [adjusted hazard ratio (aHR) 1.29, 95% confidence interval (CI) 0.88-1.89], 15 to 28 (aHR 1.60, 95% CI 0.98-2.61), and >28 times/wk (aHR 2.39, 95% CI 1.35-4.23) were at increased risk of BV. Higher BV incidence was also associated with the use of cloth for intravaginal cleansing (aHR 1.48, 95% CI 1.06-2.08) and with recent unprotected intercourse (aHR 1.75, 95% CI 1.47-2.08). Women using depot medroxyprogesterone acetate contraception were at lower risk for BV (aHR 0.59, 95% CI 0.48-0.73). CONCLUSIONS: Vaginal washing and unprotected intercourse were associated with increased risk of BV. These findings could help to inform the development of novel vaginal health approaches for HIV-1 risk reduction in women.

The response pattern of specific antibodies to the microfilarial sheath (sheath-Ab) of the mosquito-borne filarial parasite Wuchereria bancrofti was investigated in individuals from two East African communities with different levels of endemicity. Individuals from both communities presented a strong inverse relationship between positivity for sheath-Ab and being positive for microfilariae (mf) and circulating filarial antigens (CFA). The prevalence of sheath-Ab positivity was highest in young individuals, but peaked at a younger age in the high (1-14 years) than the low (15-19 years) endemicity community. IgG1, IgG2, IgG3 and IgE intensities to a crude adult filarial worm antigen were higher, and IgG4 intensities were lower, in sheath-Ab positive than in sheath-Ab negative individuals, probably reflecting the infection status of individuals. From the study it appears that individuals become sheath-Ab positive before mf and/or CFA can be detected in the peripheral blood, and only after later disappearance of sheath-Ab from the circulation can CFA and mf be diagnosed. In light of the findings, possible roles of the distinct sheath-Ab in the host-parasite relationship are discussed, and a hypothesis is proposed which suggests that sheath-Ab play an important role in the regulation of host microfilaraemia.

BACKGROUND: An understanding of the health of potential volunteers in Africa is essential for the safe and efficient conduct of clinical trials, particularly for trials of preventive technologies such as vaccines that enroll healthy individuals. Clinical safety laboratory values used for screening, enrolment and follow-up of African clinical trial volunteers have largely been based on values derived from industrialized countries in Europe and North America. This report describes baseline morbidity during recruitment for a multi-center, African laboratory reference intervals study. METHODS: Asymptomatic persons, aged 18-60 years, were invited to participate in a cross-sectional study at seven sites (Kigali, Rwanda; Masaka and Entebbe, Uganda; Kangemi, Kenyatta National Hospital and Kilifi, Kenya; and Lusaka, Zambia). Gender equivalency was by design. Individuals who were acutely ill, pregnant, menstruating, or had significant clinical findings were not enrolled. Each volunteer provided blood for hematology, immunology, and biochemistry parameters and urine for urinalysis. Enrolled volunteers were excluded if found to be positive for HIV, syphilis or Hepatitis B and C. Laboratory assays were conducted under Good Clinical Laboratory Practices (GCLP). RESULTS AND CONCLUSIONS: Of the 2990 volunteers who were screened, 2387 (80%) were enrolled, and 2107 (71%) were included in the analysis (52% men, 48% women). Major reasons for screening out volunteers included abnormal findings on physical examination (228/603, 38%), significant medical history (76, 13%) and inability to complete the informed consent process (73, 13%). Once enrolled, principle reasons for exclusion from analysis included detection of Hepatitis B surface antigen (106/280, 38%) and antibodies against Hepatitis C (95, 34%). This is the first large scale, multi-site study conducted to the standards of GCLP to describe African laboratory reference intervals applicable to potential volunteers in clinical trials. Approximately one-third of all potential volunteers screened were not eligible for analysis; the majority were excluded for medical reasons.

BACKGROUND: Studies of the effect of hormonal contraceptive use on the risk of HIV-1 acquisition have generated conflicting results. A recent study from Uganda and Zimbabwe found that women using hormonal contraception were at increased risk for HIV-1 if they were seronegative for herpes simplex virus type 2 (HSV-2), but not if they were HSV-2 seropositive. OBJECTIVE: To explore the effect of HSV-2 infection on the relationship between hormonal contraception and HIV-1 in a high-risk population. Hormonal contraception has previously been associated with increased HIV-1 risk in this population. METHODS: Data were from a prospective cohort study of 1206 HIV-1 seronegative sex workers from Mombasa, Kenya who were followed monthly. Multivariate Cox proportional hazards analyses were used to adjust for demographic and behavioral measures and incident sexually transmitted diseases. RESULTS:: Two hundred and thirty-three women acquired HIV-1 (8.7/100 person-years). HSV-2 prevalence (81%) and incidence (25.4/100 person-years) were high. In multivariate analysis, including adjustment for HSV-2, HIV-1 acquisition was associated with use of oral contraceptive pills [adjusted hazard ratio (HR), 1.46; 95% confidence interval (CI), 1.00-2.13] and depot medroxyprogesterone acetate (adjusted HR, 1.73; 95% CI, 1.28-2.34). The effect of contraception on HIV-1 susceptibility did not differ significantly between HSV-2 seronegative versus seropositive women. HSV-2 infection was associated with elevated HIV-1 risk (adjusted HR, 3.58; 95% CI, 1.64-7.82). CONCLUSIONS: In this group of high-risk African women, hormonal contraception and HSV-2 infection were both associated with increased risk for HIV-1 acquisition. HIV-1 risk associated with hormonal contraceptive use was not related to HSV-2 serostatus.

