RESUMO
OBJECTIVES: In the general population, the lower socioeconomic status (SES) associates with greater systemic and arterial inflammation and a greater risk of cardiovascular disease. Because arterial inflammation is heightened in individuals living with HIV, we tested the hypothesis that SES associates with arterial inflammation in this population. SETTINGS: Prospective cohort study. METHODS: Men living with HIV were recruited. Arterial inflammation and leukopoietic activity (ie, bone marrow activity) were measured using 18F-fluorodeoxyglucose positron emission tomography/computed tomography. Zip code-level SES measures were derived from the US Census Bureau. Linear regression and mediation analyses were used to assess associations between SES, arterial inflammation, leukopoietic activity, C-reactive protein (CRP), and interleukin-6. RESULTS: Thirty-nine virologically suppressed men living with HIV were studied (mean ± SD age 50.5 ± 11.1 years). The median CD4 count was 663 cells/mm3 (interquartile range: 399-922); 82% were receiving antiretroviral therapies. Local median income inversely associated with arterial inflammation [standardized ß (95% confidence interval): -0.42 (-0.76 to -0.08)] after adjusting for age, Framingham risk score, statin use, antiretroviral use, and nadir CD4 count. The high-school graduation rate independently associated with arterial inflammation [-0.45 (-0.78 to -0.12)] and CRP [-0.49 (-0.86 to -0.012)]. Mediation analysis demonstrated the impact of SES on arterial inflammation was partially mediated by heightened circulating inflammatory levels: ↓SES (as high school graduation rate) â↑CRP â↑arterial inflammation accounting for 44% of the total effect (P < 0.05). CONCLUSION: In individuals living with HIV, lower SES independently associated with higher leukopoietic activity, circulating markers of inflammation, and arterial inflammation. Furthermore, the link between SES and arterial inflammation was mediated by increased systemic inflammation.
Assuntos
Arterite/complicações , Infecções por HIV/complicações , Classe Social , Adulto , Arterite/diagnóstico por imagem , Biomarcadores , Proteína C-Reativa , Contagem de Linfócito CD4 , Humanos , Renda , Inflamação/complicações , Interleucina-6 , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Estudos Prospectivos , Fatores de Risco , Estados UnidosRESUMO
In light of the increasing global burden of new HIV infections, growing financial requirements, and shifting funding landscape, the global health community must accelerate the development and delivery of an HIV cure to complement existing prevention modalities. An effective curative intervention could prevent new infections, overcome the limitations of antiretroviral treatment, combat stigma and discrimination, and provide a sustainable financial solution for pandemic control. We propose steps to plan for an HIV cure now, including defining a target product profile and establishing the HIV Cure Africa Acceleration Partnership (HCAAP), a multidisciplinary public-private partnership that will catalyse and promote HIV cure research through diverse stakeholder engagement. HCAAP will convene stakeholders, including people living with HIV, at an early stage to accelerate the design, social acceptability, and rapid adoption of HIV-cure products.
Assuntos
Infecções por HIV/epidemiologia , HIV , Gerenciamento Clínico , Desenvolvimento de Medicamentos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/prevenção & controle , Infecções por HIV/virologia , Pesquisas sobre Atenção à Saúde , Recursos em Saúde , Humanos , Parcerias Público-Privadas , Qualidade de Vida , Estigma Social , Fatores SocioeconômicosRESUMO
Despite considerable global investment, only 60% of people who live with HIV currently receive antiretroviral therapy. The sustainability of current programmes remains unknown and key incidence rates are declining only modestly. Given the complexities and expenses associated with lifelong medication, developing an effective curative intervention is now a global priority. Here we review why and where a cure is needed, and how it might be achieved. We argue for expanding these efforts from resource-rich regions to sub-Saharan Africa and elsewhere: for any intervention to have an effect, region-specific biological, therapeutic and implementation issues must be addressed.
