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Schistosomiasis is a disease caused by parasitic flatworms of the Schistosoma spp., and is increasingly recognized to alter the immune system, and the potential to respond to vaccines. The impact of endemic infections on protective immunity is critical to inform vaccination strategies globally. We assessed the influence of Schistosoma mansoni worm burden on multiple host vaccine-related immune parameters in a Ugandan fishing cohort (n = 75) given three doses of a Hepatitis B (HepB) vaccine at baseline and multiple timepoints post-vaccination. We observed distinct differences in immune responses in instances of higher worm burden, compared to low worm burden or non-infected. Concentrations of pre-vaccination serum schistosome-specific circulating anodic antigen (CAA), linked to worm burden, showed a significant bimodal distribution associated with HepB titers, which was lower in individuals with higher CAA values at month 7 post-vaccination (M7). Comparative chemokine/cytokine responses revealed significant upregulation of CCL19, CXCL9 and CCL17 known to be involved in T cell activation and recruitment, in higher CAA individuals, and CCL17 correlated negatively with HepB titers at month 12 post-vaccination. We show that HepB-specific CD4+ T cell memory responses correlated positively with HepB titers at M7. We further established that those participants with high CAA had significantly lower frequencies of circulating T follicular helper (cTfh) subpopulations pre- and post-vaccination, but higher regulatory T cells (Tregs) post-vaccination, suggesting changes in the immune microenvironment in high CAA could favor Treg recruitment and activation. Additionally, we found that changes in the levels of innate-related cytokines/chemokines CXCL10, IL-1ß, and CCL26, involved in driving T helper responses, were associated with increasing CAA concentration. This study provides further insight on pre-vaccination host responses to Schistosoma worm burden which will support our understanding of vaccine responses altered by pathogenic host immune mechanisms and memory function and explain abrogated vaccine responses in communities with endemic infections.
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Esquistosomiasis mansoni , Animales , Esquistosomiasis mansoni/epidemiología , Antígenos Helmínticos , Schistosoma mansoni , Citocinas , Vacunación , InmunidadRESUMEN
INTRODUCTION: Hepatitis B (HBV) prevalence remains high in Sub Saharan Africa and among some key populations such as those with continued exposure through sexual contact. We assessed the HBV status among potential participants who were screened for simulated HIV vaccine efficacy trials in Kenya and Uganda. METHODS: We conducted a cross sectional analysis of data collected from individuals who were screened in Kenya (Nairobi) and Uganda (Entebbe and Kampala). The studies followed hypothetical procedures of an HIV vaccine efficacy trial and aimed to enroll HIV negative key and vulnerable populations at elevated risk of HIV acquisition. HBV status was the main outcome categorized using Hepatitis B surface antigen (HBsAg) and total Hepatitis B core antibody (HBcAb). Baseline characteristics potentially associated with never being infected were analyzed using logistic regression. RESULTS: We screened 1,366 participants with mean age (SD) 28.7 (7.3) years. Overall, 46.6% were from Entebbe, 50.7% had secondary or higher level of education, 76.4% had informal high-risk jobs and 56.3% were male. Kampala had only female participants contributing 60.6% of females screened. Of the screened participants, 94.7% and 3.4% were negative and positive for HBsAg respectively. The prevalence on HBV infection was 3.9% among males and 2.8% among females while prevalence by site was: Entebbe (4.9%); Kampala (4.1%) and Nairobi (0.3%). The highest HBV prevalence was found among participants aged 25-29-years (5.2%), those with primary level education (4.5%), and those in informal low risk jobs (6.5%). Considering 1265 participants with complete data on HBsAg and HBcAb-Total, HBV status was never infected (67.9%), past infection (28.5%), chronic infection (3.2%) and acute infection (0.5%). Of 859 who were never infected, 685 (79.7%) were tested for anti-HBs titers of whom 60 (8.8%) had titers >10IU/L (immune due to vaccination). The odds of never being HBV infected were lower among older individuals 25-29 years (AOR 0.51; 95%CI 0.36-0.71) and ≥30 years (AOR 0.35; 95% CI 0.25-0.49). The odds were higher among participants with informal high-risk jobs from Kampala (AOR 2.21; 95% CI 1.41-3.47) and Nairobi (AOR 2.61; 95% CI 1.72-4.00) compared to those from Entebbe. CONCLUSION: HBV prevalence and immunity due to vaccination were low among HIV negative individuals who are eligible for HIV vaccine trials and prevalence varies by age, education level and main occupation. Younger individuals and those recruited from existing cohorts/ clinics have a higher likelihood of having no prior HBV infection. HIV prevention intervention trials are a platform to identify individuals that need HBV vaccination.