We investigated the effect of human immunodeficiency virus type 1 (HIV-1) subtype on disease progression among 145 Kenyan women followed from the time of HIV-1 acquisition. Compared with those infected with subtype A, women infected with subtype D had higher mortality (hazard ratio, 2.3 [95% confidence interval, 1.0-5.6]) and a faster rate of CD4 cell count decline (P=.003). The mortality risk persisted after adjustment for plasma HIV-1 load. There were no differences in plasma viral load by HIV-1 subtype during follow-up. HIV-1 subtype D infection is associated with a >2-fold higher risk of death than subtype A infection, in spite of similar plasma HIV-1 loads.

We investigated the effect of human immunodeficiency virus type 1 (HIV-1) subtype on disease progression among 145 Kenyan women followed from the time of HIV-1 acquisition. Compared with those infected with subtype A, women infected with subtype D had higher mortality (hazard ratio, 2.3 [95% confidence interval, 1.0-5.6]) and a faster rate of CD4 cell count decline (P=.003). The mortality risk persisted after adjustment for plasma HIV-1 load. There were no differences in plasma viral load by HIV-1 subtype during follow-up. HIV-1 subtype D infection is associated with a >2-fold higher risk of death than subtype A infection, in spite of similar plasma HIV-1 loads.

BACKGROUND: Antiretroviral therapy (ART) may decrease HIV-1 infectivity in women by reducing genital HIV-1 shedding. OBJECTIVES: To evaluate the time course and magnitude of decay in cervical and vaginal HIV-1 shedding as women initiate ART. METHODS: This prospective, observational study of 20 antiretroviral-naive women initiating ART with stavudine, lamivudine, and nevirapine measured HIV-1 RNA in plasma, cervical secretions, and vaginal secretions. Qualitative polymerase chain reaction estimated HIV-1 DNA in cervical and vaginal samples. Perelson's two-phase viral decay model and non-linear random effects were used to compare RNA decay rates. Decreases in proviral DNA were evaluated using logistic regression and generalized estimating equations. RESULTS: Significant decreases in the quantity of HIV-1 RNA were observed by day 2 in plasma (P < 0.001), day 2 in cervical secretions (P = 0.001), and day 4 in vaginal secretions (P < 0.001). Modeled initial and subsequent RNA decay rates in plasma, cervical secretions, and vaginal secretions were 0.6, 0.8, and 1.2 log10 virions/day, and 0.04, 0.05, and 0.06 log10 virions/day, respectively. The initial decay rate for vaginal HIV-1 RNA was more rapid than for plasma RNA (P = 0.02). Detection of HIV-1 DNA decreased significantly in vaginal secretions during the first week (P < 0.001). At day 28, 10 women had detectable HIV-1 RNA or proviral DNA in genital secretions. CONCLUSIONS: Genital HIV-1 shedding decreased rapidly after ART initiation, consistent with a rapid decrease in infectivity. However, incomplete viral suppression in half of these women may indicate an ongoing risk of transmission.

We compared the age profiles of infection and specific antibody intensities in two communities with different transmission levels in East Africa to examine the contribution of humoral responses to human immunity to the vector-borne helminth Wuchereria bancrofti. The worm intensities were higher and exhibited a nonlinear age pattern in a high-transmission community, Masaika, in contrast to the low but linearly increasing age infection profile observed for a low-transmission community, Kingwede. The mean levels of specific immunoglobulin G1 (IgG1), IgG2, IgG4, and IgE were also higher in Masaika, but intriguingly, the IgG3 response was higher in Kingwede. The age-antibody patterns differed in the two communities but in a manner apparently contrary to a role in acquired immunity when the data were assessed using simple correlation methods. By contrast, multivariate analyses showed that the antibody response to infection may be classified into three types and that two of these types, a IgG3-type response and a response measuring a trade-off in host production of IgG4 and IgG3 versus production of IgG1, IgG2, and IgE, had a negative effect on Wuchereria circulating antigen levels in a manner that supported a role for these responses in the generation of acquired immunity to infection. Mathematical modeling supported the conclusions drawn from empirical data analyses that variations in both transmission and worm intensity can explain community differences in the age profiles and impacts of these antibody response types. This study showed that parasite-specific antibody responses may be associated with the generation of acquired immunity to human filarial infection but in a form which is dependent on worm transmission intensity and interactions between immune components.

OBJECTIVE: There is substantial epidemiological evidence that infection by Herpes simplex virus type 2 (HSV2) enhances both HIV susceptibility and subsequent sexual transmission. Both infections are extremely common in female sex workers (FSWs) in sub-Saharan Africa, and up to 80% of new HIV infections in urban men in the region are acquired via transactional sex. The present study aimed to elucidate the mucosal immune interactions between HIV and HSV2 in the genital tract. METHODS: Endocervical immune cell populations, cytokine/chemokine protein levels in cervico-vaginal secretions and cervical immune gene expression profiles were measured in a well-defined cohort of HIV-infected and uninfected Kenyan FSWs. Associations between the genital immune milieu and infection by and/or shedding of common genital co-pathogens were examined. RESULTS: HIV-infected FSWs were much more likely to be infected by HSV2, and to shed HSV2 DNA in the genital tract. There was also a profound negative 'mucosal synergy' between these viruses. In HIV uninfected FSWs, HSV2 infection was associated with a ten-fold increase in cervical immature dendritic cells (iDC) expressing DC-SIGN, and a three-fold increase in cervical CD4+ T cells expressing CCR5. HIV infection was associated with iDC depletion in the cervix, and with increased HSV2 genital reactivation, which in turn was associated with HIV shedding levels. CONCLUSIONS: The findings suggest a mucosal vicious circle in which HSV2 infection increases HIV target cells in the genital mucosa, subsequent HIV infection impairs HSV2 mucosal immune control, and local HSV2 reactivation enhances both HSV2 and HIV transmission.

