Fostensavir trometamol 600 mg para o tratamento de indivíduos adultos vivendo com HIV multirresistentes aos antirretrovirais / Fostensavir trometamol 600 mg for the treatment of individuals adults living with multidrug-resistant HIV

INTRODUÇÃO: O HIV-1 é um vírus que apresenta em seu envelope viral a glicoproteína gp120, capaz de se ligar aos receptores CD4+ dos linfócitos T do hospedeiro, inviabilizando o funcionamento normal ou levando à destruição das células do sistema imune da pessoa vivendo com esse agente infeccioso. No contexto do tratamento contra o vírus, as quasispécies de HIV-1 podem sofrer uma ou mais mutações genéticas que afetam a atividade de um ou mais ARVs que já foram efetivos anteriormente, processo que é denominado resistência. Segundo a Organização Mundial de Saúde (OMS), observa-se em diversos países que a resistência atinge mais de 10% dos indivíduos em início ou reinício do tratamento contra o HIV. PERGUNTA: Fostensavir 600 mg é eficaz, custo-efetivo e seguro no tratamento de pessoas adultas vivendo com HIV-1 multirresistente aos ARVs? EVIDÊNCIAS CLÍNICAS: A partir da pergunta de pesquisa, foi desenvolvida estratégia de busca nas bases de dados MEDLINE via PubMed e EMBASE. A busca realizada resultou em 318 publicações. Foram inicialmente excluídas 72 por serem duplicatas. Posteriormente, foram excluídas outras 220 após triagem. Após leitura dos textos completos, chegou-se ao resultado de cinco publicações elegíveis, todas fruto do ensaio clínico randomizado de fase III, BRIGHTE. Foram relatados os desfechos de média de redução de carga viral, resposta virológica, falha virológica, variação média de linfócitos T CD4+, eventos adversos, morte, qualidade de vida e adesão ao tratamento. Em geral, o nível de certeza das evidências foi classificado como baixo, com risco de viés grave. AVALIAÇÃO ECONÔMICA: Utilizando um modelo de árvore de decisão, foi realizada uma análise para estimar a razão de custo-efetividade incremental (RCEI) do fostensavir 600 mg para pessoas vivendo com HIV-Aids, adultos e com multirresistência a pelo menos quatro classes terapêuticas de antirretrovirais desde que combinado a pelo menos um ARV totalmente ativo para um ano. O modelo comparou o fostensavir à terapia de base otimizada (TBO) apresentada no estudo pivotal BRIGHTE. ANÁLISE DE IMPACTO ORÇAMENTÁRIO: Foram projetados dois cenários de incorporação para a difusão do fostensavir: conservador e moderado. No cenário de difusão conservador (market share 10% ao ano), o impacto da incorporação do fostensavir em cinco anos variou entre R$ 10.975.053,60 e R$ 65.109.874,58, de 2024 a 2028 respectivamente. O impacto orçamentário acumulado em cinco anos no cenário conservador foi R$ 185.241.468,80. No cenário de difusão moderado (market share 20% ao ano), o impacto da incorporação em cinco anos variou entre R$ 10.975.053,60 e R$ 117.197.774,25, de 2024 a 2028. O impacto orçamentário acumulado em cinco anos no cenário de difusão moderado foi R$ 310.435.446,95. Monitoramento do horizonte tecnológico: Foram identificadas duas tecnologias para o tratamento de pessoas adultas convivendo com HIV multirresistente. Lenacapavir, que está registrado nas agências EMA e FDA, e ibalizumabe, com registro na FDA. PERSPECTIVA DO PACIENTE: A chamada pública nº 30/2023 ficou aberta entre 14 e 24 de agosto de 2023. Duas pessoas se inscreveram. O representante titular contou que tem 50 anos e há 25 vive com HIV. Acredita já ter usado todas as classes de medicamentos por conta da multirresistência do HIV aos ARV, chegando a ficar sem opção terapêutica por cinco ou seis anos. Atualmente utiliza a combinação maraviroque, dolutegravir, tenofovir, lamivudina, darunavir e ritonavir, com a qual consegue obter a supressão da carga viral. Ressaltou que quem vive com HIV há muito tempo corre o risco de ficar sem opção de medicamentos e que a incorporação de novas tecnologias pode beneficiar pessoas como ele. RECOMENDAÇÃO PRELIMINAR DA CONITEC: Os membros do Comitê de Medicamentos presentes na 125ª Reunião Ordinária, realizada no dia 6 de dezembro de 2023, deliberaram, por unanimidade, encaminhar o tema para consulta pública com recomendação preliminar favorável à incorporação do fostensavir trometamol 600 mg para o tratamento de pessoas vivendo com HIV-Aids multirresistentes a terapia antirretroviral. Considerou-se a oportunidade de uma opção terapêutica aos indivíduos multirresitentes, a capacidade das Câmaras Técnicas Estaduais e da área técnica do Ministério da Saúde no monitoramento dos benefícios clínicos e dos eventos adversos do fostensavir e a expectativa de uma nova proposta de preço encaminhada pela empresa durante a consulta pública. CONSULTA PÚBLICA: A consulta pública (CP) nº 69/2023 foi realizada entre os dias 29/12/2023 e 17/01/2024. Foram recebidas 11 contribuições, sendo sete pelo formulário para contribuições técnico-científico e quatro pelo formulário pra contribuições sobre experiência ou opinião de pacientes, familiares, amigos ou cuidadores de pacientes, profissionais de saúde ou pessoas interessadas no tema. Sobre as contribuições técnicas, todas foram favoráveis às recomendações preliminares da Conitec e uma possuía referencial teórico para a abordagem técnico-científica. Entretanto, não se identificou nenhuma evidência científica adicional que pudesse modificar o entendimento preliminar da Conitec. Nas contribuições de experiência ou opinião, todos os participantes manifestaram-se favoráveis à recomendação preliminar da tecnologia avaliada. Os argumentos relevantes foram classificados em "Sobrevida do paciente", uma vez que a abordagem foi especificamente quanto às falhas terapêuticas do uso de outros antirretrovirais e a evolução para complicações e óbito. Metade dos respondedores apontaram ter experiência com o fostensavir. No que diz respeito à experiência com outras tecnologias, um dos três respondentes, o paciente, mencionou o uso de medicamentos, como tenofovir, lamivudina, efavirenz e dolutegravir e apontou como evento negativo os seus efeitos colaterais. Além disso, destacaram o valor elevado da aquisição do fostensavir como uma das principais dificuldades para acesso a este tratamento. NOVA PROPOSTA COMERCIAL: Foi submetida ao DGITS/SECTICS/MS o valor de USD 38,67 por comprimido, com uma quantidade mínima de aquisição estabelecida em 360.000 (trezentos e sessenta mil) unidades. Considerando o novo valor proposto, o custo mensal do tratamento será de R$ 11.513,40, representando aproximadamente 65,59% de desconto em relação ao preço CMED PMVG 18% e uma redução de 1,66% em relação à proposta apresentada em 2023. Ainda com base no novo valor proposto, atualizou-se a avaliação econômica e a AIO. Os critérios considerados englobam os termos da recente proposta comercial e a taxa de câmbio do dólar no dia 15 de fevereiro de 2024, fixada em 1 USD = R$ 4,9624. A RCEI foi estimada em R$ 257.370,65, apresentando uma efetividade incremental de 0,54. No cenário conservador da nova AIO, levando em consideração uma participação de mercado de 10% ao ano, o impacto orçamentário incremental em cinco anos foi R$ 100.714.577,75. Já no cenário moderado, com um aumento de 20% após o primeiro ano, o impacto orçamentário acumulado em cinco anos foi R$ 247.300.234,85. RECOMENDAÇÃO FINAL DA CONITEC: Os membros do Comitê de Medicamentos presentes na 127ª Reunião Ordinária, realizada no dia 6 de março de 2024, deliberaram, por unanimidade, recomendar a incorporação do fostensavir trometamol 600 mg para o tratamento de indivíduos adultos vivendo com HIV multirresistentes aos antirretrovirais, conforme Protocolo Clínico do Ministério da Saúde. Considerou-se as expectativas da ampliação das opções terapêuticas e da redução da carga viral aos pacientes multirresistentes. Foi assinado o Registro de Deliberação nº 881/2024. DECISÃO: incorporar, no âmbito do Sistema Único de Saúde - SUS, o fostensavir trometamol 600 mg para o tratamento de indivíduos adultos vivendo com HIV multirresistente aos antirretrovirais, conforme Protocolo Clínico do Ministério da Saúde, publicada no Diário Oficial da União nº 77, seção 1, página 177, em 22 de abril de 2024.