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Vacunas contra el SIDA , Infecciones por VIH , Hepatitis B , Humanos , Masculino , Femenino , Adulto , Antígenos de Superficie de la Hepatitis B , Uganda/epidemiología , Kenia/epidemiología , Estudios Transversales , Eficacia de las Vacunas , Hepatitis B/epidemiología , Hepatitis B/prevención & control , Hepatitis B/complicaciones , Virus de la Hepatitis B , Vacunas contra Hepatitis B , Anticuerpos contra la Hepatitis B , Prevalencia , Infecciones por VIH/epidemiología , Infecciones por VIH/prevención & control , Infecciones por VIH/complicacionesRESUMEN
The impact of endemic infections on protective immunity is critical to inform vaccination strategies. In this study, we assessed the influence of Schistosoma mansoni infection on host responses in a Ugandan fishing cohort given a Hepatitis B (HepB) vaccine. Concentrations of schistosome-specific circulating anodic antigen (CAA) pre-vaccination showed a significant bimodal distribution associated with HepB titers, which were lower in individuals with high CAA. We established that participants with high CAA had significantly lower frequencies of circulating T follicular helper (cTfh) subpopulations pre- and post-vaccination and higher regulatory T cells (Tregs) post-vaccination. Polarization towards higher frequencies of Tregs: cTfh cells can be mediated by changes in the cytokine environment favoring Treg differentiation. In fact, we observed higher levels of CCL17 and soluble IL-2R pre-vaccination (important for Treg recruitment and development), in individuals with high CAA that negatively associated with HepB titers. Additionally, alterations in pre-vaccination monocyte function correlated with HepB titers, and changes in innate-related cytokines/chemokine production were associated with increasing CAA concentration. We report, that by influencing the immune landscape, schistosomiasis has the potential to modulate immune responses to HepB vaccination. These findings highlight multiple Schistosoma -related immune associations that could explain abrogated vaccine responses in communities with endemic infections. Author Summary: Schistosomiasis drives host immune responses for optimal pathogen survival, potentially altering host responses to vaccine-related antigen. Chronic schistosomiasis and co-infection with hepatotropic viruses are common in countries where schistosomiasis is endemic. We explored the impact of Schistosoma mansoni ( S. mansoni ) infection on Hepatitis B (HepB) vaccination of individuals from a fishing community in Uganda. We demonstrate that high schistosome-specific antigen (circulating anodic antigen, CAA) concentration pre-vaccination, is associated with lower HepB antibody titers post-vaccination. We show higher pre-vaccination levels of cellular and soluble factors in instances of high CAA that are negatively associated with HepB antibody titers post-vaccination, which coincided with lower frequencies of circulating T follicular helper cell populations (cTfh), proliferating antibody secreting cells (ASCs), and higher frequencies of regulatory T cells (Tregs). We also show that monocyte function is important in HepB vaccine responses, and that high CAA is associated with alterations in the early innate cytokine/chemokine microenvironment. Our findings suggest that in individuals with high CAA and likely high worm burden, schistosomiasis creates and sustains an environment that is polarized against optimal host immune responses to the vaccine, which puts many endemic communities at risk for infection against HepB and other diseases that are preventable by vaccines.
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INTRODUCTION: Family planning knowledge is poor and use is low in Ugandan fishing communities. We compared the effectiveness of enhanced family planning (FP) education with routine counselling on FP knowledge and use. METHODS: Individuals aged 15-49 years were randomly assigned to intervention or control arm. The intervention constituted enhanced FP education based on a simplified handout extracted from the WHO FP guidance tool called, "Family planning: A global handbook for FP providers" which participants took home for additional reading. The control arm constituted FP counselling following Uganda Ministry of Health guidelines. FP knowledge score and contraceptive prevalence rate (CPR) were compared between trial arms at baseline and at 12 months. Negative binomial regression models were used to estimate the effect of the intervention on FP knowledge and use. RESULTS: Overall, 1410 participants were screened to enrol 1004 (502 per study arm, 48.5% women). Subsequently, 384 (76.5%) and 383 (76.3%) completed the 12 months' follow-up in the intervention and control arms respectively. At baseline, a median FP knowledge score of 8 and a < 70% FP knowledge score was observed for all participants with a CPR of 36.8%. At month-12, the median FP knowledge score improved in both arms, higher in the intervention arm than the control arm (46 vs 30; p < 0.001). In the intervention arm, 304 (79.2%) had a score of ≥70 compared with 21 (5.5%) in the control arm (p < 0.001). In the negative binomial regression model, the change in FP knowledge score was 47% higher in the intervention arm than in the control arm (score ratio: 1.47, 95%CI: 1. 43-1.51, p < 0.001). The change in CPR was 16% higher in the intervention arm than in the control arm (Prevalence ratio: 1.16, 95%CI: 1.01-1.34, p < 0.040). INTERPRETATION: Enhanced FP education using a simplified FP education handout was more effective in increasing FP knowledge and use compared to routine FP counselling for people living in fishing communities. Innovative FP education interventions are recommended for improving FP knowledge and optimizing uptake in remote-rural settings where literacy levels are low. TRIAL REGISTRATION: The study was registered by the Pan African Clinical Trial Registry on 03 July 2021 with a Trial Registration Number PACTR202107891858045 . "Retrospectively registered".
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Servicios de Planificación Familiar , Educación Sexual , Anticonceptivos , Femenino , Humanos , Caza , Lagos , Masculino , Uganda/epidemiologíaRESUMEN
BACKGROUND: Oral pre-exposure prophylaxis has been introduced in more than 70 countries, including many in sub-Saharan Africa, but women experience considerable barriers to daily pill-taking, such as stigma, judgement, and the fear of violence. Safe and effective long-acting agents for HIV prevention are needed for women. We aimed to evaluate the safety and efficacy of injectable cabotegravir compared with daily oral tenofovir diphosphate plus emtricitabine (TDF-FTC) for HIV prevention in HIV-uninfected women. METHODS: HPTN 084 was a phase 3, randomised, double-blind, double-dummy, active-controlled, superiority trial in 20 clinical research sites in seven countries in sub-Saharan Africa. Participants were eligible for enrolment if they were assigned female sex at birth, were aged 18-45 years, reported at least two episodes of vaginal intercourse in the previous 30 days, were at risk of HIV infection based on an HIV risk score, and agreed to use a long-acting reversible contraceptive method. Participants were randomly assigned (1:1) to either active cabotegravir with TDF-FTC placebo (cabotegravir group) or active TDF-FTC with cabotegravir placebo (TDF-FTC group). Study staff and participants were masked to study group allocation, with the exception of the site pharmacist who was responsible for study product preparation. Participants were prescribed 5 weeks of daily oral product followed by intramuscular injections every 8 weeks after an initial 4-week interval load, alongside daily oral pills. Participants who discontinued injections were offered open-label daily TDF-FTC for 48 weeks. The primary endpoints of the study were incident HIV infection in the intention-to-treat population, and clinical and laboratory events that were grade 2 or higher in all women who had received at least one dose of study product. This study is registered with ClinicalTrials.gov, NCT03164564. FINDINGS: From Nov 27, 2017, to Nov 4, 2020, we enrolled 3224 participants (1614 in the cabotegravir group and 1610 in the TDF-FTC group). Median age was 25 years (IQR 22-30); 1755 (54·7%) of 3209 had two or more partners in the preceding month. 40 incident infections were observed over 3898 person-years (HIV incidence 1·0% [95% CI 0·73-1·40]); four in the cabotegravir group (HIV incidence 0·2 cases per 100 person-years [0·06-0·52]) and 36 in the TDF-FTC group (1·85 cases per 100 person-years [1·3-2·57]; hazard ratio 0·12 [0·05-0·31]; p<0·0001; risk difference -1·6% [-1·0% to -2·3%]. In a random subset of 405 TDF-FTC participants, 812 (42·1%) of 1929 plasma samples had tenofovir concentrations consistent with daily use. Injection coverage was 93% of the total number of person-years. Adverse event rates were similar across both groups, apart from injection site reactions, which were more frequent in the cabotegravir group than in the TDF-FTC group (577 [38·0%] of 1519 vs 162 [10·7%] of 1516]) but did not result in injection discontinuation. Confirmed pregnancy incidence was 1·3 per 100 person-years (0·9-1·7); no congenital birth anomalies were reported. INTERPRETATION: Although both products for HIV prevention were generally safe, well tolerated, and effective, cabotegravir was superior to TDF-FTC in preventing HIV infection in women. FUNDING: National Institute of Allergy and Infectious Diseases, ViiV Healthcare, and the Bill & Melinda Gates Foundation. Additional support was provided through the National Institute of Mental Health, the National Institute on Drug Abuse, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. ViiV Healthcare and Gilead Sciences provided pharmaceutical support.