OBJECTIVE: There is substantial epidemiological evidence that infection by Herpes simplex virus type 2 (HSV2) enhances both HIV susceptibility and subsequent sexual transmission. Both infections are extremely common in female sex workers (FSWs) in sub-Saharan Africa, and up to 80% of new HIV infections in urban men in the region are acquired via transactional sex. The present study aimed to elucidate the mucosal immune interactions between HIV and HSV2 in the genital tract. METHODS: Endocervical immune cell populations, cytokine/chemokine protein levels in cervico-vaginal secretions and cervical immune gene expression profiles were measured in a well-defined cohort of HIV-infected and uninfected Kenyan FSWs. Associations between the genital immune milieu and infection by and/or shedding of common genital co-pathogens were examined. RESULTS: HIV-infected FSWs were much more likely to be infected by HSV2, and to shed HSV2 DNA in the genital tract. There was also a profound negative 'mucosal synergy' between these viruses. In HIV uninfected FSWs, HSV2 infection was associated with a ten-fold increase in cervical immature dendritic cells (iDC) expressing DC-SIGN, and a three-fold increase in cervical CD4+ T cells expressing CCR5. HIV infection was associated with iDC depletion in the cervix, and with increased HSV2 genital reactivation, which in turn was associated with HIV shedding levels. CONCLUSIONS: The findings suggest a mucosal vicious circle in which HSV2 infection increases HIV target cells in the genital mucosa, subsequent HIV infection impairs HSV2 mucosal immune control, and local HSV2 reactivation enhances both HSV2 and HIV transmission.

There is an urgent need for low-cost assays for HIV-1 quantitation to ensure adequate follow-up of HIV-infected patients on antiretroviral therapy (ART) in resource-limited countries. Two low-cost viral load assays are evaluated, a reverse transcriptase activity assay (ExavirLoad v2, Cavidi) and a real-time reverse transcriptase PCR assay (Generic HIV viral load, Biocentric). Both tests were compared with the ultrasensitive HIV Amplicor Monitor assay. Samples were collected in Mombasa, Kenya, from 20 HIV-1 seronegative and 150 HIV-1 seropositive individuals of whom 50 received antiretroviral treatment (ART). The ExavirLoad and the Generic HIV viral load assay were performed in a local laboratory in Mombasa, the Amplicor Monitor assay (version 1.5, Roche Diagnostics) was performed in Ghent, Belgium. ExavirLoad and Generic HIV viral load reached a sensitivity of 98.3% and 100% and a specificity of 80.0% and 90.0%, respectively. Linear regression analyses revealed good correlations between the Amplicor Monitor and the Generic HIV viral load (r=0.935, p<0.001) with high accuracy (100.1%), good precision (5.5%) and a low percent similarity coefficient of variation (5.4%). Bland-Altman analysis found 95% of the samples within clinically acceptable limits of agreement (-1.19 to 0.87logcopies/ml). Although, the ExavirLoad also showed a good linear correlation with the Amplicor Monitor (r=0.901, p<0.001), a problem with false positive results was more significant. The cost per test remains relatively high (US$ 30 for ExavirLoad and US$ 20 for the Generic HIV viral load). Hence, false positive results and the need for an expensive PCR instrument for the Generic HIV viral load assays still limit the implementation of these tests in less equipped, less experienced laboratories.

BACKGROUND: Two parallel studies evaluated safety and immunogenicity of a prophylactic HIV-1 vaccine in 192 HIV-seronegative, low-risk volunteers. Modified vaccinia virus Ankara (MVA) and plasmid DNA (pTHr) expressed HIV-1 clade A gag p24 and p17 fused to a string of 25 overlapping CD8+ T cell epitopes (HIVA). METHODS: These studies compared intramuscular, subcutaneous, and intradermal MVA at dosage levels ranging from 5x10(6)-2.5x10(8) pfu. In Study IAVI-010, DNA vaccine was given as a prime at months 0 and 1, followed by MVA as a boost at months 5 and 8. In Study IAVI-011, MVA alone was given at months 0 and 2. Regular safety monitoring was performed. Immunogenicity was measured by the interferon (IFN)-gamma ELISPOT assay on peripheral blood mononuclear cells (PBMC). RESULTS: No serious adverse events were attributed to either vaccine; most adverse events were mild or moderate, although MVA resulted in some severe local reactions. Five vaccine recipients had at least one positive IFN-gamma ELISPOT response, but none were sustained. CONCLUSION: This HIV-1 vaccine candidate was in general safe and well-tolerated. Local reactions were common, but tolerable. Detectable immune responses were infrequent.

The effect of host infection, chronic clinical disease, and transmission intensity on the patterns of specific antibody responses in Bancroftian filariasis was assessed by analyzing specific IgG1, IgG2, IgG3, IgG4, and IgE profiles among adults from two communities with high and low Wuchereria bancrofti endemicity. In the high endemicity community, intensities of the measured antibodies were significantly associated with infection status. IgG1, IgG2, and IgE were negatively associated with microfilaria (MF) status, IgG3 was negatively associated with circulating filarial antigen (CFA) status, and IgG4 was positively associated with CFA status. None of the associations were significantly influenced by chronic lymphatic disease status. In contrast, IgG1, IgG2, and IgG4 responses were less vigorous in the low endemicity community and, except for IgG4, did not show any significant associations with MF or CFA status. The IgG3 responses were considerably more vigorous in the low endemicity community than in the high endemicity one. Only IgG4 responses exhibited a rather similar pattern in the two communities, being significantly positively associated with CFA status in both communities. The IgG4:IgE ratios were higher in infection-positive individuals than in infection-negative ones, and higher in the high endemicity community than in the low endemicity one. Overall, these results indicate that specific antibody responses in Bancroftian filariasis are more related to infection status than to chronic lymphatic disease status. They also suggest that community transmission intensity play a dominant but subtle role in shaping the observed response patterns.