Assuntos
Terapia Combinada , Infecções por HIV/terapia , Recursos em Saúde , Necessidades e Demandas de Serviços de Saúde , Avaliação das Necessidades , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/uso terapêutico , Saúde Global , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Infecções por HIV/imunologia , HIV-1/efeitos dos fármacos , HIV-1/genética , HIV-1/imunologia , Humanos , Receptores CCR5/deficiência , Receptores CCR5/genética , Linfócitos T Citotóxicos/imunologiaRESUMO
Quantitative viral outgrowth assays (QVOA) use limiting dilutions of CD4+ T cells to measure the size of the latent HIV-1 reservoir, a major obstacle to curing HIV-1. Efforts to reduce the reservoir require assays that can reliably quantify its size in blood and tissues. Although QVOA is regarded as a "gold standard" for reservoir measurement, little is known about its accuracy and precision or about how cell storage conditions or laboratory-specific practices affect results. Owing to this lack of knowledge, confidence intervals around reservoir size estimates-as well as judgments of the ability of therapeutic interventions to alter the size of the replication-competent but transcriptionally inactive latent reservoir-rely on theoretical statistical assumptions about dilution assays. To address this gap, we have carried out a Bayesian statistical analysis of QVOA reliability on 75 split samples of peripheral blood mononuclear cells (PBMC) from 5 antiretroviral therapy (ART)-suppressed participants, measured using four different QVOAs at separate labs, estimating assay precision and the effect of frozen cell storage on estimated reservoir size. We found that typical assay results are expected to differ from the true value by a factor of 1.6 to 1.9 up or down. Systematic assay differences comprised a 24-fold range between the assays with highest and lowest scales, likely reflecting differences in viral outgrowth readout and input cell stimulation protocols. We also found that controlled-rate freezing and storage of samples did not cause substantial differences in QVOA compared to use of fresh cells (95% probability of < 2-fold change), supporting continued use of frozen storage to allow transport and batched analysis of samples. Finally, we simulated an early-phase clinical trial to demonstrate that batched analysis of pre- and post-therapy samples may increase power to detect a three-fold reservoir reduction by 15 to 24 percentage points.
Assuntos
Infecções por HIV/virologia , HIV-1 , Carga Viral/métodos , Latência Viral , Fármacos Anti-HIV/uso terapêutico , Teorema de Bayes , Linfócitos T CD4-Positivos/virologia , Biologia Computacional , Simulação por Computador , Infecções por HIV/tratamento farmacológico , HIV-1/fisiologia , Humanos , Leucócitos Mononucleares/virologia , Funções Verossimilhança , Cadeias de Markov , Método de Monte Carlo , Reprodutibilidade dos Testes , Carga Viral/estatística & dados numéricos , Replicação ViralRESUMO
BACKGROUND: Clinical guidelines vary with respect to the optimal monitoring frequency of HIV-positive individuals. We compared dynamic monitoring strategies based on time-varying CD4 cell counts in virologically suppressed HIV-positive individuals. METHODS: In this observational study, we used data from prospective studies of HIV-positive individuals in Europe (France, Greece, the Netherlands, Spain, Switzerland, and the UK) and North and South America (Brazil, Canada, and the USA) in The HIV-CAUSAL Collaboration and The Centers for AIDS Research Network of Integrated Clinical Systems. We compared three monitoring strategies that differ in the threshold used to measure CD4 cell count and HIV RNA viral load every 3-6 months (when below the threshold) or every 9-12 months (when above the threshold). The strategies were defined by the threshold CD4 counts of 200 cells per µL, 350 cells per µL, and 500 cells per µL. Using inverse probability weighting to adjust for baseline and time-varying confounders, we estimated hazard ratios (HRs) of death and of AIDS-defining illness or death, risk ratios of virological failure, and mean differences in CD4 cell count. FINDINGS: 47â635 individuals initiated an antiretroviral therapy regimen between Jan 1, 2000, and Jan 9, 2015, and met the eligibility criteria for inclusion in our study. During follow-up, CD4 cell count was measured on average every 4·0 months and viral load every 3·8 months. 464 individuals died (107 in threshold 200 strategy, 157 in threshold 350, and 200 in threshold 500) and 1091 had AIDS-defining illnesses or died (267 in threshold 200 strategy, 365 in threshold 350, and 459 in threshold 500). Compared with threshold 500, the mortality HR was 1·05 (95% CI 0·86-1·29) for threshold 200 and 1·02 (0·91·1·14) for threshold 350. Corresponding estimates for death or AIDS-defining illness were 1·08 (0·95-1·22) for threshold 200 and 1·03 (0·96-1·12) for threshold 350. Compared with threshold 500, the 24 month risk ratios of virological failure (viral load more than 200 copies per mL) were 2·01 (1·17-3·43) for threshold 200 and 1·24 (0·89-1·73) for threshold 350, and 24 month mean CD4 cell count differences were 0·4 (-25·5 to 26·3) cells per µL for threshold 200 and -3·5 (-16·0 to 8·9) cells per µL for threshold 350. INTERPRETATION: Decreasing monitoring to annually when CD4 count is higher than 200 cells per µL compared with higher than 500 cells per µL does not worsen the short-term clinical and immunological outcomes of virally suppressed HIV-positive individuals. However, more frequent virological monitoring might be necessary to reduce the risk of virological failure. Further follow-up studies are needed to establish the long-term safety of these strategies. FUNDING: National Institutes of Health.