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Fármacos Anti-VIH , Infecciones por VIH , Seropositividad para VIH , VIH-1 , Adulto , Niño , Dicetopiperazinas , Emtricitabina/uso terapéutico , Femenino , Infecciones por VIH/inducido químicamente , Infecciones por VIH/epidemiología , Infecciones por VIH/prevención & control , Seropositividad para VIH/tratamiento farmacológico , Humanos , Recién Nacido , Embarazo , Piridonas/uso terapéuticoRESUMEN
BACKGROUND: HIV Prevention Trials Network 084 demonstrated that long-acting injectable cabotegravir (CAB) was superior to daily oral tenofovir (TFV) disoproxil fumarate (TDF)/emtricitabine (FTC) for preventing human immunodeficiency virus (HIV) infection in sub-Saharan African women. This report describes HIV infections that occurred in the trial before unblinding. METHODS: Testing was performed using HIV diagnostic assays, viral load testing, a single-copy RNA assay, and HIV genotyping. Plasma CAB, plasma TFV, and intraerythrocytic TFV-diphosphate concentrations were determined by liquid chromatography-tandem mass spectrometry. RESULTS: Forty HIV infections were identified (CAB arm, 1 baseline infection, 3 incident infections; TDF/FTC arm, 36 incident infections). The incident infections in the CAB arm included 2 with no recent drug exposure and no CAB injections and 1 with delayed injections; in 35 of 36 cases in the TDF/FTC arm, drug concentrations indicated low or no adherence. None of the cases had CAB resistance. Nine women in the TDF/FTC arm had nonnucleoside reverse-transcriptase inhibitor resistance; 1 had the nucleoside reverse-transcriptase inhibitor resistance mutation, M184V. CONCLUSIONS: Almost all incident HIV infections occurred in the setting of unquantifiable or low drug concentrations. CAB resistance was not detected. Transmitted nonnucleoside reverse-transcriptase inhibitor resistance was common; 1 woman may have acquired nucleoside reverse-transcriptase inhibitor resistance from study drug exposure.
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Fármacos Anti-VIH , Infecciones por VIH , Profilaxis Pre-Exposición , Fármacos Anti-VIH/uso terapéutico , ARN Polimerasas Dirigidas por ADN , Dicetopiperazinas , Emtricitabina/uso terapéutico , Femenino , VIH , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/prevención & control , Humanos , Nucleósidos/uso terapéutico , Piridonas , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Tenofovir/uso terapéuticoRESUMEN
INTRODUCTION: Hepatitis B is a serious potentially fatal hepatocellular disease caused by the hepatitis B virus. In the fishing communities of Lake Victoria Uganda, the hepatitis B virus infection burden is largely unknown. This study assessed the prevalence and incidence of hepatitis B in these communities. METHODS: This was a retrospective cohort study that tested serum samples collected from 13 to 49-year-old study participants that were residing in two Ugandan Lake Victoria fishing communities of Kasenyi (a mainland) and Jaana (an island). The samples were collected between 2013 and 2015 during the conduct of an HIV epidemiological cohort study in these communities. A total of 467 twelve-month follow-up and 50 baseline visit samples of participants lost to follow-up were tested for hepatitis B serological markers to determine prevalence. To determine hepatitis B virus incidence, samples that were hepatitis B positive at the follow-up visit had their baseline samples tested to identify hepatitis B negative samples whose corresponding follow-up samples were thus incident cases. RESULTS: The baseline mean age of the 517 study participants was 31.1 (SD ± 8.4) years, 278 (53.8%) of whom were females. A total of 36 (7%) study participants had hepatitis B virus infection, 22 (61.1%) of whom were male. Jaana had a higher hepatitis B virus prevalence compared to Kasenyi (10.2% vs 4.0%). In total, 210 (40.6%) study participants had evidence of prior hepatitis B virus infection while 48.6% had never been infected or vaccinated against this disease. A total of 20 (3.9%) participants had results suggestive of prior hepatitis B vaccination. Hepatitis B incidence was 10.5 cases/100PY (95% CI: 7.09-15.53). Being above 25 years of age and staying in Jaana were significant risk factors for hepatitis B virus acquisition (AOR 1.6, 95% CI: 1.1-2.2; p < 0.01 and 1.4, 95% CI: 1.1-1.8; p < 0.01 respectively). CONCLUSION: Hepatitis B virus incidence in Lake Victoria fishing communities of Uganda is very high, particularly in the islands. Interventions to lower hepatitis B virus transmission in these communities are urgently needed.