BACKGROUND: Changes in sexual risk behaviour may occur following HIV-1 infection. OBJECTIVE: To test the hypothesis that HIV-1 seroconversion and disease progression are associated with changes in risk behaviours, using data from a cohort of Kenyan female sex workers (FSWs). METHODS: HIV-1-seronegative FSWs were enrolled in a prospective cohort study of risk factors for HIV-1 acquisition. At monthly visits, standardized interviews were conducted to assess sexual risk behaviour and HIV-1 serologic testing was performed. Seroconverters were invited to continue with follow-up. Between 1993 and 2004 (when antiretroviral therapy was introduced in the cohort), 265 women seroconverted for HIV-1 (incidence 7.7/100 person-years) and were included in this analysis. RESULTS: Unprotected intercourse was reported at 546/2037 (27%) pre-seroconversion visits versus 557/3732 (15%) post-seroconversion visits (P < 0.001). These findings remained significant after adjustment for potential confounding factors [adjusted odds ratio (AOR) 0.69; 95% confidence interval (CI), 0.55-0.86]. Compared with HIV-1-seronegative women, there was a progressive stepwise decrease in unprotected intercourse among HIV-1-seropositive women with CD4 cell counts > or = 500 (AOR, 0.93; 95% CI, 0.62-1.39), 200-499 (AOR, 0.58; 95% CI, 0.41-0.82) and < 200 cells/microl (AOR, 0.45; 95% CI, 0.25-0.82). Decreases in unprotected intercourse reflected increases in both abstinence and 100% condom use. Women also reported fewer partners and fewer episodes of intercourse after HIV-1 seroconversion. CONCLUSIONS: HIV-1 seroconversion and disease progression were associated with decreases in sexual risk behaviour among Kenyan FSWs.

The effect of eight half-yearly treatment rounds with diethylcarbamazine (DEC; 6mg/kg bodyweight) on Wuchereria bancrofti-specific circulating filarial antigen (CFA), a marker of adult worm infection, was followed in 79 individuals who were CFA-positive before start of treatment. Half of these were also microfilariae (mf)-positive. Microfilaraemia decreased rapidly after onset of treatment and became undetectable after four treatments. Circulating antigenaemia also decreased progressively, but at a much slower rate. After two, four and eight treatment rounds, the mean CFA intensity was reduced by 81, 94 and 98%, and the prevalence of CFA positivity was 85, 66 and 57%, compared with pre-treatment, respectively. CFA clearance rates were negatively related to pre-treatment CFA intensities, and were higher among pre-treatment mf-negative individuals than among pre-treatment mf-positive individuals. Even among patients who had pre-treatment CFA intensities above the upper measuring level (32000antigen units), and who continued to have intensities above this level after treatment, a decrease in post-treatment CFA intensities was obvious from a continuous decrease in ELISA optical density values. Repeated DEC therapy thus appears to have a slow but profound and persistent macrofilaricidal effect, which in the long run may be beneficial to populations undergoing DEC-based control interventions by reducing the probability of future morbidity development.

The effect of eight half-yearly treatment rounds with diethylcarbamazine (DEC; 6mg/kg bodyweight) on Wuchereria bancrofti-specific circulating filarial antigen (CFA), a marker of adult worm infection, was followed in 79 individuals who were CFA-positive before start of treatment. Half of these were also microfilariae (mf)-positive. Microfilaraemia decreased rapidly after onset of treatment and became undetectable after four treatments. Circulating antigenaemia also decreased progressively, but at a much slower rate. After two, four and eight treatment rounds, the mean CFA intensity was reduced by 81, 94 and 98%, and the prevalence of CFA positivity was 85, 66 and 57%, compared with pre-treatment, respectively. CFA clearance rates were negatively related to pre-treatment CFA intensities, and were higher among pre-treatment mf-negative individuals than among pre-treatment mf-positive individuals. Even among patients who had pre-treatment CFA intensities above the upper measuring level (32000antigen units), and who continued to have intensities above this level after treatment, a decrease in post-treatment CFA intensities was obvious from a continuous decrease in ELISA optical density values. Repeated DEC therapy thus appears to have a slow but profound and persistent macrofilaricidal effect, which in the long run may be beneficial to populations undergoing DEC-based control interventions by reducing the probability of future morbidity development.

MRC Human Immunology Unit, University of Oxford, Oxford, UK. The IFN-y enzyme-linked immunospot (ELI-Spot) assay is often used to map HIV-specific CD8 T-cell responses. We compared overlapping 15-mer pools with optimized CD8 epitopes to screen ELISpot responses in HIV-infected individuals. The 15-mer pools detected responses to previously undefined epitopes, but often missed low-level responses to predefined epitopes, particularly when the epitope was central in the 15-mer, rather than at the N-terminus or C-terminus. These factors should be considered in the monitoring of HIV vaccine trials.

MRC Human Immunology Unit, University of Oxford, Oxford, UK. The IFN-y enzyme-linked immunospot (ELI-Spot) assay is often used to map HIV-specific CD8 T-cell responses. We compared overlapping 15-mer pools with optimized CD8 epitopes to screen ELISpot responses in HIV-infected individuals. The 15-mer pools detected responses to previously undefined epitopes, but often missed low-level responses to predefined epitopes, particularly when the epitope was central in the 15-mer, rather than at the N-terminus or C-terminus. These factors should be considered in the monitoring of HIV vaccine trials.