Assuntos
Monitoramento de Medicamentos/métodos , Infecções por HIV/tratamento farmacológico , Adolescente , Adulto , Fármacos Anti-HIV/economia , Fármacos Anti-HIV/uso terapêutico , Contagem de Linfócito CD4 , Países Desenvolvidos , Monitoramento de Medicamentos/economia , Europa (Continente) , Feminino , Infecções por HIV/sangue , Infecções por HIV/economia , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/genética , HIV-1/isolamento & purificação , HIV-1/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Carga Viral , Adulto JovemRESUMO
BACKGROUND: It is unknown what properties would be required to make an intervention in low income countries that can eradicate or control human immunodeficiency virus (HIV) without antiretroviral therapy (ART) cost-effective. METHODS: We used a model of HIV and ART to investigate the effect of introducing an ART-free viral suppression intervention in 2022 using Zimbabwe as an example country. We assumed that the intervention (cost: $500) would be accessible for 90% of the population, be given to those receiving effective ART, have sufficient efficacy to allow ART interruption in 95%, with a rate of viral rebound of 5% per year in the first 3 months, and a 50% decline in rate with each successive year. RESULTS: An ART-free viral suppression intervention with these properties would result in >0.53 million disability-adjusted-life-years averted over 2022-2042, with a reduction in HIV program costs of $300 million (8.7% saving). An intervention of this efficacy costing anything up to $1400 is likely to be cost-effective in this setting. CONCLUSIONS: Interventions aimed at curing HIV infection have the potential to improve overall disease burden and to reduce costs. Given the effectiveness and cost of ART, such interventions would have to be inexpensive and highly effective.
Assuntos
Fármacos Anti-HIV/economia , Fármacos Anti-HIV/uso terapêutico , Análise Custo-Benefício/tendências , Infecções por HIV/tratamento farmacológico , Infecções por HIV/economia , Adolescente , Adulto , Idoso , Feminino , Previsões , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Modelos Teóricos , Pobreza , Adulto Jovem , Zimbábue/epidemiologiaRESUMO
BACKGROUND: HIV infection increases cardiovascular risk. Coronary artery calcification (CAC) and mitral annular calcification (MAC) identify patients at risk for cardiovascular disease (CVD). The purpose of this study was to examine the association between MAC, CAC and mortality in HIV-infected individuals. METHODS AND RESULTS: We studied 152 asymptomatic HIV-infected individuals with transthoracic echocardiography (TTE) and computed tomography (CT). MAC was identified on TTE using standardized criteria. Presence of CAC, CAC score and CAC percentiles were determined using the modified Agatston criteria. Mortality data was obtained from the Social Security and National Death Indices (SSDI/NDI). The median age was 49 years; 87% were male. The median duration of HIV was 16 years; 84% took antiretroviral therapy; 64% had an undetectable viral load. CVD risk factors included hypertension (35%), smoking (62%) and dyslipidemia (35%). Twenty-five percent of individuals had MAC, and 42% had CAC. Over a median follow-up of 8 years, 11 subjects died. Subjects with CAC had significantly higher mortality compared to those with MAC only or no MAC. The Harrell's C-statistic of CAC was 0.66 and increased to 0.75 when MAC was added (p = 0.05). MAC, prior CVD, age and HIV viral load were independently associated with higher age- and gender-adjusted CAC percentiles in an adjusted model (p < 0.05 for all). CONCLUSION: In HIV patients, the presence of MAC, traditional risk factors and HIV viral load were independently associated with CAC. Presence of CAC and MAC may be useful in identifying HIV-infected individuals at higher risk for death.