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Infecciones por VIH , Hepatitis B , Adolescente , Adulto , Estudios de Cohortes , Femenino , Hepatitis B/epidemiología , Humanos , Incidencia , Islas , Lagos , Masculino , Persona de Mediana Edad , Prevalencia , Estudios Retrospectivos , Uganda/epidemiología , Adulto JovenRESUMEN
INTRODUCTION: In Uganda, people living in fishing communities tend to engage in high-risk sexual activity which leads to unintended pregnancies that may end in abortions. Abortion has negative social, psychological, and medical impacts. We determined the frequency of abortion and its correlates among female fisher-folk along Lake Victoria in Uganda. METHODS: A cross-sectional survey was conducted among women aged 15- 49 years from Kigungu and Nsazi fishing communities. Data were collected on socio-demographic characteristics, abortion, and family planning use. Associations between abortion and participant characteristics were assessed using logistic regression models. RESULTS: Of the 713 women interviewed, 36, 5% were pregnant and 247, 34.6 % were using contraception. Majority (600, 84.2%) of those interviewed reported ever being pregnant. Approximately 45% of the pregnancies were un-intended while a third of those who had ever been pregnant (195, 32.5%) reported having aborted before. Slightly over a third (247, 34.6%) reported currently using or ever using family planning. Women aged 30+ years were more likely to abort compared to those aged 15-29 years (aOR: 2.7; 95% CI: 1.23-5.91). Women who had living children were less likely to abort compared to those who didn't have any living child (aOR: 0.06; 95% CI: 0.01 - 0.17). CONCLUSION: The rate of abortion among female fisher-folk in Uganda is substantial. Family planning use is still low and unintended pregnancies are common. Abortion risk increased with the age of the mother. Continuous behavioral change communication and optimization of family planning use are recommended to reduce abortions.
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BACKGROUND: Knowledge of family planning (FP) is a key determinant of contraceptive use which ultimately plays a role in attainment of good health and in conduct of clinical research. People living in fishing communities (FCs) have limited access to health services including FP and are targeted for future clinical research but their knowledge of FP and its correlates are scantily known. We determined correlates of knowledge of FP among people living in FCs of L. victoria in Uganda to inform future FP education programs in FCs. METHODS: We conducted a comparative cross-sectional survey among participants aged 15-49 years from Kigungu and Nsazi. Participants were asked if they were aware of any FP method. All those who responded in the affirmative were further asked to mention what FP methods they had heard of or knew. Those who reported knowledge of at least one FP method were asked a series of questions about FP methods and their side effects. Knowledge was categorized into good or poor knowledge based on their mean total score. Poor knowledge constituted a score below the mean while good knowledge constituted a score of more than or equal to the mean total score. To further explore attitudes and perceptions of FP, ten in-depth interviews and four focus group discussions were conducted. RESULTS: Of the 1410 screened participants, 94.5% were aware of at least one FP method. Pills and injectable hormonal methods were the most commonly known methods. Slightly over a third (38%) had good knowledge of FP. Correlates of knowledge of FP were; being female (aOR: 1.92 95% CI: 1.39-2.67), residing in Kigungu (aOR: 4.01 95% CI: 2.77-5.81), being married (aOR: 1.59 95% CI: 1.11-2.28) and currently being in a sexual relationship (aOR: 1.75 95% CI: 1.18-2.60). Concerns about safety and effectiveness of some modern FP methods exist. Misconceptions on effects of FP like sterility, cancers and foetal abnormalities were common. CONCLUSION: FP awareness among people living in FCs of L. Victoria in Uganda is high. However, good knowledge about specific methods tends to be low. Correlates of knowledge of FP include gender, residence, marital status and sexual engagement.
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Servicios de Planificación Familiar , Lagos , Adolescente , Adulto , Conducta Anticonceptiva , Estudios Transversales , Femenino , Conocimientos, Actitudes y Práctica en Salud , Humanos , Persona de Mediana Edad , Uganda , Adulto JovenRESUMEN
Introduction: Family planning (FP) is a key element in the conduct of research and is essential in managing family sizes. Although fishing communities (FCs) are targeted populations for HIV prevention research, their FP practices are poorly understood. We explored barriers and facilitators of FP use in FCs of Lake Victoria in Uganda. Methods: We employed a mixed-methods approach comprising a cross-sectional survey, in-depth interviews, and focus group discussions in 2 FCs. Multivariable logistic regression was used to analyze quantitative data and a thematic approach to generate themes from the qualitative data. Results: Up to 1410 individuals participated in the survey and 47 in the qualitative study. Just over a third (35.6%) used FP. The most commonly used methods were condoms, pills, and injectables. In Kigungu community, participants whose religion was Anglican and Muslim were more likely to use FP than Catholics (adjusted odds ratio [aOR] 1.45; 95% CI 1.05-1.99 and aOR 1.45; 95% CI 1.05-2.07, respectively). Participants were more likely to use FP if they had satisfactory FP knowledge compared to those with no satisfactory FP knowledge (aOR 1.79; 95% CI 1.23-2.61), or if they were married compared to their single counterparts (aOR 1.84; 95% CI 1.32-2.57). In both communities, participants were more likely to use FP if they had 2 or more sexual partners in the past 12 months than those with less than 2 sexual partners (aOR 1.41 95% CI 1.07-1.87 and aOR 2.60; 95% CI 1.36-4.97). Excessive bleeding and delayed fecundity; fertility desire; gender preferences of children; method stock outs and lack of FP trained personnel constituted barriers to FP use. There were also cultural influences in favor of large families. Conclusion: FP use in FCs is suboptimal. Barriers of FP use were mainly biomedical, religious, social, and cultural, which underscores a need for FP education and strengthening of FP service provision in FCs.