DBL-Institute for Health Research and Development, Jaegersborg Alle 1D, 2920 Charlottenlund, Denmark. pesimonsen@dblnet.dk The effect of eight half-yearly treatment rounds with diethylcarbamazine (DEC; 6mg/kg bodyweight) on Wuchereria bancrofti-specific circulating filarial antigen (CFA), a marker of adult worm infection, was followed in 79 individuals who were CFA-positive before start of treatment. Half of these were also microfilariae (mf)-positive. Microfilaraemia decreased rapidly after onset of treatment and became undetectable after four treatments. Circulating antigenaemia also decreased progressively, but at a much slower rate. After two, four and eight treatment rounds, the mean CFA intensity was reduced by 81, 94 and 98%, and the prevalence of CFA positivity was 85, 66 and 57%, compared with pre-treatment, respectively. CFA clearance rates were negatively related to pre-treatment CFA intensities, and were higher among pre-treatment mf-negative individuals than among pre-treatment mf-positive individuals. Even among patients who had pre-treatment CFA intensities above the upper measuring level (32000antigen units), and who continued to have intensities above this level after treatment, a decrease in post-treatment CFA intensities was obvious from a continuous decrease in ELISA optical density values. Repeated DEC therapy thus appears to have a slow but profound and persistent macrofilaricidal effect, which in the long run may be beneficial to populations undergoing DEC-based control interventions by reducing the probability of future morbidity development.

MRC Human Immunology Unit, University of Oxford, Oxford, UK. The IFN-y enzyme-linked immunospot (ELI-Spot) assay is often used to map HIV-specific CD8 T-cell responses. We compared overlapping 15-mer pools with optimized CD8 epitopes to screen ELISpot responses in HIV-infected individuals. The 15-mer pools detected responses to previously undefined epitopes, but often missed low-level responses to predefined epitopes, particularly when the epitope was central in the 15-mer, rather than at the N-terminus or C-terminus. These factors should be considered in the monitoring of HIV vaccine trials.

Department of Infectious Disease Epidemiology, Imperial College School of Medicine, London, UK. Previous attempts to determine the interactions between filariasis transmission intensity, infection and chronic disease have been limited by a lack of a theoretical framework that allows the explicit examination of mechanisms that may link these variables at the community level. Here, we show how deterministic mathematical models, in conjunction with analyses of standardized field data from communities with varying parasite transmission intensities, can provide a particularly powerful framework for investigating this topic. These models were based on adult worm population dynamics, worm initiated chronic disease and two major forms of acquired immunity (larval- versus adult-worm generated) explicitly linked to community transmission intensity as measured by the Annual Transmission Potential (ATP). They were then fitted to data from low, moderate and moderately high transmission communities from East Africa to determine the mechanistic relationships between transmission, infection and observed filarial morbidity. The results indicate a profound effect of transmission intensity on patent infection and chronic disease, and on the generation and impact of immunity on these variables. For infection, the analysis indicates that in areas of higher parasite transmission, community-specific microfilarial rates may increase proportionately with transmission intensity until moderated by the generation of herd immunity. This supports recent suggestions that acquired immunity in filariasis is transmission driven and may be significant only in areas of high transmission. In East Africa, this transmission threshold is likely to be higher than an ATP of at least 100. A new finding from the analysis of the disease data is that per capita worm pathogenicity could increase with transmission intensity such that the prevalences of both hydrocele and lymphoedema, even without immunopathological involvement, may increase disproportionately with transmission intensity. For lymphoedema, this rise may be further accelerated with the onset of immunopathology. An intriguing finding is that there may be at least two types of immunity operating in filariasis: one implicated in anti-infection immunity and generated by past experience of adult worms, the other involved in immune-mediated pathology and based on cumulative experience of infective larvae. If confirmed, these findings have important implications for the new global initiative to achieve control of this disease.

MRC Human Immunology Unit, University of Oxford, Oxford, UK. The IFN-y enzyme-linked immunospot (ELI-Spot) assay is often used to map HIV-specific CD8 T-cell responses. We compared overlapping 15-mer pools with optimized CD8 epitopes to screen ELISpot responses in HIV-infected individuals. The 15-mer pools detected responses to previously undefined epitopes, but often missed low-level responses to predefined epitopes, particularly when the epitope was central in the 15-mer, rather than at the N-terminus or C-terminus. These factors should be considered in the monitoring of HIV vaccine trials.

MRC Human Immunology Unit, University of Oxford, Oxford, UK. The IFN-y enzyme-linked immunospot (ELI-Spot) assay is often used to map HIV-specific CD8 T-cell responses. We compared overlapping 15-mer pools with optimized CD8 epitopes to screen ELISpot responses in HIV-infected individuals. The 15-mer pools detected responses to previously undefined epitopes, but often missed low-level responses to predefined epitopes, particularly when the epitope was central in the 15-mer, rather than at the N-terminus or C-terminus. These factors should be considered in the monitoring of HIV vaccine trials.

Department of Infectious Disease Epidemiology, Imperial College School of Medicine, London, UK. Previous attempts to determine the interactions between filariasis transmission intensity, infection and chronic disease have been limited by a lack of a theoretical framework that allows the explicit examination of mechanisms that may link these variables at the community level. Here, we show how deterministic mathematical models, in conjunction with analyses of standardized field data from communities with varying parasite transmission intensities, can provide a particularly powerful framework for investigating this topic. These models were based on adult worm population dynamics, worm initiated chronic disease and two major forms of acquired immunity (larval- versus adult-worm generated) explicitly linked to community transmission intensity as measured by the Annual Transmission Potential (ATP). They were then fitted to data from low, moderate and moderately high transmission communities from East Africa to determine the mechanistic relationships between transmission, infection and observed filarial morbidity. The results indicate a profound effect of transmission intensity on patent infection and chronic disease, and on the generation and impact of immunity on these variables. For infection, the analysis indicates that in areas of higher parasite transmission, community-specific microfilarial rates may increase proportionately with transmission intensity until moderated by the generation of herd immunity. This supports recent suggestions that acquired immunity in filariasis is transmission driven and may be significant only in areas of high transmission. In East Africa, this transmission threshold is likely to be higher than an ATP of at least 100. A new finding from the analysis of the disease data is that per capita worm pathogenicity could increase with transmission intensity such that the prevalences of both hydrocele and lymphoedema, even without immunopathological involvement, may increase disproportionately with transmission intensity. For lymphoedema, this rise may be further accelerated with the onset of immunopathology. An intriguing finding is that there may be at least two types of immunity operating in filariasis: one implicated in anti-infection immunity and generated by past experience of adult worms, the other involved in immune-mediated pathology and based on cumulative experience of infective larvae. If confirmed, these findings have important implications for the new global initiative to achieve control of this disease.

