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BACKGROUND: Ensovibep (MP0420) is a designed ankyrin repeat protein, a novel class of engineered proteins, under investigation as a treatment of SARS-CoV-2 infection. OBJECTIVE: To investigate if ensovibep, in addition to remdesivir and other standard care, improves clinical outcomes among patients hospitalized with COVID-19 compared with standard care alone. DESIGN: Double-blind, randomized, placebo-controlled, clinical trial. (ClinicalTrials.gov: NCT04501978). SETTING: Multinational, multicenter trial. PARTICIPANTS: Adults hospitalized with COVID-19. INTERVENTION: Intravenous ensovibep, 600 mg, or placebo. MEASUREMENTS: Ensovibep was assessed for early futility on the basis of pulmonary ordinal scores at day 5. The primary outcome was time to sustained recovery through day 90, defined as 14 consecutive days at home or place of usual residence after hospital discharge. A composite safety outcome that included death, serious adverse events, end-organ disease, and serious infections was assessed through day 90. RESULTS: An independent data and safety monitoring board recommended that enrollment be halted for early futility after 485 patients were randomly assigned and received an infusion of ensovibep (n = 247) or placebo (n = 238). The odds ratio (OR) for a more favorable pulmonary outcome in the ensovibep (vs. placebo) group at day 5 was 0.93 (95% CI, 0.67 to 1.30; P = 0.68; OR > 1 would favor ensovibep). The 90-day cumulative incidence of sustained recovery was 82% for ensovibep and 80% for placebo (subhazard ratio [sHR], 1.06 [CI, 0.88 to 1.28]; sHR > 1 would favor ensovibep). The primary composite safety outcome at day 90 occurred in 78 ensovibep participants (32%) and 70 placebo participants (29%) (HR, 1.07 [CI, 0.77 to 1.47]; HR < 1 would favor ensovibep). LIMITATION: The trial was prematurely stopped because of futility, limiting power for the primary outcome. CONCLUSION: Compared with placebo, ensovibep did not improve clinical outcomes for hospitalized participants with COVID-19 receiving standard care, including remdesivir; no safety concerns were identified. PRIMARY FUNDING SOURCE: National Institutes of Health.
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Tratamento Farmacológico da COVID-19 , Adulto , Proteínas de Repetição de Anquirina Projetadas , Método Duplo-Cego , Humanos , Proteínas Recombinantes de Fusão , SARS-CoV-2 , Resultado do TratamentoRESUMO
BACKGROUND: Emerging HIV drug resistance (HIVDR) could jeopardize the success of standardized HIV management protocols in resource-limited settings. We characterized HIVDR among antiretroviral therapy (ART)-naive and experienced participants in the African Cohort Study (AFRICOS). METHODS: From January 2013 to April 2019, adults with HIV-1 RNA >1000 copies/mL underwent ART history review and HIVDR testing upon enrollment at 12 clinics in Uganda, Kenya, Tanzania, and Nigeria. We calculated resistance scores for specific drugs and tallied major mutations to non-nucleoside reverse transcriptase inhibitors (NNRTIs), nucleoside reverse transcriptase inhibitors (NRTIs), and protease inhibitors (PIs) using Stanford HIVDB 8.8 and SmartGene IDNS software. For ART-naive participants, World Health Organization surveillance drug resistance mutations (SDRMs) were noted. RESULTS: HIVDR testing was performed on 972 participants with median age 35.7 (interquartile range [IQR] 29.7-42.7) years and median CD4 295 (IQR 148-478) cells/mm3. Among 801 ART-naive participants, the prevalence of SDRMs was 11.0%, NNRTI mutations 8.2%, NRTI mutations 4.7%, and PI mutations 0.4%. Among 171 viremic ART-experienced participants, NNRTI mutation prevalence was 83.6%, NRTI 67.8%, and PI 1.8%. There were 90 ART-experienced participants with resistance to both efavirenz and lamivudine, 33 (36.7%) of whom were still prescribed these drugs. There were 10 with resistance to both tenofovir and lamivudine, 8 (80.0%) of whom were prescribed these drugs. CONCLUSIONS: Participants on failing ART regimens had a high burden of HIVDR that potentially limited the efficacy of standardized first- and second-line regimens. Management strategies that emphasize adherence counseling while delaying ART switch may promote drug resistance and should be reconsidered.