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Servicios de Planificación Familiar , Infecciones por VIH , Niño , Estudios Transversales , Humanos , Lagos , Parejas Sexuales , UgandaRESUMEN
INTRODUCTION: Intramuscular electroporation (IM/EP) is a vaccine delivery technique that improves the immunogenicity of DNA vaccines. We evaluated the acceptability and tolerability of electroporation among healthy African study participants. METHODS: Forty-five participants were administered a DNA vaccine (HIV-MAG) or placebo by electroporation at three visits occurring at four week-intervals. At the end of each visit, participants were asked to rate pain at four times: (1) when the device was placed on the skin and vaccine injected, before the electrical stimulation, (2) at the time of electrical stimulation and muscle contraction, and (3) at 10 minutes and (4) 30 minutes after the procedure was completed. For analyses, pain level was dichotomized as either "acceptable" (none/slight/uncomfortable) or "too much" (Intense, severe, and very severe) and examined over time using repeated measures models. Optional brief comments made by participants were summarized anecdotally. RESULTS: All 45 participants completed all three vaccination visits; none withdrew from the study due to the electroporation procedure. Most (76%) reported pain levels as acceptable at every time point across all vaccination visits. The majority of "unacceptable" pain was reported at the time of electrical stimulation. The majority of the participants (97%) commented that they preferred electroporation to standard injection. CONCLUSION: Repeated intramuscular electroporation for vaccine delivery was found to be acceptable and feasible among healthy African HIV vaccine trial participants. The majority of participants reported an acceptable pain level at all vaccination time points. Further investigation may be warranted into the value of EP to improve immunization outcomes. ClinicalTrials.gov NCT01496989.
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Vacunas contra el SIDA/administración & dosificación , Electroporación , Contracción Muscular , Músculo Esquelético , Vacunación , Vacunas de ADN/administración & dosificación , Adolescente , Adulto , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
INTRODUCTION: fishing communities in Uganda are key populations for HIV, with persistently higher prevalence and incidence than the general population. METHODS: between March and August 2014, a cross sectional survey was conducted in 10 fishing communities of Lake Victoria in Uganda. Data was collected on socio-behavioural characteristics using interviewer administered questionnaires and venous blood collected for HIV testing. Prevalent HIV infections among adolescents and young people aged 13 to 24 years was estimated and the factors associated with those infections determined using multi variable logistic regression modelling. RESULTS: HIV prevalence was 10.8% among the 630 (96.5%) who provided a blood sample. Females were 3.5 times as likely to have HIV infection as males (aOR=3.52, 95% CI: 1.34-9.22). Young people aged 20-24 years were twice as likely to be HIV infected as those aged 13-19 years (aOR=1.77, 95% CI: 0.05-2.10), participants without formal education or those who had studied up to primary level were more likely to be HIV infected than those who had post primary education ((aOR=2.45, 95% CI: 1.19-5.07) or (5.29 (1.35-20.71) respectively). Reporting more than one sexual partner in the past 6 months was associated with HIV prevalent infection than those reporting no sexual partners (aOR=6.44, 95% CI: 1.27-32.83). CONCLUSION: adolescents and young people aged 13-24 years in fishing communities around Lake Victoria, Uganda, have a high HIV prevalence, with females having a three-fold higher level than males. These findings highlight-the need to improve HIV prevention among young females living in these fishing communities.
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Infecciones por VIH/epidemiología , Conducta Sexual/estadística & datos numéricos , Parejas Sexuales , Adolescente , Estudios Transversales , Escolaridad , Femenino , Humanos , Masculino , Prevalencia , Distribución por Sexo , Encuestas y Cuestionarios , Uganda/epidemiología , Adulto JovenRESUMEN
BACKGROUND: The foreskin is the main site of HIV acquisition in a heterosexual uncircumcised man, but many men in endemic countries are reluctant to undergo penile circumcision (PC). Observational studies suggest that proinflammatory anaerobic bacteria are enriched on the uncircumcised penis, where they may enhance HIV susceptibility through increased foreskin inflammatory cytokines and the recruitment of HIV-susceptible CD4+ target cells. This trial will examine the impact of systemic and topical antimicrobials on ex vivo foreskin HIV susceptibility. METHODS/DESIGN: This randomized, open-label clinical trial will randomize 125 HIV-negative Ugandan men requesting voluntary PC to one of five arms (n = 25 each). The control group will receive immediate PC, while the four intervention groups will defer PC for 1 month and be provided in the interim with either oral tinidazole, penile topical metronidazole, topical clindamycin, or topical hydrogen peroxide. The impact of these interventions on HIV entry into foreskin-derived CD4+ T cells will be quantified ex vivo at the time of PC using a clade A, R5 tropic HIV pseudovirus assay (primary endpoint); secondary endpoints include the impact of antimicrobials on immune parameters and the microbiota of the participant's penis and of the vagina of their female partner (if applicable), assessed by multiplex enzyme-linked immunosorbent assay and 16S rRNA sequencing. DISCUSSION: There is a critical need to develop acceptable, simple, and effective means of HIV prevention in men unwilling to undergo PC. This trial will provide insight into the causative role of the foreskin microbiota on HIV susceptibility, and the impact of simple microbiota-focused clinical interventions. This may pave the way for future clinical trials using low-cost, nonsurgical intervention(s) to reduce HIV risk in uncircumcised heterosexual men. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03412071 . Retrospectively registered on 26 January 2018.
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Antiinfecciosos/administración & dosificación , Bacterias/efectos de los fármacos , Linfocitos T CD4-Positivos/efectos de los fármacos , Clindamicina/administración & dosificación , Prepucio/microbiología , Infecciones por VIH/prevención & control , Peróxido de Hidrógeno/administración & dosificación , Metronidazol/administración & dosificación , Tinidazol/administración & dosificación , Administración Cutánea , Administración Oral , Antiinfecciosos/efectos adversos , Bacterias/inmunología , Bacterias/patogenicidad , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/microbiología , Circuncisión Masculina , Clindamicina/efectos adversos , Femenino , Prepucio/virología , Infecciones por VIH/inmunología , Infecciones por VIH/transmisión , Infecciones por VIH/virología , Heterosexualidad , Interacciones Huésped-Patógeno , Humanos , Peróxido de Hidrógeno/efectos adversos , Masculino , Metronidazol/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto , Factores de Tiempo , Tinidazol/efectos adversos , Resultado del Tratamiento , UgandaRESUMEN
PROBLEM: Biological mechanisms of foreskin HIV acquisition are poorly defined. The inner foreskin is preferentially infected in explant models, so we hypothesized that this site would be enriched for HIV-susceptible CD4+ T cells and proinflammatory/chemoattractant cytokines. METHOD OF STUDY: A total of 42 HIV-uninfected Ugandan men without genital symptoms provided foreskin tissues and swabs at the time of elective penile circumcision. The immune phenotype of foreskin-derived CD4+ T cells and entry of a CCR5-tropic HIV pseudovirus was characterized, and specific cytokine levels assayed by multiplexed chemiluminescent ELISA. RESULTS: Unexpectedly, outer foreskin CD4+ T cells more frequently expressed CCR5 (median 29.2% vs 22.9%, P = 0.01) and CD69 (median 36.5% vs 15%, P < 0.01), and on a per-cell basis, HIV entry was higher. However, overall CD4+ T cell density was approximately twofold higher in the inner foreskin, and several highly susceptible T cell subsets were increased at this site, including Th17 cells (20.0% vs 14.1%, P = 0.0021). Specific pro-inflammatory cytokine levels were also higher on the inner foreskin surface (IL-17, IL-8, RANTES and IL-1ß; all P < 0.05). CONCLUSION: There was marked heterogeneity in CD4+ T cell populations and immune milieu between inner and outer foreskin tissues. Despite higher per-cell viral entry into CD4+ T cells from the outer foreskin, the higher target cell density and enriched pro-inflammatory cytokines of the inner foreskin suggest that this may be a preferential site for HIV acquisition.
