Assessment of swallowability and acceptability of scored darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) fixed-dose combination (FDC) tablets in HIV-1-infected children aged ≥6 to <12 years, using matching placebo tablets: A randomized study.

BACKGROUND: Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) fixed-dose combination (FDC) was developed as a once-daily, complete antiretroviral (ARV) regimen therapy to address the need for simplified protease inhibitor-based ARV regimens. This study assessed the swallowability and acceptability for long-term use of scored placebo tablets matching the D/C/F/TAF FDC tablets in children living with HIV-1. METHODS: This study (NCT04006704) was a Phase 1, open-label, randomized, single-dose, 2-period, 2-sequence crossover study in children living with HIV-1, aged ≥6 to <12 years and weighing ≥25 to <40 kg, on a stable ARV regimen for ≥3 months. Participants were asked to swallow whole (size, 21 × 11 × 7 mm) and split matching placebo D/C/F/TAF tablets. Swallowability of the matching placebo D/C/F/TAF tablets (primary endpoint) was assessed by observers. Acceptability of taking matching placebo D/C/F/TAF tablets and current ARVs was evaluated by participants using a 3-point questionnaire. Participants rated the acceptability for long-term daily use of the placebo D/C/F/TAF tablets, and observers assessed how easily caregivers could split a scored tablet by hand, using 3-point questionnaires. RESULTS: Among the 24 participants who enrolled and completed the study, 95.8% (23/24) were able to swallow the whole and split matching placebo D/C/F/TAF tablets after 1 or 2 attempts. Most participants (>70%) rated the acceptability of tablets for long-term daily use as acceptable or good to take. Breaking the tablets was considered easy or OK by 79.2% (19/24) of caregivers. CONCLUSION: Scored D/C/F/TAF FDC tablets are swallowable - with whole favoured over split - and considered at least acceptable for long-term daily intake in children living with HIV-1 aged ≥6 to <12 years. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04006704.

Assessment of the performance of the plasma separation card for HIV-1 viral load monitoring in South Africa.

Scaling up of newer innovations that address the limitations of the dried blood spot and the logistics of plasma monitoring is needed. We employed a multi-site, cross-sectional assessment of the plasma separation card (PSC) on blood specimens collected from all consenting adults, assenting young and pediatric patients living with HIV from 10 primary healthcare clinics in South Africa. Venous blood for EDTA-plasma samples was collected and analyzed according to the standard of care assay, while collected capillary blood for the PSC samples was analyzed using the Roche COBAS AmpliPrep/Cobas TaqMan (CAP/CTM) HIV-1 Test at the National Reference laboratories. McNemar tests assessed the differences in concordance between the centrifuged plasma and dried plasma spots. The usability of PSC by blood spotting, PSC preparation, and pre-analytical work was assessed by collecting seven-point Likert-scale data from healthcare and laboratory workers. We enrolled 538 patients, mostly adults [n = 515, 95.7% (95% CI: 93.7%-97.1%)] and females [n = 322, 64.2% (95% CI: 60.0%-68.1%)]. Overall, 536 paired samples were collected using both PSC- and EDTA-plasma diagnostics, and 502 paired PSC- and EDTA-plasma samples assessed. Concordance between the paired samples was obtained for 446 samples. Analysis of these 446 paired samples at 1,000 copies per milliliter threshold yielded an overall sensitivity of 87.5% [95% CI: 73.2%-95.8%] and specificity of 99.3% [95% CI: 97.9%-99.8%]. Laboratory staff reported technical difficulties in most tasks. The usability of the PSC by healthcare workers was favorable. For policymakers to consider PSC scale-up for viral load monitoring, technical challenges around using PSC at the clinic and laboratory level need to be addressed. IMPORTANCE: Findings from this manuscript emphasize the reliability of the plasma separation card (PSC), a novel diagnostic method that can be implemented in healthcare facilities in resource-constrained settings. The agreement of the PSC with the standard of care EDTA plasma for viral load monitoring is high. Since the findings showed that these tests were highly specific, we recommend a scale-up of PSC in South Africa for diagnosis of treatment failure.