Analysis of the costs associated with the follow-up of HIV patients discontinuing antiretroviral treatment due to lack of effectiveness or unacceptable toxicity in Spain.

OBJECTIVE: To assess the use of resources and the costs associated with  following up patients infected with the human immunodeficiency virus after  discontinuation of an antiretroviral treatment and initiation of a new one due to  a lack of effectiveness or unacceptable toxicity, as compared to the costs  involved in the routine follow-up of patients on antiretroviral treatment, from  the Spanish National Health System perspective. Method: The use of resources (clinical tests, medical visits, and hospital pharmacy visits) associated with following three profiles of patients  infected with the human immunodeficiency virus (stable ones, those  discontinuing an existing antiretroviral treatment and being switched to a new  one due to a lack of effectiveness, and those discontinuing an existing antiretroviral treatment and being switched to a new one due to  unacceptable toxicity) was identified, based on clinical practice guidelines and  the findings of a multidisciplinary expert panel (n = 5). The experts agreed on  the main adverse events leading to discontinuation, classifying them into  gastrointestinal, renal, osseous, musculoskeletal, dermatological, hepatic, lipid  profile-related, neuropsychiatric and sexual alterations. Unit costs were  identified from official healthcare costs databases. The cost  (€, 2020) of  following up each patient profile was estimated, excluding the cost of the  antiretroviral treatment itself, with a time horizon of two years. RESULTS: The per-patient cost of following up stable patients over two years  was estimated at €4,148 (tests: €2,293; visits: €1,855). Patient follow-up after  discontinuation of an existing antiretroviral treatment and initiation of a  different one due to a lack of effectiveness was estimated at €5,434 (tests:  €2,777; visits: €2,657). The cost of follow-up after discontinuation of an  existing regimen and initiation of a new one due to unacceptable toxicity varied  according to the adverse event prompting the switch, ranging from  €4,690 for lipid profile dysregulation, to €5,304, for musculoskeletal  alterations. In this patient profile, the cost of tests ranged from €2,403 to  €3,017, and that of visits from €2,287 to €2,842. CONCLUSIONS: The cost associated with following up of patients infected with  the human immunodeficiency virus after discontinuation of an existing  antiretroviral regimen and initiation of a new one is higher than that of routine  follow-up, without taking the cost of drugs into account. The treatment  discontinuation rate is a relevant factor when selecting the most appropriate  therapy for each patient.