Department of Infectious Disease Epidemiology, Imperial College School of Medicine, London, UK. Previous attempts to determine the interactions between filariasis transmission intensity, infection and chronic disease have been limited by a lack of a theoretical framework that allows the explicit examination of mechanisms that may link these variables at the community level. Here, we show how deterministic mathematical models, in conjunction with analyses of standardized field data from communities with varying parasite transmission intensities, can provide a particularly powerful framework for investigating this topic. These models were based on adult worm population dynamics, worm initiated chronic disease and two major forms of acquired immunity (larval- versus adult-worm generated) explicitly linked to community transmission intensity as measured by the Annual Transmission Potential (ATP). They were then fitted to data from low, moderate and moderately high transmission communities from East Africa to determine the mechanistic relationships between transmission, infection and observed filarial morbidity. The results indicate a profound effect of transmission intensity on patent infection and chronic disease, and on the generation and impact of immunity on these variables. For infection, the analysis indicates that in areas of higher parasite transmission, community-specific microfilarial rates may increase proportionately with transmission intensity until moderated by the generation of herd immunity. This supports recent suggestions that acquired immunity in filariasis is transmission driven and may be significant only in areas of high transmission. In East Africa, this transmission threshold is likely to be higher than an ATP of at least 100. A new finding from the analysis of the disease data is that per capita worm pathogenicity could increase with transmission intensity such that the prevalences of both hydrocele and lymphoedema, even without immunopathological involvement, may increase disproportionately with transmission intensity. For lymphoedema, this rise may be further accelerated with the onset of immunopathology. An intriguing finding is that there may be at least two types of immunity operating in filariasis: one implicated in anti-infection immunity and generated by past experience of adult worms, the other involved in immune-mediated pathology and based on cumulative experience of infective larvae. If confirmed, these findings have important implications for the new global initiative to achieve control of this disease.

MRC Human Immunology Unit, University of Oxford, Oxford, UK. The IFN-y enzyme-linked immunospot (ELI-Spot) assay is often used to map HIV-specific CD8 T-cell responses. We compared overlapping 15-mer pools with optimized CD8 epitopes to screen ELISpot responses in HIV-infected individuals. The 15-mer pools detected responses to previously undefined epitopes, but often missed low-level responses to predefined epitopes, particularly when the epitope was central in the 15-mer, rather than at the N-terminus or C-terminus. These factors should be considered in the monitoring of HIV vaccine trials.

Department of Infectious Disease Epidemiology, Imperial College School of Medicine, London, UK. Previous attempts to determine the interactions between filariasis transmission intensity, infection and chronic disease have been limited by a lack of a theoretical framework that allows the explicit examination of mechanisms that may link these variables at the community level. Here, we show how deterministic mathematical models, in conjunction with analyses of standardized field data from communities with varying parasite transmission intensities, can provide a particularly powerful framework for investigating this topic. These models were based on adult worm population dynamics, worm initiated chronic disease and two major forms of acquired immunity (larval- versus adult-worm generated) explicitly linked to community transmission intensity as measured by the Annual Transmission Potential (ATP). They were then fitted to data from low, moderate and moderately high transmission communities from East Africa to determine the mechanistic relationships between transmission, infection and observed filarial morbidity. The results indicate a profound effect of transmission intensity on patent infection and chronic disease, and on the generation and impact of immunity on these variables. For infection, the analysis indicates that in areas of higher parasite transmission, community-specific microfilarial rates may increase proportionately with transmission intensity until moderated by the generation of herd immunity. This supports recent suggestions that acquired immunity in filariasis is transmission driven and may be significant only in areas of high transmission. In East Africa, this transmission threshold is likely to be higher than an ATP of at least 100. A new finding from the analysis of the disease data is that per capita worm pathogenicity could increase with transmission intensity such that the prevalences of both hydrocele and lymphoedema, even without immunopathological involvement, may increase disproportionately with transmission intensity. For lymphoedema, this rise may be further accelerated with the onset of immunopathology. An intriguing finding is that there may be at least two types of immunity operating in filariasis: one implicated in anti-infection immunity and generated by past experience of adult worms, the other involved in immune-mediated pathology and based on cumulative experience of infective larvae. If confirmed, these findings have important implications for the new global initiative to achieve control of this disease.

Department of Infectious Disease Epidemiology, Imperial College School of Medicine, London, UK. Previous attempts to determine the interactions between filariasis transmission intensity, infection and chronic disease have been limited by a lack of a theoretical framework that allows the explicit examination of mechanisms that may link these variables at the community level. Here, we show how deterministic mathematical models, in conjunction with analyses of standardized field data from communities with varying parasite transmission intensities, can provide a particularly powerful framework for investigating this topic. These models were based on adult worm population dynamics, worm initiated chronic disease and two major forms of acquired immunity (larval- versus adult-worm generated) explicitly linked to community transmission intensity as measured by the Annual Transmission Potential (ATP). They were then fitted to data from low, moderate and moderately high transmission communities from East Africa to determine the mechanistic relationships between transmission, infection and observed filarial morbidity. The results indicate a profound effect of transmission intensity on patent infection and chronic disease, and on the generation and impact of immunity on these variables. For infection, the analysis indicates that in areas of higher parasite transmission, community-specific microfilarial rates may increase proportionately with transmission intensity until moderated by the generation of herd immunity. This supports recent suggestions that acquired immunity in filariasis is transmission driven and may be significant only in areas of high transmission. In East Africa, this transmission threshold is likely to be higher than an ATP of at least 100. A new finding from the analysis of the disease data is that per capita worm pathogenicity could increase with transmission intensity such that the prevalences of both hydrocele and lymphoedema, even without immunopathological involvement, may increase disproportionately with transmission intensity. For lymphoedema, this rise may be further accelerated with the onset of immunopathology. An intriguing finding is that there may be at least two types of immunity operating in filariasis: one implicated in anti-infection immunity and generated by past experience of adult worms, the other involved in immune-mediated pathology and based on cumulative experience of infective larvae. If confirmed, these findings have important implications for the new global initiative to achieve control of this disease.