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Fármacos Anti-HIV , Infecções por HIV , HIV-1 , Adulto , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Estudos de Coortes , Farmacorresistência Viral/genética , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , HIV-1/genética , Humanos , Mutação , Uganda , Carga ViralRESUMO
OBJECTIVES: Sexually transmitted infections (STIs) are a major cause of morbidity. Understanding drivers of transmission can inform effective prevention programs. We describe STI prevalence and identify factors associated with STIs in four African countries. METHODS: The African Cohort Study is an ongoing, prospective cohort in Kenya, Nigeria, Tanzania and Uganda. At enrollment, a physical exam was conducted and STI diagnosis made by a clinician using a syndromic management approach. Multivariable logistic regression was used to estimate adjusted odds ratios (aORs) and 95% confidence intervals (95% CIs) for factors associated with an STI diagnosis. RESULTS: As of June 2020, 3544 participants were enrolled. STI prevalence was 7.7% and did not differ by HIV status (p = 0.30). Prevalence differed by syndrome (3.5% vaginal discharge, 1.5% genital ulcer, 2.1% lower abdominal pain, 0.2% inguinal bubo). The odds of having an STI were higher at all sites compared to Kisumu West, Kenya, and among those with a primary level education or below compared to those with secondary or higher (aOR: 1.77; 95% CI: 1.32-2.38). The odds of an STI diagnosis was higher among participants 18-29 years (aOR: 2.29; 95% CI: 1.35-3.87), females (aOR: 2.64; 95% CI: 1.94-3.59), and those with depression (aOR: 1.78; 95% CI: 1.32-2.38). Among PLWH, similar factors were independently associated with an STI diagnosis. Viral suppression was protective against STIs (aOR: 2.05; 95% CI: 1.32-3.20). CONCLUSIONS: Prevalence of STIs varied by site with young people and females most at risk for STIs. Mental health is a potential target area for intervention.
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Infecções por HIV , Infecções Sexualmente Transmissíveis , Adolescente , Adulto , Estudos de Coortes , Feminino , Humanos , Quênia/epidemiologia , Nigéria , Prevalência , Estudos Prospectivos , Infecções Sexualmente Transmissíveis/diagnóstico , Infecções Sexualmente Transmissíveis/epidemiologia , Tanzânia , UgandaRESUMO
Chronic inflammation associated with monocyte activation has been linked to HIV-related cognitive outcomes in resource-rich settings. Few studies have investigated this relationship in the African context where endemic non-HIV infections may modulate effects. We characterized immune activation biomarkers in Kenyan and Ugandan participants in relation to neuropsychological testing performance (NTP) from the African Cohort Study (AFRICOS). We focused on activation markers associated with monocytes (sCD14, sCD163, neopterin), T cells (HLA-DR+CD38+ on CD4+ and CD8+ T lymphocytes), and microbial translocation (intestinal fatty acid-binding protein, I-FABP). The HIV-infected (n = 290) vs. HIV-uninfected (n = 104) groups were similar in age with mean (SD) of 41 (9.5) vs. 39 (9.9) years, respectively (p = 0.072). Among HIV-infected participants, the mean (SD) current CD4+ count was 402 (232); 217 (75%) were on combination antiretroviral therapy (cART) and 199 (69%) had suppressed plasma HIV RNA. sCD14 was inversely correlated to NTP (r = - 0.14, p = 0.037) in models that included both HIV-infected and uninfected individuals, adjusted for HIV status and research site, whereas sCD163 was not (r = 0.041, p = 0.938). Neither of the T cell activation markers correlated with NTP. In the HIV-infected group, I-FABP was inversely associated with NTP (r = - 0.147, p = 0.049), even among those with suppressed plasma virus (r = - 0.0004, p = 0.025). Among the full group, HIV status did not appear to modulate the effects observed. In this cohort from East Africa, sCD14, but not sCD163, is associated with cognitive performance regardless of HIV status. Findings among both HIV-infected and HIV-uninfected groups is supportive that HIV and non-HIV-related inflammatory sources contribute to cognitive performance in this setting.
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Cognição , Infecções por HIV/imunologia , Monócitos/imunologia , Adulto , África Oriental , Idoso , Antígenos CD/sangue , Antígenos de Diferenciação Mielomonocítica/sangue , Biomarcadores/sangue , Estudos de Coortes , Feminino , Humanos , Receptores de Lipopolissacarídeos/sangue , Masculino , Pessoa de Meia-Idade , Receptores de Superfície Celular/sangueRESUMO
INTRODUCTION: With increased use of antiretroviral therapy (ART), HIV mortality rates are declining and people living with HIV (PLWH) are surviving longer. We characterized CD4 recovery and viral suppression among adults aged < 50 and ≥ 50 years living with HIV who initiated ART in the African Cohort Study (AFRICOS). METHODS: Beginning in January 2013, PLWH at twelve clinics in Kenya, Uganda, Tanzania and Nigeria underwent medical history review, CD4 and viral load testing as part of the ongoing African Cohort Study (AFRICOS). ART-naïve PLWH who initiated ART within 30 days of enrollment and had at least one year of follow-up were included in these analyses. To compare ART response in participants < 50 years and ≥ 50 years old, changes in CD4 count and viral load suppression after ART initiation were examined at different time points using linear and binomial regression with generalized estimating equations. Variables for time since ART initiation and the interaction between age group and time on ART were included in the model to evaluate longitudinal changes in CD4 recovery and viral suppression by age. RESULTS: Between January 2013 and September 2019, 2918 PLHV were enrolled in the cohort. Of these, 443 were ART naïve and initiated on ART within 30 days of enrollment, with 90% (n = 399) aged < 50 years old at ART initiation. At ART initiation, participants aged 50 and older had a higher median CD4 count compared to participants younger than 50 years of age although it did not reach statistical significance (306 cells/mm3, IQR:130-547 vs. 277cells/mm3, IQR: 132-437). In adjusted models examining CD4 recovery and viral suppression there were no significant differences by age group over time. By the end of follow-up viral suppression was high among both groups of adults (96% of adults ≥ 50 years old and 92% of adults < 50 years old). CONCLUSION: This study found no difference in long-term CD4 recovery or viral suppression by age at ART initiation. We found that particularly among younger adults participants had lower median CD4 counts at ART initiation, suggesting the importance of identifying and putting this population on treatment earlier in the disease course.