OBJETIVO: Estimar el uso de recursos y costes asociados al seguimiento de  pacientes con infección por el virus de la inmunodeficiencia humana tras  discontinuación del tratamiento antirretroviral actual debido a falta de  efectividad o toxicidad inaceptable y cambio a un nuevo tratamiento antirretroviral, comparado con el seguimiento habitual de los  pacientes con tratamiento antirretroviral, desde la perspectiva del Sistema  Nacional de Salud español.Método: Se identificó el uso de recursos (pruebas clínicas, visitas médicas,  visitas a la farmacia hospitalaria) asociado al seguimiento de pacientes con  infección por el virus de la inmunodeficiencia humana en tres perfiles de  pacientes (estable, discontinuación y cambio por falta de efectividad,  discontinuación y cambio por toxicidad inaceptable), a partir de las guías de  práctica clínica y un panel de expertos multidisciplinar (n = 5). Los expertos  consensuaron los principales eventos adversos que conducían a la  discontinuación, agrupándolos en: alteraciones gastrointestinales, renales,  óseas, musculoesqueléticas, dermatológicas, hepáticas y del perfil lipídico,  trastornos neuropsiquiátricos y sexuales. Los costes unitarios se identificaron a  partir de bases de datos oficiales  assode costes sanitarios y de la literatura.  Se estimó el coste (€, 2020) del seguimiento en cada perfil de paciente, sin  incluir el coste derivado del tratamiento antirretroviral, en un horizonte  temporal de dos años. RESULTADOS: El coste por paciente a dos años se estimó en 4.148 € (pruebas:  2.293 €; visitas: 1.855 €) para el seguimiento del paciente estable. El  seguimiento del paciente tras discontinuación por falta de efectividad y cambio  de tratamiento antirretroviral se estimó en 5.434 € (pruebas: 2.777 €; visitas:  2.657 €). El coste del seguimiento tras la discontinuación por toxicidad  inaceptable y cambio de tratamiento antirretroviral varió en función del evento  adverso que motivó el cambio, oscilando entre 4.690 € para las alteraciones  del perfil lipídico, y 5.304 € para las alteraciones musculoesqueléticas. En este  perfil de pacientes, las pruebas variaron entre 2.403 € y 3.017 € y las visitas  entre 2.287 € y 2.842 €. CONCLUSIONES: El coste asociado al seguimiento del paciente con infección por  el virus de la inmunodeficiencia humana tras discontinuación y cambio a un  nuevo tratamiento antirretroviral es mayor comparado con el seguimiento  habitual, sin tener en cuenta el coste farmacológico. La tasa de discontinuación  del tratamiento antirretroviral es un factor relevante a la hora  de seleccionar la terapia más adecuada para cada paciente.

Pharmacovigilance of antiretroviral dolutegravir in the state of Paraná

The aim of this study was to investigate adverse reactions to Dolutegravir, a drug recently made available by the Unified Health System (SUS) for treating HIV infections. The frequency, severity and sex distribution of adverse reactions to Dolutegravir were identified over the first 18 months of its availability in users in the state of Paraná. Information was obtained through the pharmacovigilance questionnaire prepared by the Ministry of Health, accessed through the Logistics Control System for Medicines(SICLOM). During the study period, dolutegravirwas dispensed to 9,865 patients in the state. However, 9,207 users (93.3%) answered the pharmacovigilance questionnaire. Among them, 1.75% reported 279 adverse reactions. This population was composed mainly of male people (69.57%), in the ratio of 2.29 men for each woman, white (67.08%), aged between 20 and 29 years (26.71%), single (45.34%) and with education between 8 and 11 years of study (41.61%). Gastrointestinal (36.92%) and nervous system (14.34%) disorders were the most prevalent. 77.78% adverse reactions were considered non-serious by users. It can be concluded that dolutegravirhad a low prevalence of adverse reactions in users in the state of Paraná, demonstrating to be safe for use by the population in therapy against HIV, in accordance with clinical trials.

Serious adverse drug reactions in sub-Saharan Africa in the era of antiretroviral treatment: A systematic review.