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Linfocitos T CD4-Positivos/inmunología , Prepucio/inmunología , Infecciones por VIH/inmunología , Subgrupos de Linfocitos T/inmunología , Adulto , Linfocitos T CD4-Positivos/virología , Citocinas/inmunología , Susceptibilidad a Enfermedades/inmunología , Células HEK293 , Humanos , Masculino , Subgrupos de Linfocitos T/virología , Uganda , Adulto JovenRESUMEN
Schistosoma mansoni (Sm) infection has been linked with an increased risk of HIV acquisition in women. Therefore, defining the mechanism(s) by which Sm alters HIV susceptibility might lead to new HIV prevention strategies. Here, we analyze the impact of standard Sm therapy in HIV-uninfected Sm+ Ugandan adult women on genital HIV susceptibility and mucosal and systemic immunology. Schistosomiasis treatment induces a profound reduction of HIV entry into cervical and blood CD4+ T cells that is sustained for up to two months, despite transient systemic and mucosal immune activation and elevated genital IL-1α levels. Genital IFN-α2a levels are also elevated post-treatment, and IFN-α2a blocks HIV entry into primary CD4+ T cells ex vivo. Transcriptomic analysis of blood mononuclear cells post-Sm treatment shows IFN-I pathway up-regulation and partial reversal of Sm-dysregulated interferon signaling. These findings indicate that Sm therapy may reduce HIV susceptibility for women with Sm infection, potentially through de-repression of IFN-I pathways.
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Linfocitos T CD4-Positivos/parasitología , VIH/efectos de los fármacos , Esquistosomiasis mansoni/tratamiento farmacológico , Esquistosomicidas/uso terapéutico , Internalización del Virus/efectos de los fármacos , Adulto , Animales , Linfocitos T CD4-Positivos/inmunología , Células Cultivadas , Cuello del Útero/citología , Cuello del Útero/inmunología , Cuello del Útero/patología , Susceptibilidad a Enfermedades , Femenino , VIH/fisiología , Infecciones por VIH/inmunología , Infecciones por VIH/prevención & control , Infecciones por VIH/virología , Humanos , Interferón-alfa/inmunología , Interferón-alfa/metabolismo , Praziquantel/farmacología , Praziquantel/uso terapéutico , Cultivo Primario de Células , Schistosoma mansoni/inmunología , Schistosoma mansoni/aislamiento & purificación , Esquistosomiasis mansoni/sangre , Esquistosomiasis mansoni/inmunología , Esquistosomiasis mansoni/parasitología , Esquistosomicidas/farmacología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunología , Uganda , Regulación hacia Arriba , Frotis Vaginal , Adulto JovenRESUMEN
Uganda is among the most HIV/AIDS-afflicted countries, and many HIV-infected persons live in remote areas with poor access to health care. The success of HIV care programs relies in part on patient monitoring using CD4 T cell counts. We conducted an evaluation of the point-of-care PIMA test using BD FACSCount as a gold standard. One hundred fifty-one participants were enrolled, provided venous blood and samples tested at the point of care with the Alere PIMA™ CD4 Analyzer and the BD FACSCount in the UVRI-IAVI main laboratory. Correlation between the methods was assessed, as was the ability of the Pima Analyzer to predict values <200, <350, and ≥500 CD4 cells/mm3 when compared with BD FACSCount as the gold standard. A near-perfect positive Pearson correlation coefficient (r = 0.948; p < .0001) between the two methods was observed. The Alere PIMA Analyzer had a mean bias of -32.5 cells/mm3. The sensitivity and specificity, for PIMA to predict CD4 lymphocyte count less than 200 cells/mm3, were 71.4% and 100%, respectively; less than 350 cells/mm3 were 84.6% and 94.6%, respectively; and at CD4 count less than 500 cells/mm3 were 94.4% and 100%. The Alere Pima Analyzer provides reliable CD4 cell count measurement and is suitable for monitoring and screening eligible HIV patients in hard-to-reach settings.