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Fármacos Anti-HIV , Infecções por HIV , Adulto , Idoso , Fármacos Anti-HIV/uso terapêutico , Contagem de Linfócito CD4 , Estudos de Coortes , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Humanos , Quênia , Pessoa de Meia-Idade , Carga ViralRESUMO
BACKGROUND: World Health Organization (WHO) guidelines identify human immunodeficiency virus (HIV) viral load <1000 copies/mL as the goal of antiretroviral therapy (ART). However, the clinical implications of viremia below this threshold are unclear in the African context. We examined factors associated with persistent low-level viremia (pLLV) and quantified the risk of subsequent virologic. METHODS: The African Cohort Study enrolled HIV-infected adults at clinics in Uganda, Kenya, Tanzania, and Nigeria, with assessments every 6 months. We evaluated participants prescribed ART for at least 6 months without virologic failure for pLLV. We used multinomial logistic regression to evaluate associations between prespecified factors of interest and 3 levels of pLLV (<200, 200-499, and 500-999 copies/mL). We used Anderson-Gill extended Cox proportional hazards to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for viremia category associations with time to failure. RESULTS: We included 1511 participants with 4382 person-years of follow-up. PLLV <200 copies/mL was observed at 20% of visits while 2% of visits had pLLV 200-499 and 500-999 copies/mL each, with substantial variation by site. Protease inhibitor-containing ART was associated with increased risk of pLLV. Compared to undetectable viral load, pLLV ≥200 copies/mL doubled the risk of developing virologic failure (pLLV 200-499: HR, 1.81 [95% CI, 1.08-3.02]); pLLV 500-999: HR, 2.36 [95% CI, 1.52-3.67]). CONCLUSIONS: Participants with pLLV ≥200 copies/mL were at increased risk of subsequent virologic failure. Optimized HIV care in this setting should target viral suppression <200 copies/mL.
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Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Carga Viral , Viremia/tratamento farmacológico , Adulto , África/epidemiologia , Feminino , Infecções por HIV/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Modelos de Riscos Proporcionais , Estudos Prospectivos , Fatores de Risco , Falha de Tratamento , Viremia/epidemiologia , Organização Mundial da Saúde , Adulto JovemRESUMO
BACKGROUND: Noninfectious comorbid diseases (NCDs) contribute to morbidity and mortality in human immunodeficiency virus (HIV)-infected populations in resource-rich countries. With antiretroviral therapy (ART) scale-up in Africa, understanding burden NCD informs public health strategy. METHODS: At enrollment, participants at 11 HIV clinics in Kenya, Uganda, Tanzania, and Nigeria underwent medical history, physical, laboratory, and neuropsychological assessments to identify elevated blood pressure, hypercholesterolemia, dysglycemia, renal insufficiency, and cognitive impairment. Poisson regression models estimated adjusted relative risks (ARRs) and 95% confidence intervals (CIs) for the number of NCDs associated with factors of interest. Logistic regression was used to evaluate each NCD separately among HIV-infected participants. RESULTS: Among 2720 participants with complete NCD data, 2159 (79.4%) were HIV-infected. Of those, 1426 (66.0%) were taking ART and 813 (37.7%) had at least 1 NCD. HIV infection was associated with more NCDs, especially with ART (ARR, 1.42; 95% CI, 1.22-1.66). In addition to age, body mass index, and program site, ART usage was associated with more NCDs (ARR, 1.50; 95% CI, 1.27-1.78 for virologically suppressed and ARR, 1.38; 95% CI, 1.13-1.68 for viremic) among HIV-infected participants. In participants taking ART, CD4 nadir below 200 cells/mm3 was associated with more NCDs (ARR, 1.43; 95% CI, 1.06-1.93). ART use was independently associated with hypercholesterolemia and dysglycemia. Program site was significantly associated with all comorbidities except renal insufficiency. CONCLUSIONS: HIV infection was a risk for NCDs, which were common in HIV-infected participants, geographically variable, and largely consistent with metabolic complications of first-line ART.
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Infecções por HIV/epidemiologia , Doenças não Transmissíveis/epidemiologia , Adulto , África Subsaariana , Comorbidade , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: To compare national human immunodeficiency virus (HIV) policies influencing access to HIV testing and treatment services in six sub-Saharan African countries. METHODS: We reviewed HIV policies as part of a multi-country study on adult mortality in sub-Saharan Africa. A policy extraction tool was developed and used to review national HIV policy documents and guidelines published in Kenya, Malawi, South Africa, Uganda, the United Republic of Tanzania and Zimbabwe between 2003 and 2013. Key informant interviews helped to fill gaps in findings. National policies were categorized according to whether they explicitly or implicitly adhered to 54 policy indicators, identified through literature and expert reviews. We also compared the national policies with World Health Organization (WHO) guidance. FINDINGS: There was wide variation in policies between countries; each country was progressive in some areas and not in others. Malawi was particularly advanced in promoting rapid initiation of antiretroviral therapy. However, no country had a consistently enabling policy context expected to increase access to care and prevent attrition. Countries went beyond WHO guidance in certain areas and key informants reported that practice often surpassed policy. CONCLUSION: Evaluating the impact of policy differences on access to care and health outcomes among people living with HIV is challenging. Certain policies will exert more influence than others and official policies are not always implemented. Future research should assess the extent of policy implementation and link these findings with HIV outcomes.