We aimed to summarize and describe the burden of serious adverse drug reactions (ADRs) in sub-Saharan Africa (SSA) in the era of antiretroviral therapy. We searched Medline, CINAHL, Africa-Wide Information, Scopus, and Web of Science, without language restriction up to March 2021. We hand-searched reference lists, conference abstracts, and dissertation databases. We included studies reporting proportions of admissions attributed to ADRs, admissions prolonged by ADRs, or in-hospital deaths attributed to ADRs. Two reviewers independently screened the studies, reviewed the study quality using a previously published tool, and extracted the data. We tested for heterogeneity using I2 -statistics and summarized the study results using medians and interquartile ranges. Subgroup analyses summarized the results by study quality, setting, methodology, and population. From 1005 unique references identified, we included 15 studies. Median study quality was 7/10; heterogeneity was very high. Median [IQR] proportion of admissions attributed to ADRs was 4.8% [1.5% to 7.0%] (14 studies) and 6.4% [4.0% to 8.4%] in nine active surveillance studies in adults. Two pediatric studies reported the proportion of admissions prolonged by ADRs (0.29% and 0.99%). Three studies reported the proportion of in-hospital deaths attributed to ADRs (2.5%, 13%, and 16%). Antiretroviral and antituberculosis drugs were often implicated in serious ADRs. Evidence of the burden of serious ADRs in SSA is patchy and heterogeneous. A few high-quality studies suggest that the burden is considerable, and that it reflects the regional impact of the HIV pandemic. Further characterization of this burden is required, ideally in studies of standardized methodology.

Economic and modeling evidence for tuberculosis preventive therapy among people living with HIV: A systematic review and meta-analysis.

BACKGROUND: Human immunodeficiency virus (HIV) is the strongest known risk factor for tuberculosis (TB) through its impairment of T-cell immunity. Tuberculosis preventive treatment (TPT) is recommended for people living with HIV (PLHIV) by the World Health Organization, as it significantly reduces the risk of developing TB disease. We conducted a systematic review and meta-analysis of modeling studies to summarize projected costs, risks, benefits, and impacts of TPT use among PLHIV on TB-related outcomes. METHODS AND FINDINGS: We searched MEDLINE, Embase, and Web of Science from inception until December 31, 2020. Two reviewers independently screened titles, abstracts, and full texts; extracted data; and assessed quality. Extracted data were summarized using descriptive analysis. We performed quantile regression and random effects meta-analysis to describe trends in cost, effectiveness, and cost-effectiveness outcomes across studies and identified key determinants of these outcomes. Our search identified 6,615 titles; 61 full texts were included in the final review. Of the 61 included studies, 31 reported both cost and effectiveness outcomes. A total of 41 were set in low- and middle-income countries (LMICs), while 12 were set in high-income countries (HICs); 2 were set in both. Most studies considered isoniazid (INH)-based regimens 6 to 2 months long (n = 45), or longer than 12 months (n = 11). Model parameters and assumptions varied widely between studies. Despite this, all studies found that providing TPT to PLHIV was predicted to be effective at averting TB disease. No TPT regimen was substantially more effective at averting TB disease than any other. The cost of providing TPT and subsequent downstream costs (e.g. post-TPT health systems costs) were estimated to be less than $1,500 (2020 USD) per person in 85% of studies that reported cost outcomes (n = 36), regardless of study setting. All cost-effectiveness analyses concluded that providing TPT to PLHIV was potentially cost-effective compared to not providing TPT. In quantitative analyses, country income classification, consideration of antiretroviral therapy (ART) use, and TPT regimen use significantly impacted cost-effectiveness. Studies evaluating TPT in HICs suggested that TPT may be more effective at preventing TB disease than studies evaluating TPT in LMICs; pooled incremental net monetary benefit, given a willingness-to-pay threshold of country-level per capita gross domestic product (GDP), was $271 in LMICs (95% confidence interval [CI] -$81 to $622, p = 0.12) and was $2,568 in HICs (-$32,115 to $37,251, p = 0.52). Similarly, TPT appeared to be more effective at averting TB disease in HICs; pooled percent reduction in active TB incidence was 20% (13% to 27%, p < 0.001) in LMICs and 37% (-34% to 100%, p = 0.13) in HICs. Key limitations of this review included the heterogeneity of input parameters and assumptions from included studies, which limited pooling of effect estimates, inconsistent reporting of model parameters, which limited sample sizes of quantitative analyses, and database bias toward English publications. CONCLUSIONS: The body of literature related to modeling TPT among PLHIV is large and heterogeneous, making comparisons across studies difficult. Despite this variability, all studies in all settings concluded that providing TPT to PLHIV is potentially effective and cost-effective for preventing TB disease.

Genetic Diversity in Drug Transporters: Impact in African Populations.

Polymorphisms in drug transporters, like the adenosine triposphate-binding cassette (ABC) and solute carrier (SLC) superfamilies, may contribute to the observed diversity in drug response in African patients. This review aims to provide a comprehensive summary and analysis of the frequencies and distributions in African populations of ABC and SLC variants that affect drug pharmacokinetics (PK) and pharmacodynamics (PD). Of polymorphisms evaluated in African populations, SLCO1B1 rs4149056 and SLC22A6 rs1158626 were found at markedly higher frequencies than in non-African populations. SLCO1B1 rs4149056 was associated with reduction in rifampin exposure, which has implications for dosing this important anti-tuberculosis therapy. SLC22A6 rs1158626 was associated with increased affinity for antiretroviral drugs. Genetic diversity in SLC and ABC transporters in African populations has implications for conventional therapies, notably in tuberculosis and HIV. More PK and PD data in African populations are needed to assess potential for a different response to drugs compared with other global populations.

