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Background: Kenya included oral PrEP in the national guidelines as part of combination HIV prevention, and subsequently began providing PrEP to individuals who are at elevated risk of HIV infection in 2017. However, as scale-up continued, there was a recognized gap in knowledge on the cost of delivering oral PrEP. This gap limited the ability of the Government of Kenya to budget for its PrEP scale-up and to evaluate PrEP relative to other HIV prevention strategies. The following study calculated the actual costs of oral PrEP scale-up as it was being delivered in ten counties in Kenya. This costing also allowed for a comparison of various models of service delivery in different geographic regions from the perspective of service providers in Kenya. In addition, the analysis was also conducted to understand factors that indicate why some individuals place a greater value on PrEP than others, using a contingent valuation technique. Methods: Data collection was completed between November 2017 and September 2018. Costing data was collected from 44 Kenyan health facilities, consisting of 23 public facilities, 5 private facilities and 16 drop-in centers (DICEs) through a cross-sectional survey in ten counties. Financial and programmatic data were collected from financial and asset records and through interviewer administered questionnaires. The costs associated with PrEP provision were calculated using an ingredients-based costing approach which involved identification and costing of all the economic inputs (both direct and indirect) used in PrEP service delivery. In addition, a contingent valuation study was conducted at the same 44 facilities to understand factors that reveal why some individuals place a greater value on PrEP than others. Interviews were conducted with 2,258 individuals (1,940 current PrEP clients and 318 non-PrEP clients). A contingent valuation method using a "payment card approach" was used to determine the maximum willingness to pay (WTP) of respondents regarding obtaining access to oral PrEP services. Results: The weighted cost of providing PrEP was $253 per person year, ranging from $217 at health centers to $283 at dispensaries. Drop-in centers (DICEs), which served about two-thirds of the client volume at surveyed facilities, had a unit cost of $276. The unit cost was highest for facilities targeting MSM ($355), while it was lowest for those targeting FSW ($248). The unit cost for facilities targeting AGYW was $323 per person year. The largest percentage of costs were attributable to personnel (58.5%), followed by the cost of drugs, which represented 25% of all costs. The median WTP for PrEP was $2 per month (mean was $4.07 per month). This covers only one-third of the monthly cost of the medication (approximately $6 per month) and less than 10% of the full cost of delivering PrEP ($21 per month). A sizable proportion of current clients (27%) were unwilling to pay anything for PrEP. Certain populations put a higher value on PrEP services, including: FSW and MSM, Muslims, individuals with higher education, persons between the ages of 20 and 35, and households with a higher income and expenditures. Discussion: This is the most recent and comprehensive study on the cost of PrEP delivery in Kenya. These results will be used in determining resource requirements and for resource mobilization to facilitate sustainable PrEP scale-up in Kenya and beyond. This contingent valuation study does have important implications for Kenya's PrEP program. First, it indicates that some populations are more motivated to adopt oral PrEP, as indicated by their higher WTP for the service. MSM and FSW, for example, placed a higher value on PrEP than AGYW. Higher educated individuals, in turn, put a much higher value on PrEP than those with less education (which may also reflect the higher "ability to pay" among those with more education). This suggests that any attempt to increase demand or improve PrEP continuation should consider these differences in client populations. Cost recovery from existing PrEP clients would have potentially negative consequences for uptake and continuation.