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Antirretrovirais/administração & dosagem , Infecções por HIV/diagnóstico , Infecções por HIV/tratamento farmacológico , Políticas , África Subsaariana/epidemiologia , Países em Desenvolvimento , Epidemias , Infecções por HIV/epidemiologia , Promoção da Saúde/organização & administração , Acessibilidade aos Serviços de Saúde/organização & administração , Humanos , Organização Mundial da SaúdeRESUMO
Ebola virus disease (EVD) is a filoviral infection caused by virus species of the Ebolavirus genus including Zaire ebolavirus (EBOV) and Sudan ebolavirus (SUDV). We investigated the safety and immunogenicity of a heterologous prime-boost regimen involving a chimpanzee adenovirus 3 vectored Ebola vaccine [either monovalent (cAd3-EBOZ) or bivalent (cAd3-EBO)] prime followed by a recombinant modified vaccinia virus Ankara EBOV vaccine (MVA-EbolaZ) boost in two phase 1/1b randomized open-label clinical trials in healthy adults in the United States (US) and Uganda (UG). Trial US (NCT02408913) enrolled 140 participants, including 26 EVD vaccine-naïve and 114 cAd3-Ebola-experienced participants (April-November 2015). Trial UG (NCT02354404) enrolled 90 participants, including 60 EVD vaccine-naïve and 30 DNA Ebola vaccine-experienced participants (February-April 2015). All tested vaccines and regimens were safe and well tolerated with no serious adverse events reported related to study products. Solicited local and systemic reactogenicity was mostly mild to moderate in severity. The heterologous prime-boost regimen was immunogenic, including induction of durable antibody responses which peaked as early as two weeks and persisted up to one year after each vaccination. Different prime-boost intervals impacted the magnitude of humoral and cellular immune responses. The results from these studies demonstrate promising implications for use of these vaccines in both prophylactic and outbreak settings.
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BACKGROUND: While there are biomedical drugs for managing diabetes mellitus, some patients with diabetes use traditional medicine. The aim of the study was to explore why patients with diabetes use traditional medicine for the treatment of diabetes. METHODS: The study was conducted in Iganga and Bugiri districts in Eastern Uganda using four focus group discussions (FGDs) with patients with diabetes; two with female patients and two with male patients, thirteen key informant interviews (KIIs); nine with health workers working with patients with diabetes and four with herbalists. FGDs and KIIs focused on what respondents perceived as reasons for patients with diabetes taking traditional medicine. Analysis was done using content analysis. RESULTS: Reasons for taking traditional medicine included finding difficulties accessing hospitals, diabetic drugs being out of stock, traditional medicine being acceptable and available within community, as well as being supplied in big quantities. Others were traditional medicine being cheaper than biomedical treatment and payment for it being done in installments. Traditional medicine was also more convenient to take and was marketed aggressively by the herbalists. Influence of family and friends as well as traditional healers contributed to use of traditional medicine. CONCLUSIONS: Possibilities of putting diabetic drugs at facilities closer to patients need to be considered and health facilities should have a constant supply of diabetic drugs. Community members need to be sensitized on the proper treatment for diabetes mellitus and on the dangers of taking traditional medicine.
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Diabetes Mellitus/terapia , Medicinas Tradicionais Africanas/psicologia , Medicinas Tradicionais Africanas/estatística & dados numéricos , Adolescente , Adulto , Idoso , Comportamento de Escolha , Características da Família , Feminino , Grupos Focais , Conhecimentos, Atitudes e Prática em Saúde , Acessibilidade aos Serviços de Saúde , Humanos , Masculino , Medicinas Tradicionais Africanas/economia , Pessoa de Meia-Idade , Fatores Socioeconômicos , Uganda/epidemiologia , Adulto JovemRESUMO
BACKGROUND: Sudan Ebola virus can cause severe viral disease, with an average case fatality rate of 54%. A recent outbreak of Sudan Ebola virus in Uganda caused 55 deaths among 164 confirmed cases in the second half of 2022. Although vaccines and therapeutics specific for Zaire Ebola virus have been approved for use during outbreak situations, Sudan Ebola virus is an antigenically distinct virus with no approved vaccines available. METHODS: In this phase 1, open-label, dose-escalation trial we evaluated the safety, tolerability, and immunogenicity of a monovalent chimpanzee adenovirus 3 vaccine against Sudan Ebola virus (cAd3-EBO S) at Makerere University Walter Reed Project in Kampala, Uganda. Study participants were recruited from the Kampala metropolitan area using International Review Board-approved written and electronic media explaining the trial intervention. Healthy adults without previous receipt of Ebola, Marburg, or cAd3 vectored-vaccines were enrolled to receive cAd3-EBO S at either 1 × 1010 or 1 × 1011 particle units (PU) in a single intramuscular vaccination and were followed up for 48 weeks. Primary safety and tolerability endpoints were assessed in all vaccine recipients by reactogenicity for the first 7 days, adverse events for the first 28 days, and serious adverse events throughout the study. Secondary immunogenicity endpoints included evaluation of binding antibody and T-cell responses against the Sudan Ebola virus glycoprotein, and neutralising antibody responses against the cAd3 vector at 4 weeks after vaccination. This study is registered with ClinicalTrials.gov, NCT04041570, and is completed. FINDINGS: 40 healthy adults were enrolled between July 22 and Oct 1, 2019, with 20 receiving 1 × 1010 PU and 20 receiving 1 × 1011 PU of cAd3-EBO S. 38 (95%) participants completed all follow-up visits. The cAd3-EBO S vaccine