Analysis of factors associated with dropping-out from HIV antiretroviral therapy in Kunming City, China.

BACKGROUND: The implementation of national antiretroviral therapy (ART) and expanded ART policies results in that more and more HIV-infected patients receive ART in Kunming, Yunnan province, China. At the same time, however, the number of patients, who drop-out from ART, are also increasing. In this study, we explored the factors that may account for drop-out. METHODS: Four hundred and thirty-nine HIV-infected patients, who received or used to receive ART, were recruited in this study. Their age is among 18 and 75. All patients were divided into two group: ART group (187 patients) and drop-out group (252 patients). Appropriate bio-statistics analysis, including univariate analysis and Multivariate analysis, were used to identify factors associated with drop-out. RESULTS: Data from all patients were analyzed. Univariate analysis suggested that the factors associated with drop-out may include age, residential area, educational level, occupation, monthly income, the access to minimum living allowance, HIV transmission route, and living status. On the other hand, factors including area, monthly income, the access to minimum living allowance, and referral methods of follow-up institutions account for drop-out in multivariate analysis. CONCLUSIONS: This study identified a number of factors associated with drop out from ART. Based on our findings,appropriate interventions should be introduced decrease drop-out.

Initial Antiretroviral Therapy in an Integrase Inhibitor Era: Can We Do Better?

With the second-generation integrase inhibitors (dolutegravir and bictegravir) extending the attributes of earlier integrase inhibitors, three-drug regimens containing integrase inhibitors plus two nucleos(t)ide reverse transcriptase inhibitors are now widely recommended for first-line (initial) treatment of human immunodeficiency virus-1 infection. Led by dolutegravir plus lamivudine, two-drug therapy is emerging as a way to reduce antiretroviral therapy cost and adverse effects without compromising treatment options should virologic failure occur. Initial two-drug therapy has limitations, including the relative incompatibility with the coemerging concept of same-day antiretroviral therapy initiation.

Is symptom prevalence and burden associated with HIV treatment status and disease stage among adult HIV outpatients in Kenya? A cross-sectional self-report study.

People with HIV experience a high prevalence and burden of physical and psychological symptoms throughout their disease trajectory. These have important public and clinical health implications. We aimed to measure: the seven-day period prevalence of symptoms, the most burdensome symptoms, and determine if self-reported symptom burden is associated with treatment status, clinical stage and physical performance. We conducted a cross-sectional study among adult (aged at least 18 years) patients with HIV, attending HIV outpatient care in Kenya. Data was gathered through self-report using the Memorial Symptom Assessment Scale-Short Form (MSAS-SF), file extraction (sociodemographic data, treatment status, CD4 count, clinical stage) and through observation using the Karnofsky Performance Scale (KPS). Multivariable ordinal logistic regression assessed the association of symptom burden (MSAS-SF) controlling for demographic and clinical variables. Of the 475 participants approached, 400 (84.2%) participated. Ordinal logistic regression showed that being on HIV treatment was associated lower global distress index (in quartiles) (odds ratio .45, 95% CI .23 to .88; p = 0.019). Pain and symptom burden still persist in the era of antiretroviral therapy. Routine clinical practice should incorporate assessment and management of pain and symptoms irrespective of disease stage and treatment status in order to achieve the proposed fourth "90" in the UNAIDS 90-90-90 targets (that is good quality of life).

Factors Contributing to Missed Visits for Medical Care among Human Immunodeficiency Virus-Infected Adults in Seoul, Korea.

BACKGROUND: It is important that patients with human immunodeficiency virus (HIV) remain under medical care to improve their health and to reduce the potential for HIV transmission. We explored factors associated with missed visits for HIV medical care according to age group. METHODS: Data were derived from a city-wide, cross-sectional survey of 812 HIV-infected adults in Seoul. Multiple logistic analyses were used to explore predictors of missed visits. RESULTS: Of the 775 subjects, 99.3% were treated with antiretroviral therapy (ART) and 12.5% had missed a scheduled appointment for HIV medical care during the past 12 months. Compared with the group aged ≥ 50 years, the 20-34-years and 35-49-years groups were strongly associated with missed visits (adjusted odds ratio [aOR], 5.0 and 2.2, respectively). When divided by age group, lower education level (aOR, 3.0) in subjects aged 20-34 years, low income (aOR, 3.5), National Medical Aid beneficiary (aOR, 0.3), and treatment interruption due to side effects of ART (aOR, 3.4) in subjects aged 35-49 years, and National Medical Aid beneficiary (aOR, 7.1) in subjects aged ≥ 50 years were associated with missed visits. CONCLUSION: In conclusion, younger age was a strong predictor of missed visits for HIV medical care. However, the risk factors differed according to age group, and the strongest predictor in each age group was related to socioeconomic status.