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We have previously demonstrated that androgen-dependent prostate cancer (PCa) cell lines enter a state of senescence following exposure to androgen deprivation therapies (ADT). ADT-induced senescence was found to be transient, as senescent cells develop castration resistance and re-emerge into a proliferative state even under continuous androgen deprivation in vitro. Moreover, the BCL-XL/BCL-2 inhibitor, ABT-263 (navitoclax), an established senolytic agent, promoted apoptosis of senescent PCa cells, suppressing proliferative recovery and subsequent tumor cell outgrowth. As this strategy has not previously been validated in vivo, we used a clinically relevant, syngeneic murine model of PCa, where mice were either castrated or castrated followed by the administration of ABT-263. Our results largely confirm the outcomes previously reported in vitro; specifically, castration alone results in a transient tumor growth suppression with characteristics of senescence, which is prolonged by exposure to ABT-263. Most critically, mice that underwent castration followed by ABT-263 experienced a statistically significant prolongation in survival, with an increase of 14.5 days in median survival time (56 days castration alone vs. 70.5 days castration + ABT-263). However, as is often the case in studies combining the promotion of senescence with a senolytic (the "one-two" punch approach), the suppression of tumor growth by the inclusion of the senolytic agent was transient, allowing for tumor regrowth once the drug treatment was terminated. Nevertheless, the results of this work suggest that the "one-two" punch senolytic strategy in PCa may effectively interfere with, diminish, or delay the development of the lethal castration-resistant phenotype.
Assuntos
Compostos de Anilina , Senescência Celular , Neoplasias da Próstata , Sulfonamidas , Masculino , Animais , Camundongos , Senescência Celular/efeitos dos fármacos , Senescência Celular/fisiologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Compostos de Anilina/farmacologia , Compostos de Anilina/uso terapêutico , Sulfonamidas/farmacologia , Humanos , Linhagem Celular Tumoral , Senoterapia/farmacologia , Senoterapia/uso terapêutico , Antagonistas de Androgênios/farmacologia , Antagonistas de Androgênios/uso terapêutico , Androgênios/metabolismo , Androgênios/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Camundongos Endogâmicos C57BLRESUMO
Introduction: In 2016, UNAIDS set ambitious targets to reduce global HIV infections by 75% by 2020 and 90% by 2030, based on the 2.1 million new infections reported in 2010. However, by 2022, new HIV infections had only decreased by 38%, from 2.1 million in 2010 to 1.3 million in 2022, raising concerns about reaching the 2030 goal. Female sex workers (FSWs) in sub-Saharan Africa face a disproportionately high risk of HIV acquisition, contributing 5%-20% of all new infections in several countries in the region. This analysis investigates HIV seroconversion and associated factors among FSWs, offering insights into critical interventions for preventing HIV transmission in this population and advancing the goal of ending the HIV pandemic by 2030. Methods: We conducted a retrospective cohort study involving 17,977 FSWs who initially tested HIV negative upon enrollment in the Sauti project between October 2016 and September 2018. HIV incidence rates were calculated by dividing the number of new HIV cases by observed person-time within the cohort. Cox regression analysis identified factors associated with seroconversion. Results: The study revealed an HIV incidence rate of 8.6 per 100 person-years among FSWs [95% confidence interval (CI): 8.1-9.1]. Factors independently associated with HIV seroconversion included age 35 years or older [adjusted hazard ratio (aHR): 2.53; 95% CI: 2.03-3.14], unprotected sex (aHR: 1.27; 95% CI: 1.13-1.42), STI symptoms (aHR: 1.99; 95% CI: 1.67-2.38), and alcohol consumption before sex (aHR: 1.20; 95% CI: 1.07-1.34). Conclusion: Targeted interventions are vital in curbing HIV transmission among FSWs, with a focus on expanding access to primary HIV prevention services, particularly for older FSWs who face heightened risk. Tailored sexual health education programs are imperative to encourage consistent condom use and enable informed decision-making. Accessible and timely STI screening and treatment services are crucial to mitigate HIV transmission risk. Collaborative partnerships between healthcare providers, community organizations, and government agencies are essential in implementing these interventions among FSWs.