Department of Infectious Disease Epidemiology, Imperial College School of Medicine, London, UK. Previous attempts to determine the interactions between filariasis transmission intensity, infection and chronic disease have been limited by a lack of a theoretical framework that allows the explicit examination of mechanisms that may link these variables at the community level. Here, we show how deterministic mathematical models, in conjunction with analyses of standardized field data from communities with varying parasite transmission intensities, can provide a particularly powerful framework for investigating this topic. These models were based on adult worm population dynamics, worm initiated chronic disease and two major forms of acquired immunity (larval- versus adult-worm generated) explicitly linked to community transmission intensity as measured by the Annual Transmission Potential (ATP). They were then fitted to data from low, moderate and moderately high transmission communities from East Africa to determine the mechanistic relationships between transmission, infection and observed filarial morbidity. The results indicate a profound effect of transmission intensity on patent infection and chronic disease, and on the generation and impact of immunity on these variables. For infection, the analysis indicates that in areas of higher parasite transmission, community-specific microfilarial rates may increase proportionately with transmission intensity until moderated by the generation of herd immunity. This supports recent suggestions that acquired immunity in filariasis is transmission driven and may be significant only in areas of high transmission. In East Africa, this transmission threshold is likely to be higher than an ATP of at least 100. A new finding from the analysis of the disease data is that per capita worm pathogenicity could increase with transmission intensity such that the prevalences of both hydrocele and lymphoedema, even without immunopathological involvement, may increase disproportionately with transmission intensity. For lymphoedema, this rise may be further accelerated with the onset of immunopathology. An intriguing finding is that there may be at least two types of immunity operating in filariasis: one implicated in anti-infection immunity and generated by past experience of adult worms, the other involved in immune-mediated pathology and based on cumulative experience of infective larvae. If confirmed, these findings have important implications for the new global initiative to achieve control of this disease.

Department of Infectious Disease Epidemiology, Imperial College School of Medicine, London, UK. Previous attempts to determine the interactions between filariasis transmission intensity, infection and chronic disease have been limited by a lack of a theoretical framework that allows the explicit examination of mechanisms that may link these variables at the community level. Here, we show how deterministic mathematical models, in conjunction with analyses of standardized field data from communities with varying parasite transmission intensities, can provide a particularly powerful framework for investigating this topic. These models were based on adult worm population dynamics, worm initiated chronic disease and two major forms of acquired immunity (larval- versus adult-worm generated) explicitly linked to community transmission intensity as measured by the Annual Transmission Potential (ATP). They were then fitted to data from low, moderate and moderately high transmission communities from East Africa to determine the mechanistic relationships between transmission, infection and observed filarial morbidity. The results indicate a profound effect of transmission intensity on patent infection and chronic disease, and on the generation and impact of immunity on these variables. For infection, the analysis indicates that in areas of higher parasite transmission, community-specific microfilarial rates may increase proportionately with transmission intensity until moderated by the generation of herd immunity. This supports recent suggestions that acquired immunity in filariasis is transmission driven and may be significant only in areas of high transmission. In East Africa, this transmission threshold is likely to be higher than an ATP of at least 100. A new finding from the analysis of the disease data is that per capita worm pathogenicity could increase with transmission intensity such that the prevalences of both hydrocele and lymphoedema, even without immunopathological involvement, may increase disproportionately with transmission intensity. For lymphoedema, this rise may be further accelerated with the onset of immunopathology. An intriguing finding is that there may be at least two types of immunity operating in filariasis: one implicated in anti-infection immunity and generated by past experience of adult worms, the other involved in immune-mediated pathology and based on cumulative experience of infective larvae. If confirmed, these findings have important implications for the new global initiative to achieve control of this disease.

Department of Infectious Disease Epidemiology, Imperial College School of Medicine, London, UK. Previous attempts to determine the interactions between filariasis transmission intensity, infection and chronic disease have been limited by a lack of a theoretical framework that allows the explicit examination of mechanisms that may link these variables at the community level. Here, we show how deterministic mathematical models, in conjunction with analyses of standardized field data from communities with varying parasite transmission intensities, can provide a particularly powerful framework for investigating this topic. These models were based on adult worm population dynamics, worm initiated chronic disease and two major forms of acquired immunity (larval- versus adult-worm generated) explicitly linked to community transmission intensity as measured by the Annual Transmission Potential (ATP). They were then fitted to data from low, moderate and moderately high transmission communities from East Africa to determine the mechanistic relationships between transmission, infection and observed filarial morbidity. The results indicate a profound effect of transmission intensity on patent infection and chronic disease, and on the generation and impact of immunity on these variables. For infection, the analysis indicates that in areas of higher parasite transmission, community-specific microfilarial rates may increase proportionately with transmission intensity until moderated by the generation of herd immunity. This supports recent suggestions that acquired immunity in filariasis is transmission driven and may be significant only in areas of high transmission. In East Africa, this transmission threshold is likely to be higher than an ATP of at least 100. A new finding from the analysis of the disease data is that per capita worm pathogenicity could increase with transmission intensity such that the prevalences of both hydrocele and lymphoedema, even without immunopathological involvement, may increase disproportionately with transmission intensity. For lymphoedema, this rise may be further accelerated with the onset of immunopathology. An intriguing finding is that there may be at least two types of immunity operating in filariasis: one implicated in anti-infection immunity and generated by past experience of adult worms, the other involved in immune-mediated pathology and based on cumulative experience of infective larvae. If confirmed, these findings have important implications for the new global initiative to achieve control of this disease.