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Recuento de Linfocito CD4/métodos , Consejo , Infecciones por VIH/diagnóstico , Tamizaje Masivo/métodos , Sistemas de Atención de Punto/normas , Adulto , Recuento de Linfocito CD4/instrumentación , Recuento de Linfocito CD4/normas , Femenino , Citometría de Flujo , Humanos , Lagos , Masculino , Tamizaje Masivo/instrumentación , Unidades Móviles de Salud , Población Rural , Sensibilidad y Especificidad , UgandaRESUMEN
BACKGROUND: Schistosoma mansoni infection has been associated with increased risk of HIV transmission in African women. This association might be causal or mediated through shared socio-behavioural factors and associated co-infections. We tested the latter hypothesis in a cross-sectional pilot study in a cohort of women from a S. mansoni endemic region of Uganda. To validate the immunological effects of S. mansoni in this cohort, we additionally assessed known schistosomiasis biomarkers. METHODS: HIV-uninfected non-pregnant adult women using public health services were tested for schistosomiasis using the urine circulating cathodic antigen test, followed by serology and Schistosoma spp.-specific PCR. Blood was obtained for herpes simplex virus (HSV)-2 serology, eosinophil counts and cytokine analysis. Samples collected from the genitourinary tract were used to test for classical sexually transmitted infections (STI), for bacterial vaginosis and to assess recent sexual activity via prostate-specific antigen testing. Questionnaires were used to capture a range of socio-economic and behavioral characteristics. RESULTS: Among 58 participants, 33 (57%) had schistosomiasis, which was associated with elevated levels of interleukin (IL)-10 (0.32 vs. 0.19 pg/ml; p = 0.038) and a trend toward increased tumour necrosis factor (TNF) (1.73 vs. 1.42 pg/ml; p = 0.081). Eosinophil counts correlated with levels of both cytokines (r = 0.53, p = 0.001 and r = 0.38, p = 0.019, for IL-10 and TNF, respectively); the association of eosinophilia with schistosomiasis was not significant (OR = 2.538, p = 0.282). Further, schistosomiasis was associated with lower age (per-year OR = 0.910, p = 0.047), being unmarried (OR = 0.263, p = 0.030), less frequent hormonal contraceptive (HC) use (OR = 0.121, p = 0.002, dominated by long acting injectable contraceptives) and a trend to longer time since penile-vaginal sex (OR = 0.350, p = 0.064). All women infected by Chlamydia trachomatis (n = 5), were also positive for schistosomiasis (Fisher's exact p = 0.064). CONCLUSIONS: Intestinal schistosomiasis in adult women was associated with systemic immune alterations, suggesting that associations with immunological correlates of HIV susceptibility warrant further investigation. S. mansoni associations with socio-behavioral parameters and C. trachomatis, which may alter both genital immunity and HIV exposure and/or acquisition risk, means that future studies should carefully control for potential confounders. These findings have implications for the design and interpretation of clinical studies on the effects of schistosomiasis on HIV acquisition.
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Infecciones por VIH/epidemiología , Asunción de Riesgos , Esquistosomiasis mansoni/epidemiología , Adolescente , Adulto , Animales , Estudios de Cohortes , Estudios Transversales , Femenino , VIH/aislamiento & purificación , Infecciones por VIH/complicaciones , Infecciones por VIH/parasitología , Humanos , Persona de Mediana Edad , Proyectos Piloto , Factores de Riesgo , Schistosoma mansoni/inmunología , Schistosoma mansoni/aislamiento & purificación , Esquistosomiasis mansoni/complicaciones , Enfermedades de Transmisión Sexual/complicaciones , Enfermedades de Transmisión Sexual/epidemiología , Enfermedades de Transmisión Sexual/parasitología , Factores Socioeconómicos , Uganda/epidemiología , Adulto JovenRESUMEN
BACKGROUND: High retention (follow-up) rates improve the validity and statistical power of outcomes in longitudinal studies and the effectiveness of programs with prolonged administration of interventions. We assessed participant retention in a potential HIV vaccine trials population of fishing communities along Lake Victoria, Uganda. METHODS: In a community-based individual randomized trial, 662 participants aged 15-49 years were randomized to either mobile phone or physical contact tracing reminders and followed up at months 1, 2, 3, 6, 12 and 18 post-enrolment. The visit schedules aimed at mimicking a vaccine efficacy trial representing an early interval (months 1-6) where most vaccinations would be administered and a later period of post-vaccination follow-up. The primary outcome was retention measured as the proportion of post-baseline follow up visits completed by a participant. Retention was estimated in early and later follow-up intervals, and overall for all the six follow-up visits. Adjusted differences in retention between the study arms were determined by multivariable logistic regression using Stata® 14. One participant was later dropped from the analysis because of age ineligibility discovered after enrolment. RESULTS: Of the expected total follow up visits of 3966 among 661 participants, 84.1% (3334) were attained; 82.1% (1626/1980) in the phone arm and 86% (1708/1986) in the physical tracing arm (p = 0.001). No statistically significant differences in retention were observed between the study arms in the first 6 months but thereafter, retention was significantly higher for physical contact reminders than mobile phones; 91.5% versus 82.1% (p < 0.0001) at month 12 and 82.8% versus 75.4%, (p = 0.021) at month 18. Controlling for sex, age, education, occupation, community location, length of stay and marital status, the odds of good retention (completing 5 out of 6 follow-up visits) were 1.56 (95% CI;1.08-2.26, p = 0.018) for physical contact tracing compared to mobile phone tracing. Other statistically significant predictors of good retention were residing on islands and having stayed in the fishing communities for 5 or more years. CONCLUSIONS: Among fishing communities of Lake Victoria, Uganda, 84% of follow-up visits can be attained and participant retention is higher using physical contact reminders than mobile phones. TRIAL REGISTRATION NUMBER: PACTR201311000696101 ( http://www.pactr.org/ ). retrospectively registered on 05 November, 2013.