was well tolerated with no severe adverse events. The most common reactogenicity symptoms were pain or tenderness at the injection site (34 [85%] of 40), fatigue (29 [73%] of 40), and headache (26 [65%] of 40), and were mild to moderate in severity. Positive responses for glycoprotein-specific binding antibodies were induced by 2 weeks in 31 (78%) participants, increased to 34 (85%) participants by 4 weeks, and persisted to 48 weeks in 31 (82%) participants. Most participants developed glycoprotein-specific T-cell responses (20 [59%, 95% CI 41-75] of 34; six participants were removed from the T cell analysis after failing quality control parameters) by 4 weeks after vaccination, and neutralising titres against the cAd3 vector were also increased from baseline (90% inhibitory concentration of 47, 95% CI 30-73) to 4 weeks after vaccination (196, 125-308). INTERPRETATION: The cAd3-EBO S vaccine was safe at both doses, rapidly inducing immune responses in most participants after a single injection. The rapid onset and durability of the vaccine-induced antibodies make this vaccine a strong candidate for emergency deployment in Sudan Ebola virus outbreaks. FUNDING: National Institutes of Health via interagency agreement with Walter Reed Army Institute of Research.
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Adenovirus dos Símios , Vacinas contra Ebola , Ebolavirus , Doença pelo Vírus Ebola , Animais , Humanos , Adulto , Doença pelo Vírus Ebola/prevenção & controle , Pan troglodytes , Uganda , Sudão , Ebolavirus/genética , Anticorpos Antivirais , Adenovirus dos Símios/genética , Adenoviridae/genética , Glicoproteínas , Imunogenicidade da Vacina , Método Duplo-CegoRESUMO
A significant minority of people living with HIV (PLWH) achieve viral suppression (VS) on antiretroviral therapy (ART) but do not regain healthy CD4 counts. Clinical factors affecting this immune non-response (INR) and its effect on incident serious non-AIDS events (SNAEs) have been challenging to understand due to confounders that are difficult to control in many study settings. The U.S. Military HIV Natural History Study (NHS) and African Cohort Study (AFRICOS). PLWH with sustained VS (< 400 copies/ml for at least two years) were evaluated for INR (CD4 < 350 cells/µl at the time of sustained VS). Logistic regression estimated adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for factors associated with INR. Cox proportional hazards regression produced adjusted hazard ratios (aHRs) for factors associated with incident SNAE after sustained VS. INR prevalence was 10.8% and 25.8% in NHS and AFRICOS, respectively. Higher CD4 nadir was associated with decreased odds of INR (aOR = 0.34 [95% CI 0.29, 0.40] and aOR = 0.48 [95% CI 0.40, 0.57] per 100 cells/µl in NHS and AFRICOS, respectively). After adjustment, INR was associated with a 61% increase in relative risk of SNAE [95% CI 1.12, 2.33]. Probability of "SNAE-free" survival at 15 years since sustained VS was approximately 20% lower comparing those with and without INR; nearly equal to the differences observed by 15-year age groups. CD4 monitoring before and after VS is achieved can help identify PLWH at risk for INR. INR may be a useful clinical indicator of future risk for SNAEs.
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Infecções por HIV/imunologia , Adulto , África/epidemiologia , Antirretrovirais/uso terapêutico , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Humanos , Estudos Longitudinais , Masculino , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: Washington, DC, and sub-Saharan Africa are both affected by generalized HIV epidemics. However, care for persons living with HIV (PLWH) and clinical outcomes may differ in these geographically and culturally diverse areas. We compared patient and clinical site characteristics among adult persons living with HIV (PLWH) enrolled in two longitudinal HIV cohort studies-the African Cohort Study (AFRICOS) and the DC Cohort. METHODS: The DC Cohort is a clinic-based city-wide longitudinal cohort comprised of PLWH attending 15 HIV clinics in Washington, DC. Patients' socio-demographic characteristics, clinical evaluations, and laboratory data are retrospectively collected from electronic medical records and limited manual chart abstraction. AFRICOS is a prospective observational cohort of PLWH and uninfected volunteers attending 12 select HIV care and treatment facilities in Nigeria, Kenya, Uganda and Tanzania. AFRICOS study participants are a subset of clinic patients who complete protocol-specific visits every 6 months with history and physical examination, questionnaire administration, and blood/sputum collection for ascertainment of HIV outcomes and comorbidities, and neurocognitive and functional assessments. Among participants aged ≥ 18 years, we generated descriptive statistics for demographic and clinical characteristics at enrollment and follow up and compared them using bivariable analyses. RESULTS: The study sample included 2,774 AFRICOS and 8,420 DC Cohort participants who enrolled from January 2013 (AFRICOS)/January 2011 (DC Cohort) through March 2018. AFRICOS participants were significantly more likely to be women (58.8% vs 27.1%) and younger (83.3% vs 61.1% aged < 50 years old) and significantly less likely to be MSM (only 0.1% of AFRICOS population reported MSM risk factor) than DC Cohort. Similar rates of current viral suppression (about 75% of both samples), hypertension, hepatitis B coinfection and alcohol use were observed. However, AFRICOS participants had significantly higher rates of CD4<200 and tuberculosis and significantly lower rates of obesity, DM, hepatitis C coinfection and syphilis. CONCLUSIONS: With similar viral suppression outcomes, but many differences between our cohorts noted, the combined sample provides unique opportunities to assess and compare HIV care and treatment outcomes in the U.S. and sub-Saharan Africa. Comparing these two cohorts may inform care and treatment practices and may pave the way for future pathophysiologic analyses.