Assuntos
Vasos Coronários/diagnóstico por imagem , Infecções por HIV/complicações , Valva Mitral/diagnóstico por imagem , Calcificação Vascular/epidemiologia , Adulto , Feminino , Infecções por HIV/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Ultrassonografia , Calcificação Vascular/complicações , Calcificação Vascular/mortalidadeRESUMO
HIV risk behaviors, susceptibility to HIV acquisition, progression of disease after infection, and response to antiretroviral therapy all vary by age. In those living with HIV, current effective treatment has increased the median life expectancy to >70 years of age. Biologic, medical, individual, social, and societal issues change as one ages with HIV infection, but there has been only a small amount of research in this field. Therefore, the Office of AIDS Research of the National Institutes of Health commissioned a working group to develop an outline of the current state of knowledge and areas of critical need for research in HIV and Aging; the working groups' findings and recommendations are summarized in this report. Key overarching themes identified by the group included the following: multimorbidity, polypharmacy, and the need to emphasize maintenance of function; the complexity of assessing HIV versus treatment effects versus aging versus concurrent disease; the inter-related mechanisms of immune senescence, inflammation, and hypercoagulability; the utility of multivariable indices for predicting outcomes; a need to emphasize human studies to account for complexity; and a required focus on issues of community support, caregivers, and systems infrastructure. Critical resources are needed to enact this research agenda and include expanded review panel expertise in aging, functional measures, and multimorbidity, and facilitated use and continued funding to allow long-term follow-up of cohorts aging with HIV.
Assuntos
Envelhecimento , Infecções por HIV , Pesquisa sobre Serviços de Saúde , Idoso , Fármacos Anti-HIV/uso terapêutico , Biomarcadores/análise , Comorbidade , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Infecções por HIV/fisiopatologia , Necessidades e Demandas de Serviços de Saúde , Humanos , Pessoa de Meia-Idade , Avaliação das Necessidades , PolimedicaçãoRESUMO
Lamivudine therapy selects for the M184V mutation. Although this mutation reduces the replicative capacity of human immunodeficiency virus in vitro, its impact on viral fitness in vivo has not been well defined. We used quantitative allele-specific PCR to precisely calculate the fitness differences between the mutated M184V virus and one that had reverted to the wild type in a cohort of patients by selectively interrupting reverse transcriptase inhibitor therapy, and we found that the M184V variants were consistently 4 to 8% less fit than the wild type in the absence of drug. After a lag phase of variable duration, wild-type variants emerged due to continued evolution of pol and back mutation rather than through emergence of an archived wild-type variant.
Assuntos
Fármacos Anti-HIV/farmacologia , Farmacorresistência Viral Múltipla , Infecções por HIV/virologia , Transcriptase Reversa do HIV/genética , HIV-1/crescimento & desenvolvimento , Lamivudina/farmacologia , Mutação de Sentido Incorreto , Infecções por HIV/tratamento farmacológico , HIV-1/classificação , HIV-1/efeitos dos fármacos , HIV-1/genética , Humanos , Filogenia , Análise de Sequência de DNAAssuntos
Terapia Antirretroviral de Alta Atividade/efeitos adversos , Infecções por HIV/tratamento farmacológico , HIV/fisiologia , Replicação Viral/efeitos dos fármacos , Terapia Antirretroviral de Alta Atividade/economia , Contagem de Linfócito CD4 , Feminino , Humanos , Masculino , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de RiscoRESUMO
The emergence of drug-resistant human immunodeficiency virus (HIV) type 1 in the setting of antiretroviral therapy failure limits the number of drugs available for use in subsequent therapy regimens. To quantify the relative HIV-1-resistance costs associated with various antiretroviral therapy strategies, we developed 2 related measures of future drug options (FDOs) by use of rule-based genotype-interpretation systems. The FDO1 metric assesses the number of drug classes that remain useful; the FDO2 metric assesses the number of drug classes that remain useful and the number of active drugs within each class. Application of these methods is illustrated with data from a randomized study of 3 therapy regimens in nucleoside analog-experienced patients. Each therapy regimen resulted in a unique pattern of drug-resistance (and cross-resistance) mutations. The regimen with the highest virologic failure rate preserved greater future drug options. Quantification of future drug options as an outcome of antiretroviral therapy trials may complement traditional clinical, virologic, and immunologic end points, thereby providing novel insights.