Cardiovascular disease burden among human immunodeficiency virus-infected individuals.

Human Immunodeficiency Virus (HIV) infection affects 36.7 million people worldwide, it accounted for 1.1 million deaths in 2015. The advent of combined antiretroviral therapy (cART) has been associated with a decrease in HIV-related morbidity and mortality. However, there are increasing concerns about long-lasting effects of chronic inflammation and immune activation, leading to premature aging and HIV-related mortality. Cardiovascular diseases, especially coronary artery disease, are among the leading causes of death in HIV-infected patients, accounting for up to 15% of total deaths in high income countries. Furthermore, as cART availability expands to low-income countries, the burden of cardiovascular related mortality is likely to rise. Hence, over the next decade HIV-associated cardiovascular disease burden is expected to increase globally. In this review, we summarize our understanding of the pathogenesis and risk factors associated with HIV infection and cardiovascular disease, in particular coronary artery disease.

Use of Nonantiretroviral Medications That May Impact Neurocognition: Patterns and Predictors in a Large, Long-Term HIV Cohort Study.

BACKGROUND: Neurocognitive impairment is a frequent and often disabling comorbidity of HIV infection. In addition to antiretroviral therapies, individuals with HIV infection may commonly use nonantiretroviral medications that are known to cause neurocognitive adverse effects (NC-AE). The contribution of NC-AE to neurocognitive impairment is rarely considered in the context of HIV and could explain part of the variability in neurocognitive performance among individuals with HIV. SETTING: Women's Interagency HIV Study, a prospective, multisite, observational study of US women with and without HIV. METHODS: After a literature review, 79 medications (excluding statins) with NC-AE were identified and reported by Women's Interagency HIV Study participants. We examined factors associated with self-reported use of these medications over a 10-year period. Generalized estimating equations for binary outcomes were used to assess sociodemographic, behavioral, and clinical characteristics associated with NC-AE medication use. RESULTS: Three thousand three hundred women (71% with HIV) and data from ∼42,000 visits were studied. HIV infection was associated with NC-AE medication use (odds ratio = 1.52; 95% confidence interval: 1.35 to 1.71). After adjustment for HIV infection status, other predictors of NC-AE medication use included having health insurance, elevated depressive symptoms, prior clinical AIDS, noninjection recreational drug use, and an annual household income of <$12,000 (Ps < 0.004). NC-AE medication use was less likely among women who drank 1-7 or 8-12 alcoholic drinks/week (vs. abstaining) (P < 0.04). CONCLUSIONS: HIV infection was associated with NC-AE medication use, which may influence determinations of HIV-associated neurocognitive impairment. Providers should consider the impact of NC-AE medications when evaluating patients with HIV and concurrent neurocognitive symptoms.

Visceral Leishmaniasis and HIV Co-Infection in Northwest Ethiopia: Antiretroviral Treatment and Burden of Disease among Patients Enrolled in HIV Care.

The approach to treatment of visceral leishmaniasis (VL)-HIV co-infection in East Africa has not been systematically examined. Although antiretroviral treatment (ART) should be initiated for all co-infected persons, the extent of ART prescription is not known. We conducted a retrospective cohort study including all VL-HIV co-infected adults at selected referral and district hospitals in northwest Ethiopia from 2010 to 2015. Purposes of the study were to compare the proportion of VL diagnoses made in previously diagnosed HIV-patients versus diagnosis concurrent with HIV diagnosis and to quantify utilization of ART. We included 112 patients and 58 patients at the referral and district hospital, respectively (median age: 30 years, 98% males). Of all VL cases, 56% (63/112) and 19% (11/58) occurred in known HIV patients at the referral and district hospital, respectively, with a median CD4 count at VL diagnosis of 45 cells/µL and 248 cells/µL at the referral and district hospital, respectively. Seventy-six percent (56/44) were on ART at VL diagnosis and nine (12%) started ART after VL diagnosis. The remaining 96 (56%) patients had both infections diagnosed concurrently, with a median CD4 count of 56 and 143 cells/µL at the referral and district hospital, respectively. Among cured patients, ART initiation was 67% and 36% at the referral and district hospital, respectively. A substantial proportion of VL-HIV cases occur while in HIV care, requiring further evaluation of preventive strategies. Among newly diagnosed VL-HIV co-infected patients, ART initiation was low. The reasons, including poor documentation and information exchange, should be assessed.

Epidemiology of ischemic heart disease in HIV.

PURPOSE OF REVIEW: The purpose of this review is to summarize and synthesize recent data on the risk of ischemic heart disease (IHD) in HIV-infected individuals. RECENT FINDINGS: Recent studies in the field demonstrate an increasing impact of cardiovascular disease (CVD) on morbidity and mortality in HIV relative to AIDS-related diagnoses. Studies continue to support an approximately 1.5 to two-fold increased risk of IHD conferred by HIV, with specific risk varying by sex and virologic/immunologic status. Risk factors include both traditional CVD risk factors and novel, HIV-specific factors including inflammation and immune activation. Specific antiretroviral therapy (ART) drugs may increase CVD risk, yet the net effect of ART with viral suppression is beneficial with regard to CVD risk. Management of cardiovascular risk and prevention of CVD is complex, because current general population strategies target traditional CVD risk factors only. Extensive investigation is being directed at developing tailored CVD risk prediction algorithms and interventions to reduce CVD risk in HIV. SUMMARY: Increased IHD risk is a significant clinical and public health challenge in HIV. The development and application of HIV-specific interventions to manage CVD risk factors and reduce CVD risk will improve the long-term health of this ageing population.