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Coinfecção , Infecções por HIV , Adulto , Estudos de Coortes , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Humanos , Quênia , Pessoa de Meia-Idade , Estudos Retrospectivos , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: Immune activation is a significant contributor to HIV pathogenesis and disease progression. In virally-suppressed individuals on ART, low-level immune activation has been linked to several non-infectious comorbid diseases. However, studies have not been systematically performed in sub-Saharan Africa and thus the impact of demographics, ART and regional endemic co-infections on immune activation is not known. We therefore comprehensively evaluated in a large multinational African cohort markers for immune activation and its distribution in various settings. METHODS: 2747 specimens from 2240 people living with HIV (PLWH) and 477 without HIV from the observational African Cohort Study (AFRICOS) were analyzed for 13 immune parameters. Samples were collected along with medical history, sociodemographic and comorbidity data at 12 HIV clinics across 5 programs in Uganda, Kenya, Tanzania and Nigeria. Data were analyzed with univariate and multivariate methods such as random forests and principal component analysis. FINDINGS: Immune activation was markedly different between PLWH with detectable viral loads, and individuals without HIV across sites. Among viremic PLWH, we found that all immune parameters were significantly correlated with viral load except for IFN-α. The overall inflammatory profile was distinct between men and women living with HIV, in individuals off ART and with HIV viremia. We observed stronger differences in the immune activation profile with increasing viremia. Using machine learning methods, we found that geographic differences contributed to unique inflammatory profiles. We also found that among PLWH, age and the presence of infectious and/or noninfectious comorbidities showed distinct inflammatory patterns, and biomarkers may be used to predict the presence of some comorbidities. INTERPRETATION: Our findings show that chronic immune activation in HIV-1 infection is influenced by HIV viral load, sex, age, region and ART use. These predictors, as well as associations among some biomarkers and coinfections, influence biomarkers associated with noncommunicable diseases. FUNDING: This work was supported by the President's Emergency Plan for AIDS Relief via a cooperative agreement between the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., and the U.S. Department of Defense [W81XWH-11-2-0174, W81XWH-18-2-0040]. The investigators have adhered to the policies for protection of human subjects as prescribed in AR 70-25. This article was prepared while Michael A. Eller was employed at Henry M. Jackson Foundation for the Advancement of Military Medicine for the U.S. Military HIV Research Program. The views expressed are those of the authors and should not be construed to represent the positions of the US Army or the Department of Defense. The opinions expressed in this article are the author's own, and do not reflect the view of the National Institutes of Health, the U.S. Department of Health and Human Services, or the U.S. government.
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Fármacos Anti-HIV , Infecções por HIV , HIV-1 , Fármacos Anti-HIV/uso terapêutico , Estudos de Coortes , Feminino , Humanos , Masculino , Viremia/tratamento farmacológicoRESUMO
The protection provided by natural versus hybrid immunity from COVID-19 is unclear. We reflect on the challenges from trying to conduct a randomized post-SARS-CoV-2 infection vaccination trial study with rapidly evolving scientific data, vaccination guidelines, varying international policies, difficulties with vaccine availability, vaccine hesitancy, and a constantly evolving virus.
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Vacinas contra COVID-19 , COVID-19 , Vacinação , COVID-19/prevenção & controle , COVID-19/terapia , Humanos , Pacientes Internados , Ensaios Clínicos Controlados Aleatórios como Assunto , Vacinação/métodosRESUMO
OBJECTIVE: HIV and hepatitis B virus (HBV) coinfection can accelerate morbidity and mortality, especially in sub-Saharan Africa where both infections are common. Although inflammation contributes to disease progression, more information is needed to better understand the pathology. This study compared markers of cirrhosis and inflammation in HIV/HBV-coinfected individuals compared with monoinfected and uninfected patients. SETTING: The HIV/HBV-coinfected subjects from the Ugandan arm of the prospective African Cohort Study were selected for evaluation and matched by age and gender with HIV-monoinfected, HBV-monoinfected, and uninfected controls. METHODS: Plasma samples were used to quantify markers of immune activation and inflammation. The FIB-4 (a simple index to predict significant liver fibrosis) score was used to estimate liver fibrosis. Demographic and laboratory characteristics were compared across the groups. RESULTS: Together, 31 HIV/HBV-coinfected participants were identified and compared with 62 HIV-monoinfected, 7 HBV-monoinfected, and 62 uninfected controls. The HIV/HBV-coinfected group had generally higher levels of inflammation. Most notably, matrix metalloproteinase-2, matrix metalloproteinase-9, and fibroblast growth factor-19 levels were dysregulated among the HIV/HBV-coinfected individuals. Furthermore, the FIB-4 score was higher in the HIV/HBV-coinfected group compared with the HIV-monoinfected group and revealed that 11% of HIV/HBV-coinfected individuals had evidence of undiagnosed advanced liver disease. CONCLUSIONS: Differences in levels of inflammation exist between individuals with HIV/HBV coinfection compared with monoinfected and uninfected controls. A distinct signature of inflammation was associated with HIV/HBV coinfection that could reflect the mechanism of liver fibrosis and increased risk for disease progression. Finally, there may be an underappreciated amount of undiagnosed advanced liver disease in sub-Saharan Africa.