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Simian immunodeficiency virus (SIV) vaccines based upon 68-1 Rhesus Cytomegalovirus (RhCMV) vectors show remarkable protection against pathogenic SIVmac239 challenge. Across multiple independent rhesus macaque (RM) challenge studies, nearly 60% of vaccinated RM show early, complete arrest of SIVmac239 replication after effective challenge, whereas the remainder show progressive infection similar to controls. Here, we performed viral sequencing to determine whether the failure to control viral replication in non-protected RMs is associated with the acquisition of viral escape mutations. While low level viral mutations accumulated in all animals by 28 days-post-challenge, which is after the establishment of viral control in protected animals, the dominant circulating virus in virtually all unprotected RMs was nearly identical to the challenge stock, and there was no difference in mutation patterns between this cohort and unvaccinated controls. These data definitively demonstrate that viral mutation does not explain lack of viral control in RMs not protected by RhCMV/SIV vaccination. We further demonstrate that during chronic infection RhCMV/SIV vaccinated RMs do not acquire escape mutation in epitopes targeted by RhCMV/SIV, but instead display mutation in canonical MHC-Ia epitopes similar to unvaccinated RMs. This suggests that after the initial failure of viral control, unconventional T cell responses induced by 68-1 RhCMV/SIV vaccination do not exert strong selective pressure on systemically replicating SIV.
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Macaca mulatta , Mutação , Vacinas contra a SAIDS , Síndrome de Imunodeficiência Adquirida dos Símios , Vírus da Imunodeficiência Símia , Animais , Vírus da Imunodeficiência Símia/imunologia , Vírus da Imunodeficiência Símia/genética , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Síndrome de Imunodeficiência Adquirida dos Símios/prevenção & controle , Vacinas contra a SAIDS/imunologia , Vacinas contra a SAIDS/genética , Citomegalovirus/imunologia , Citomegalovirus/genética , Replicação Viral/imunologia , Vacinação , Evasão da Resposta Imune/genéticaRESUMO
Current antiretroviral therapy (ART) regimens efficiently limit HIV replication, thereby improving life expectancy of people living with HIV, but also cause metabolic side effects. The ongoing obesity epidemic has resulted in more people with metabolic comorbidities at the time of HIV infection, yet the impact of pre-existing metabolic dysregulation on infection sequelae and response to ART is unclear. Here, to investigate the impact of preexisting obesity and insulin resistance on acute infection and subsequent long-term ART, we infected a cohort of lean and obese adult male macaques with SIV and administered ART. The responses of lean and obese macaques to SIV and ART were similar with respect to plasma and cell-associated viral loads, ART drug levels in plasma and tissues, SIV-specific immune responses, adipose tissue and islet morphology, and colon inflammation, with baseline differences between lean and obese groups largely maintained. Both groups exhibited a striking depletion of CD4+ T cells from adipose tissue that did not recover with ART. However, differential responses to SIV and ART were observed for body weight, omental adipocyte size, and the adiponectin/leptin ratio, a marker of cardiometabolic risk. Thus, obesity and insulin resistance had limited effects on multiple responses to acute SIV infection and ART, while several factors that underlie long-term metabolic comorbidities were influenced by prior obesity and insulin resistance. These studies provide the foundation for future investigations into the efficacy of adjunct therapies such as metformin and glucagon-like peptide-1 receptor agonists in the prevention of metabolic comorbidities in people living with HIV.
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An influenza vaccine approach that overcomes the problem of viral sequence diversity and provides long-lived heterosubtypic protection is urgently needed to protect against pandemic influenza viruses. Here, to determine if lung-resident effector memory T cells induced by cytomegalovirus (CMV)-vectored vaccines expressing conserved internal influenza antigens could protect against lethal influenza challenge, we immunize Mauritian cynomolgus macaques (MCM) with cynomolgus CMV (CyCMV) vaccines expressing H1N1 1918 influenza M1, NP, and PB1 antigens (CyCMV/Flu), and challenge with heterologous, aerosolized avian H5N1 influenza. All six unvaccinated MCM died by seven days post infection with acute respiratory distress, while 54.5% (6/11) CyCMV/Flu-vaccinated MCM survived. Survival correlates with the magnitude of lung-resident influenza-specific CD4 + T cells prior to challenge. These data demonstrate that CD4 + T cells targeting conserved internal influenza proteins can protect against highly pathogenic heterologous influenza challenge and support further exploration of effector memory T cell-based vaccines for universal influenza vaccine development.