Impact of early initiation versus national standard of care of antiretroviral therapy in Swaziland's public sector health system: study protocol for a stepped-wedge randomized trial.

BACKGROUND: There is robust clinical evidence to support offering early access to antiretroviral treatment (ART) to all HIV-positive individuals, irrespective of disease stage, to both improve patient health outcomes and reduce HIV incidence. However, as the global treatment guidelines shift to meet this evidence, it is still largely unknown if early access to ART for all (also referred to as "treatment as prevention" or "universal test and treat") is a feasible intervention in the resource-limited countries where this approach could have the biggest impact on the course of the HIV epidemics. The MaxART Early Access to ART for All (EAAA) implementation study was designed to determine the feasibility, acceptability, clinical outcomes, affordability, and scalability of offering early antiretroviral treatment to all HIV-positive individuals in Swaziland's public sector health system. METHODS: This is a three-year stepped-wedge randomized design with open enrollment for all adults aged 18 years and older across 14 government-managed health facilities in Swaziland's Hhohho Region. Primary endpoints are retention and viral suppression. Secondary endpoints include ART initiation, adherence, drug resistance, tuberculosis, HIV disease progression, patient satisfaction, and cost per patient per year. Sites are grouped to transition two at a time from the control (standard of care) to intervention (EAAA) stage at each four-month step. This design will result in approximately one half of the total observation time to accrue in the intervention arm and the other half in the control arm. Our estimated enrolment number, which is supported by conservative power calculations, is 4501 patients over the course of the 36-month study period. A multidisciplinary, mixed-methods approach will be adopted to supplement the randomized controlled trial and meet the study aims. Additional study components include implementation science, social science, economic evaluation, and predictive HIV incidence modeling. DISCUSSION: A stepped-wedge randomized design is a causally strong and robust approach to determine if providing antiretroviral treatment for all HIV-positive individuals is a feasible intervention in a resource-limited, public sector health system. We expect our study results to contribute to health policy decisions related to the HIV response in Swaziland and other countries in sub-Saharan Africa. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02909218 . Registered on 10 July 2016.

Assessment and management of musculoskeletal disorders among patients living with HIV.

HIV is a global pandemic. However, anti-retroviral therapy has transformed the prognosis and, providing compliance is good, a normal life expectancy can be anticipated. This has led to increasing numbers of people with chronic prevalent, treated infection living to older ages. Musculoskeletal pain is commonly reported by HIV patients and, with resumption of near-normal immune function, HIV-infected patients develop inflammatory rheumatic diseases that require assessment and management in rheumatology clinics. Moreover, it is becoming apparent that avascular necrosis and osteoporosis are common comorbidities of HIV. This review will contextualize the prevalence of musculoskeletal symptoms in HIV, informed by data from a UK-based clinic, and will discuss the management of active inflammatory rheumatic diseases among HIV-infected patients taking anti-retroviral therapy, highlighting known drug interactions.

How food insecurity contributes to poor HIV health outcomes: Qualitative evidence from the San Francisco Bay Area.

RATIONALE: Food-insecure people living with HIV/AIDS (PLHIV) consistently exhibit worse clinical outcomes than their food-secure counterparts. This relationship is mediated in part through non-adherence to antiretroviral therapy (ART), sub-optimal engagement in HIV care, and poor mental health. An in-depth understanding of how these pathways operate in resource-rich settings, however, remains elusive. OBJECTIVE: We aimed to understand the relationship between food insecurity and HIV health among low-income individuals in the San Francisco Bay Area using qualitative methods. METHODS: Semi-structured in-depth interviews were conducted with 34 low-income PLHIV receiving food assistance from a non-profit organization. Interviews explored experiences with food insecurity and its perceived effects on HIV-related health, mental health, and health behaviors including taking ART and attending clinics. Thematic content analysis of transcripts followed an integrative inductive-deductive approach. RESULTS: Food insecurity was reported to contribute to poor ART adherence and missing scheduled clinic visits through various mechanisms, including exacerbated ART side effects in the absence of food, physical feelings of hunger and fatigue, and HIV stigma at public free-meal sites. Food insecurity led to depressive symptoms among participants by producing physical feelings of hunger, aggravating pre-existing struggles with depression, and nurturing a chronic self-perception of social failure. Participants further explained how food insecurity, depression, and ART non-adherence could reinforce each other in complex interactions. CONCLUSION: Our study demonstrates how food insecurity detrimentally shapes HIV health behavior and outcomes through complex and interacting mechanisms, acting via multiple socio-ecological levels of influence in this setting. The findings emphasize the need for broad, multisectoral approaches to tackling food insecurity among urban poor PLHIV in the United States.