Assuntos
Coinfecção/epidemiologia , Infecções por HIV/complicações , Inflamação/epidemiologia , Cirrose Hepática/epidemiologia , Estudos de Casos e Controles , Estudos de Coortes , Progressão da Doença , Infecções por HIV/epidemiologia , Vírus da Hepatite B , Humanos , Inflamação/complicações , Cirrose Hepática/complicações , Metaloproteinase 2 da Matriz/sangue , Metaloproteinase 9 da Matriz/sangue , Estudos Prospectivos , Uganda/epidemiologiaRESUMO
BACKGROUND: In Sub-Saharan Africa, herbal therapy continues to be utilized for HIV-1 disease management. However, the therapeutic benefits of these substances remain ambiguous. To date, little is known about the effects of these plant extracts on chronic CD4 + T-cell activation and exhaustion which is partly driven by HIV-1 associated microbial translocation. METHODS: Effects of Azadirachta indica, Momordica foetida and Moringa oleifera ethanol: water mixtures on cell viability were evaluated using the Guava PCA system. Then, an in-vitro cell culture model was developed to mimic CD4+ T cell exposures to antigens following HIV-1 microbial translocation. In this, peripheral blood mononuclear cells (PBMCs) isolated from HIV negative (n = 13), viral load < 1000 copies per mL (n = 10) and viral load > 1000 copies per mL (n = 6) study participants from rural Uganda were treated with Staphylococcus enterotoxin B (SEB). Then, the candidate plant extract (A. indica) was added to test the potential to inhibit corresponding CD4+ T cell activation. Following BD Facs Canto II event acquisition, variations in %CD38, %CD69, Human Leukocyte Antigen -DR (HLA-DR), Programmed cell death protein 1 (PD-1), T-cell immunoglobulin and mucin domain-containing protein 3 (Tim-3), interferon gamma (IFN γ) and interleukin 2 (IL-2) CD4 + T cell expression were evaluated. RESULTS: Following exposure to SEB, only A. indica demonstrated a concentration-dependent ability to downregulate the levels of CD4 + T cell activation. At the final concentration of 0.500 µg/mL of A. indica, a significant downregulation of CD4 + CD38 + HLA-DR+ expression was observed in HIV negative (p < 0.0001) and both HIV infected groups (P = 0.0313). This plant extract also significantly lowered SEB induced % CD4+ T cell HLADR, PD-1 and Tim-3 levels. PD-1 and CD69 markers were only significantly downmodulated in only the HIV negative ((p = 0.0001 and p = 0.0078 respectively) and viral load< 1000 copies per ml (p = 0.0078) groups. CONCLUSION: A. indica exhibited the in-vitro immunomodulatory potential to inhibit the continuum of SEB induced CD4+ T-cell activation/ exhaustion without impacting general T-cell specific functions such as cytokine secretion. Additional studies are needed to confirm A. indica as a source of natural products for targeting persistent immune activation and inflammation during ART.
Assuntos
Azadirachta , Linfócitos T CD4-Positivos/efeitos dos fármacos , Infecções por HIV/tratamento farmacológico , Ativação Linfocitária/efeitos dos fármacos , Extratos Vegetais/farmacologia , Adolescente , Adulto , Técnicas de Cultura de Células , Etanol/química , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fitoterapia , Uganda , Água/química , Adulto JovemRESUMO
Consistent condom use is an inexpensive and efficacious HIV prevention strategy. Understanding factors associated with condom use and barriers to use can inform strategies to increase condom uptake. The ongoing African Cohort Study prospectively enrolls adults at 12 clinical sites in Uganda, Kenya, Tanzania, and Nigeria. At enrollment, participants are asked about condom use at last sex with a regular partner. Robust Poisson regression models were used to evaluate predictors of self-reported condom use. Participants who reported not using condoms were asked to provide reasons. From January 2013 to September 2019, 2482 participants reported having at least one regular sexual partner in the preceding 6 months. Of those, 1577 (63.5%) reported using a condom at last sex. Condom use was more common among older participants, males, HIV-infected participants, and those with an HIV-infected partner. Married participants, those with a partner of unknown HIV status, and those reporting alcohol use were less likely to report condom use at last sex. Condom use at last sex also varied significantly by clinical site. Partner disapproval or refusal to use a condom was a consistent driver of disparities in condom use among participants who were HIV infected, female, and aged 18-24 years. Effective HIV prevention programs should integrate condom education with the tools necessary to negotiate condom use with regular partners.