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Vacunas contra el SIDA/uso terapéutico , Teléfono Celular , Trazado de Contacto/métodos , Programas de Inmunización , Participación del Paciente , Sistemas Recordatorios , Adolescente , Adulto , Atención Ambulatoria/estadística & datos numéricos , Trazado de Contacto/estadística & datos numéricos , Femenino , Humanos , Programas de Inmunización/métodos , Programas de Inmunización/organización & administración , Lagos , Perdida de Seguimiento , Masculino , Persona de Mediana Edad , Ocupaciones , Participación del Paciente/métodos , Participación del Paciente/estadística & datos numéricos , Examen Físico/métodos , Examen Físico/estadística & datos numéricos , Vigilancia de la Población/métodos , Sistemas Recordatorios/normas , Estudios Retrospectivos , Telemedicina/métodos , Telemedicina/organización & administración , Uganda/epidemiología , Vacunación/estadística & datos numéricos , Adulto JovenRESUMEN
BACKGROUND: More than 1·8 million new cases of HIV-1 infection were diagnosed worldwide in 2016. No licensed prophylactic HIV-1 vaccine exists. A major limitation to date has been the lack of direct comparability between clinical trials and preclinical studies. We aimed to evaluate mosaic adenovirus serotype 26 (Ad26)-based HIV-1 vaccine candidates in parallel studies in humans and rhesus monkeys to define the optimal vaccine regimen to advance into clinical efficacy trials. METHODS: We conducted a multicentre, randomised, double-blind, placebo-controlled phase 1/2a trial (APPROACH). Participants were recruited from 12 clinics in east Africa, South Africa, Thailand, and the USA. We included healthy, HIV-1-uninfected participants (aged 18-50 years) who were considered at low risk for HIV-1 infection. We randomly assigned participants to one of eight study groups, stratified by region. Participants and investigators were blinded to the treatment allocation throughout the study. We primed participants at weeks 0 and 12 with Ad26.Mos.HIV (5â×â1010 viral particles per 0·5 mL) expressing mosaic HIV-1 envelope (Env)/Gag/Pol antigens and gave boosters at weeks 24 and 48 with Ad26.Mos.HIV or modified vaccinia Ankara (MVA; 108 plaque-forming units per 0·5 mL) vectors with or without high-dose (250 µg) or low-dose (50 µg) aluminium adjuvanted clade C Env gp140 protein. Those in the control group received 0·9% saline. All study interventions were administered intramuscularly. Primary endpoints were safety and tolerability of the vaccine regimens and Env-specific binding antibody responses at week 28. Safety and immunogenicity were also assessed at week 52. All participants who received at least one vaccine dose or placebo were included in the safety analysis; immunogenicity was analysed using the per-protocol population. We also did a parallel study in rhesus monkeys (NHP 13-19) to assess the immunogenicity and protective efficacy of these vaccine regimens against a series of six repetitive, heterologous, intrarectal challenges with a rhesus peripheral blood mononuclear cell-derived challenge stock of simian-human immunodeficiency virus (SHIV-SF162P3). The APPROACH trial is registered with ClinicalTrials.gov, number NCT02315703. FINDINGS: Between Feb 24, 2015, and Oct 16, 2015, we randomly assigned 393 participants to receive at least one dose of study vaccine or placebo in the APPROACH trial. All vaccine regimens demonstrated favourable safety and tolerability. The most commonly reported solicited local adverse event was mild-to-moderate pain at the injection site (varying from 69% to 88% between the different active groups vs 49% in the placebo group). Five (1%) of 393 participants reported at least one grade 3 adverse event considered related to the vaccines: abdominal pain and diarrhoea (in the same participant), increased aspartate aminotransferase, postural dizziness, back pain, and malaise. The mosaic Ad26/Ad26 plus high-dose gp140 boost vaccine was the most immunogenic in humans; it elicited Env-specific binding antibody responses (100%) and antibody-dependent cellular phagocytosis responses (80%) at week 52, and T-cell responses at week 50 (83%). We also randomly assigned 72 rhesus monkeys to receive one of five different vaccine regimens or placebo in the NHP 13-19 study. Ad26/Ad26 plus gp140 boost induced similar magnitude, durability, and phenotype of immune responses in rhesus monkeys as compared with humans and afforded 67% protection against acquisition of SHIV-SF162P3 infection (two-sided Fisher's exact test p=0·007). Env-specific ELISA and enzyme-linked immunospot assay responses were the principal immune correlates of protection against SHIV challenge in monkeys. INTERPRETATION: The mosaic Ad26/Ad26 plus gp140 HIV-1 vaccine induced comparable and robust immune responses in humans and rhesus monkeys, and it provided significant protection against repetitive heterologous SHIV challenges in rhesus monkeys. This vaccine concept is currently being evaluated in a phase 2b clinical efficacy study in sub-Saharan Africa (NCT03060629). FUNDING: Janssen Vaccines & Prevention BV, National Institutes of Health, Ragon Institute of MGH, MIT and Harvard, Henry M Jackson Foundation for the Advancement of Military Medicine, US Department of Defense, and International AIDS Vaccine Initiative.
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Vacunas contra el SIDA/administración & dosificación , VIH-1/inmunología , Vacunas contra el SIDA/efectos adversos , Dolor Abdominal/etiología , Adenoviridae , Adolescente , Adulto , Animales , Aspartato Aminotransferasas/análisis , Dolor de Espalda/etiología , Diarrea/etiología , Mareo/etiología , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Fatiga/etiología , Vectores Genéticos , Voluntarios Sanos , Humanos , Inmunidad Celular , Inmunidad Humoral , Macaca mulatta , Persona de Mediana Edad , Adulto JovenRESUMEN
Here, the anti-malarial activity of two gold(i) phosphine compounds auranofin and [Au(d2pype)2]Cl (where d2pype is 1,2-bis(di-2-pyridylphosphino)ethane), were examined to inform their use as potential drugs and malaria parasite-attenuating agents. In vitro, the gold compounds were active against Plasmodium falciparum and P. knowlesi as well as the rodent parasite P. chabaudi AS. Attenuation of the parasite was observed when mice were inoculated with P. chabaudi AS infected red blood cells treated in vitro with [Au(d2pype)2]Cl (1 or 2 µM) or auranofin (2 µM) for 2 or 3 h. Quantitative PCR data showed persistence of low levels of parasite DNA up to 8 days post inoculation. In some experiments, there was microscopically detectable parastiemia following inoculation which subsequently cleared. Following 1 or 3 doses of gold compound-treated parasitized red blood cells (pRBCs), protection was not observed when these mice were subsequently challenged with wild type P. chabaudi AS. In experiments where microscopically detectable parasites were observed following in vivo inoculation, mice were subsequently fully protected against a challenge infection with wildtype parasites. In an infect-and-treat rodent model, the gold compounds were unable to inhibit P. chabaudi AS growth in vivo when administered orally. Gold compounds act via the inhibition of antioxidant systems which are critical in the pathogen's survival from attack by the host oxidants. In vitro, they directly inhibit the parasite thioredoxin reductase, hence the observed suppressive activity. On the other hand, in vivo, the gold compounds may not be readily available for absorption and thus pharmacokinetic studies will be required to further examine drug bioavailability following administration. With structural differences in redox mechanisms of P. falciparum and the human host being identified, gold compounds can be better designed to more efficiently target and selectively inhibit the parasite.