BREATHER (PENTA 16) short-cycle therapy (SCT) (5 days on/2 days off) in young people with chronic human immunodeficiency virus infection: an open, randomised, parallel-group Phase II/III trial.

BACKGROUND: For human immunodeficiency virus (HIV)-infected adolescents facing lifelong antiretroviral therapy (ART), short-cycle therapy (SCT) with long-acting agents offers the potential for drug-free weekends, less toxicity, better adherence and cost savings. OBJECTIVES: To determine whether or not efavirenz (EFV)-based ART in short cycles of 5 days on and 2 days off is as efficacious (in maintaining virological suppression) as continuous EFV-based ART (continuous therapy; CT). Secondary objectives included the occurrence of new clinical HIV events or death, changes in immunological status, emergence of HIV drug resistance, drug toxicity and changes in therapy. DESIGN: Open, randomised, non-inferiority trial. SETTING: Europe, Thailand, Uganda, Argentina and the USA. PARTICIPANTS: Young people (aged 8-24 years) on EFV plus two nucleoside reverse transcriptase inhibitors and with a HIV-1 ribonucleic acid level [viral load (VL)] of < 50 copies/ml for > 12 months. INTERVENTIONS: Young people were randomised to continue daily ART (CT) or change to SCT (5 days on, 2 days off ART). MAIN OUTCOME MEASURES: Follow-up was for a minimum of 48 weeks (0, 4 and 12 weeks and then 12-weekly visits). The primary outcome was the difference between arms in the proportion with VL > 50 copies/ml (confirmed) by 48 weeks, estimated using the Kaplan-Meier method (12% non-inferiority margin) adjusted for region and age. RESULTS: In total, 199 young people (11 countries) were randomised (n = 99 SCT group, n = 100 CT group) and followed for a median of 86 weeks. Overall, 53% were male; the median age was 14 years (21% ≥ 18 years); 13% were from the UK, 56% were black, 19% were Asian and 21% were Caucasian; and the median CD4% and CD4 count were 34% and 735 cells/mm(3), respectively. By week 48, only one participant (CT) was lost to follow-up. The SCT arm had a 27% decreased drug exposure as measured by the adherence questionnaire and a MEMSCap(™) Medication Event Monitoring System (MEMSCap Inc., Durham, NC, USA) substudy (median cap openings per week: SCT group, n = 5; CT group, n = 7). By 48 weeks, six participants in the SCT group and seven in the CT group had a confirmed VL > 50 copies/ml [difference -1.2%, 90% confidence interval (CI) -7.3% to 4.9%] and two in the SCT group and four in the CT group had a confirmed VL > 400 copies/ml (difference -2.1%, 90% CI -6.2% to 1.9%). All six participants in the SCT group with a VL > 50 copies/ml resumed daily ART, of whom five were resuppressed, three were on the same regimen and two with a switch; two others on SCT resumed daily ART for other reasons. Overall, three participants in the SCT group and nine in the CT group (p = 0.1) changed ART regimen, five because of toxicity, four for simplification reasons, two because of compliance issues and one because of VL failure. Seven young people (SCT group, n = 2; CT group, n = 5) had major non-nucleoside reverse transcriptase inhibitor mutations at VL failure, of whom two (n = 1 SCT group, n = 1 CT group) had the M184V mutation. Two young people had new Centers for Disease Control B events (SCT group, n = 1; CT group, n = 1). There were no significant differences between SCT and CT in grade 3/4 adverse events (13 vs. 14) or in serious adverse events (7 vs. 6); there were fewer ART-related adverse events in the SCT arm (2 vs. 14; p = 0.02). At week 48 there was no evidence that SCT led to increased inflammation using an extensive panel of markers. Young people expressed a strong preference for SCT in a qualitative substudy and in pre- and post-trial questionnaires. In total, 98% of the young people are taking part in a 2-year follow-up extension of the trial. CONCLUSIONS: Non-inferiority of VL suppression in young people on EFV-based first-line ART with a VL of < 50 copies/ml was demonstrated for SCT compared with CT, with similar resistance, safety and inflammatory marker profiles. The SCT group had fewer ART-related adverse events. Further evaluation of the immunological and virological impact of SCT is ongoing. A limitation of the trial is that the results cannot be generalised to settings where VL monitoring is either not available or infrequent, nor to use of low-dose EFV. Two-year extended follow-up of the trial is ongoing to confirm the durability of the SCT strategy. Further trials of SCT in settings with infrequent VL monitoring and with other antiretroviral drugs such as tenofovir alafenamide, which has a long intracellular half-life, and/or dolutegravir, which has a higher barrier to resistance, are planned. TRIAL REGISTRATION: Current Controlled Trials ISRCTN97755073; EUDRACT 2009-012947-40; and CTA 27505/0005/001-0001. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme (projects 08/53/25 and 11/136/108), the European Commission through EuroCoord (FP7/2007/2015), the Economic and Social Research Council, the PENTA Foundation, the Medical Research Council and INSERM SC10-US19, France, and will be published in full in Health Technology Assessment; Vol. 20, No. 49. See the NIHR Journals Library website for further project information.