Assuntos
Preservativos/estatística & dados numéricos , Infecções por HIV/prevenção & controle , Parceiros Sexuais , Adolescente , Adulto , África , Estudos de Coortes , Feminino , Humanos , Masculino , Estudos Prospectivos , Comportamento Sexual , Adulto JovemRESUMO
BACKGROUND: Medication adherence is a critical issue in achieving viral suppression targets, particularly in resource-limited countries. As HIV-related cognitive impairment (CI) impacts adherence, we examined frequency and predictors of CI in the African Cohort Study. SETTING: Cross-sectional examination of enrollment data from President's Emergency Plan for AIDS Relief supported clinic sites. METHODS: In a 30-minute cognitive assessment, CI was defined as -1SD on 2 tests or -2SD on one, as compared with 429 controls. We performed univariable and multivariable logistic and linear models examining clinical and demographic factors associated with CI and global neuropsychological performance (NP-6). RESULTS: Two thousand four hundred seventy-two HIV+ participants from Kenya (n = 1503), Tanzania (n = 469), and Uganda (n = 500). The mean (SD) age was 39.7 (10.7) years, and 1452 (59%) were women. The majority reported completing or partially completing primary school (n = 1584, 64%). Mean (SD) current and nadir CD4 count were 463 (249) and 204 (221) cells/mm, respectively; 1689 (68%) were on combination antiretroviral therapy. Nine hundred thirty-nine (38%) HIV+ versus 113 (26%) HIV- individuals showed CI: (P < 0.001). We found significant effects of literacy [odds ratio (OR): 0.3; 95% CI: 0.2 to 0.4; P < 0.001] and World Health Organization stage 4 (OR: 1.5; 95% CI: 1.0 to 2.q; P = 0.046) on CI. Tanzanians (OR: 3.2; 95% CI: 2.4 to 4.3; P < 0.001) and Kenyans (OR: 2.0; 95% CI: 1.6 to 2.6; P < 0.001) had higher risk of CI compared with Ugandans. Results were relatively unchanged in predictive models of NP-6, with the only difference being an additional significant effect of current CD4 cell count (coeff: 0.0; 95% CI: 0.0 to 0.0; P = 0.005). CONCLUSIONS: Literacy, country, World Health Organization stage, and current CD4 cell count were associated with increased risk of cognitive dysfunction. Our findings help optimize care practices in Africa, illustrating the importance of strategies for early and effective viral-immunological control.
Assuntos
Disfunção Cognitiva/complicações , Disfunção Cognitiva/epidemiologia , Infecções por HIV/complicações , Infecções por HIV/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Fármacos Anti-HIV/uso terapêutico , Contagem de Linfócito CD4 , Estudos de Coortes , Estudos Transversais , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Quênia , Modelos Lineares , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Razão de Chances , Tanzânia , Uganda , Adulto JovemRESUMO
INTRODUCTION: World Health Organization (WHO) guidelines have shifted over time to recommend earlier initiation of antiretroviral therapy (ART) and now encourage ART initiation on the day of HIV diagnosis, if possible. However, barriers to ART access may delay initiation in resource-limited settings. We characterized temporal trends and other factors influencing the interval between HIV diagnosis and ART initiation among participants enrolled in a clinic-based cohort across four African countries. METHODS: The African Cohort Study enrols adults engaged in care at 12 sites in Uganda, Kenya, Tanzania and Nigeria. Participants provide a medical history, complete a physical examination and undergo laboratory assessments every six months. Participants with recorded dates of HIV diagnosis were categorized by WHO guideline era (<2006, 2006 to 2009, 2010 to 2012, 2013 to 2015, ≥2016) at the time of diagnosis. Cox proportional hazard modelling was used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CI) for time to ART initiation. RESULTS AND DISCUSSION: From January 2013 to September 2019, a total of 2888 adults living with HIV enrolled with known diagnosis dates. Median time to ART initiation decreased from 22.0 months (interquartile range (IQR) 4.0 to 77.3) among participants diagnosed prior to 2006 to 0.5 months (IQR 0.2 to 1.8) among those diagnosed in 2016 and later. Comparing those same periods, CD4 nadir increased from a median of 166 cells/mm3 (IQR: 81 to 286) to 298 cells/mm3 (IQR: 151 to 501). In the final adjusted model, participants diagnosed in each subsequent WHO guideline era had increased rates of ART initiation compared to those diagnosed before 2006. CD4 nadir ≥500 cells/mm3 was independently associated with a lower rate of ART initiation as compared to CD4 nadir <200 cells/mm3 (HR: 0.32; 95% CI: 0.28 to 0.37). Age >50 years at diagnosis was independently associated with shorter time to ART initiation as compared to 18 to 29 years (HR: 1.38; 95% CI: 1.19 to 1.61). CONCLUSIONS: Consistent with changing guidelines, the interval between diagnosis and ART initiation has decreased over time. Still, many adults living with HIV initiated treatment with low CD4, highlighting the need to diagnose HIV earlier while improving access to immediate ART after diagnosis.