Department of Infectious Disease Epidemiology, Imperial College School of Medicine, London, UK. Previous attempts to determine the interactions between filariasis transmission intensity, infection and chronic disease have been limited by a lack of a theoretical framework that allows the explicit examination of mechanisms that may link these variables at the community level. Here, we show how deterministic mathematical models, in conjunction with analyses of standardized field data from communities with varying parasite transmission intensities, can provide a particularly powerful framework for investigating this topic. These models were based on adult worm population dynamics, worm initiated chronic disease and two major forms of acquired immunity (larval- versus adult-worm generated) explicitly linked to community transmission intensity as measured by the Annual Transmission Potential (ATP). They were then fitted to data from low, moderate and moderately high transmission communities from East Africa to determine the mechanistic relationships between transmission, infection and observed filarial morbidity. The results indicate a profound effect of transmission intensity on patent infection and chronic disease, and on the generation and impact of immunity on these variables. For infection, the analysis indicates that in areas of higher parasite transmission, community-specific microfilarial rates may increase proportionately with transmission intensity until moderated by the generation of herd immunity. This supports recent suggestions that acquired immunity in filariasis is transmission driven and may be significant only in areas of high transmission. In East Africa, this transmission threshold is likely to be higher than an ATP of at least 100. A new finding from the analysis of the disease data is that per capita worm pathogenicity could increase with transmission intensity such that the prevalences of both hydrocele and lymphoedema, even without immunopathological involvement, may increase disproportionately with transmission intensity. For lymphoedema, this rise may be further accelerated with the onset of immunopathology. An intriguing finding is that there may be at least two types of immunity operating in filariasis: one implicated in anti-infection immunity and generated by past experience of adult worms, the other involved in immune-mediated pathology and based on cumulative experience of infective larvae. If confirmed, these findings have important implications for the new global initiative to achieve control of this disease.

Department of Infectious Disease Epidemiology, Imperial College School of Medicine, London, UK. Previous attempts to determine the interactions between filariasis transmission intensity, infection and chronic disease have been limited by a lack of a theoretical framework that allows the explicit examination of mechanisms that may link these variables at the community level. Here, we show how deterministic mathematical models, in conjunction with analyses of standardized field data from communities with varying parasite transmission intensities, can provide a particularly powerful framework for investigating this topic. These models were based on adult worm population dynamics, worm initiated chronic disease and two major forms of acquired immunity (larval- versus adult-worm generated) explicitly linked to community transmission intensity as measured by the Annual Transmission Potential (ATP). They were then fitted to data from low, moderate and moderately high transmission communities from East Africa to determine the mechanistic relationships between transmission, infection and observed filarial morbidity. The results indicate a profound effect of transmission intensity on patent infection and chronic disease, and on the generation and impact of immunity on these variables. For infection, the analysis indicates that in areas of higher parasite transmission, community-specific microfilarial rates may increase proportionately with transmission intensity until moderated by the generation of herd immunity. This supports recent suggestions that acquired immunity in filariasis is transmission driven and may be significant only in areas of high transmission. In East Africa, this transmission threshold is likely to be higher than an ATP of at least 100. A new finding from the analysis of the disease data is that per capita worm pathogenicity could increase with transmission intensity such that the prevalences of both hydrocele and lymphoedema, even without immunopathological involvement, may increase disproportionately with transmission intensity. For lymphoedema, this rise may be further accelerated with the onset of immunopathology. An intriguing finding is that there may be at least two types of immunity operating in filariasis: one implicated in anti-infection immunity and generated by past experience of adult worms, the other involved in immune-mediated pathology and based on cumulative experience of infective larvae. If confirmed, these findings have important implications for the new global initiative to achieve control of this disease.

Department of Infectious Disease Epidemiology, Imperial College School of Medicine, London, UK. Previous attempts to determine the interactions between filariasis transmission intensity, infection and chronic disease have been limited by a lack of a theoretical framework that allows the explicit examination of mechanisms that may link these variables at the community level. Here, we show how deterministic mathematical models, in conjunction with analyses of standardized field data from communities with varying parasite transmission intensities, can provide a particularly powerful framework for investigating this topic. These models were based on adult worm population dynamics, worm initiated chronic disease and two major forms of acquired immunity (larval- versus adult-worm generated) explicitly linked to community transmission intensity as measured by the Annual Transmission Potential (ATP). They were then fitted to data from low, moderate and moderately high transmission communities from East Africa to determine the mechanistic relationships between transmission, infection and observed filarial morbidity. The results indicate a profound effect of transmission intensity on patent infection and chronic disease, and on the generation and impact of immunity on these variables. For infection, the analysis indicates that in areas of higher parasite transmission, community-specific microfilarial rates may increase proportionately with transmission intensity until moderated by the generation of herd immunity. This supports recent suggestions that acquired immunity in filariasis is transmission driven and may be significant only in areas of high transmission. In East Africa, this transmission threshold is likely to be higher than an ATP of at least 100. A new finding from the analysis of the disease data is that per capita worm pathogenicity could increase with transmission intensity such that the prevalences of both hydrocele and lymphoedema, even without immunopathological involvement, may increase disproportionately with transmission intensity. For lymphoedema, this rise may be further accelerated with the onset of immunopathology. An intriguing finding is that there may be at least two types of immunity operating in filariasis: one implicated in anti-infection immunity and generated by past experience of adult worms, the other involved in immune-mediated pathology and based on cumulative experience of infective larvae. If confirmed, these findings have important implications for the new global initiative to achieve control of this disease.