External quality assessment to support the WHO ProSPeRo study for the evaluation of two dual HIV/syphilis point-of-care tests in seven countries.

BACKGROUND: Sexually transmitted infections (STIs) such as syphilis and HIV remain to be a significant public health issue worldwide. Dual rapid point-of-care tests (POCTs) have shown promise for detecting antibodies to HIV and syphilis but have not been fully evaluated in the field. Our study supported the WHO ProSPeRo study on Sexually Transmitted Infection Point-of-Care Testing (STI POCT) by providing external quality assessment (EQA) for HIV and syphilis testing in reference laboratories and their associated clinical sites in seven countries. METHODS: HIV/syphilis serum liquid and dried tube specimen (DTS) panels were prepared by CDC. Liquid panels were distributed to the reference laboratories for three rounds of testing using commercially and locally available laboratory-based serological tests. DTS panels were sent to the clinical testing sites for 8 rounds of POC testing using the Abbott SD BIOLINE HIV/Syphilis Duo test (hereafter referred to as SD BIOLINE) and the Chembio Dual Path Platform (DPP) HIV-Syphilis assay. EQA panels were tested at CDC using the Rapid Plasma Reagin (RPR) test and the Treponema pallidum Particle Agglutination assay (TP-PA) for syphilis antibodies. Genetic Systems HIV-1/HIV-2 Plus O EIA, Geenius HIV Supplemental Assay and the Oraquick Advance HIV test were used to detect HIV antibodies in the EQA panels. Results from the reference laboratories and POCT sites were compared to those obtained at the CDC and a percentage agreement was calculated. RESULTS: Qualitative RPR and TP-PA performed at the reference laboratories demonstrated 95.4-100% agreement with CDC results while quantitative RPR and TP-PA tests demonstrated 87.7% and 89.2% agreement, respectively. A 93.8% concordance rate was observed for qualitative HIV testing in laboratories. EQA testing at clinical sites using dual tests showed 98.7% and 99.1% agreement for detection of HIV antibodies and eight out of 10 sites had > 95.8% agreement for syphilis testing. However, two clinical sites showed only 65.0-66.7% agreement for SD BIOLINE and 84.0-86.7% for DPP, respectively, for syphilis testing. CONCLUSIONS: Overall, laboratories demonstrated high EQA performance in this study. Both HIV/syphilis POCTs gave expected results in the clinic-based evaluations using DTS. However, testing errors were identified in a few testing sites suggesting the necessity for continuous training and monitoring the quality of POC testing.

Global HIV Incidence Analysis and Implications for Affordability Using Long-Acting Cabotegravir Versus Continuous and Event-Driven Oral Preexposure Prophylaxis.

BACKGROUND: The HIV Prevention Trials Network (HPTN) 083/084 trials showed up to 88% increased efficacy of long-acting cabotegravir (CAB-LA) versus continuous oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC). However, CAB-LA's high price limits the number of people who can be treated within fixed prevention budgets. Global human immunodeficiency virus (HIV) prevention budgets are highly limited, with TDF/FTC widely available as a low-cost generic. In randomized clinical trials, event-driven TDF/FTC has shown similar preventive efficacy to continuous TDF/FTC. METHODS: A systematic review of global HIV incidence studies was conducted. Weighted incidence was calculated in each at-risk population. HIV infection rates were evaluated for 5 prevention strategies, with additional HIV testing, education, and service access costs assumed for each ($18 per person per year). Assumed efficacies were 90% (continuous CAB-LA), 60% (continuous TDF/FTC), and 60% (event-driven TDF/FTC). Using weighted incidence and an assumed 100 000 target population, annual HIV infection rates by population were calculated for each prevention strategy. RESULTS: Ninety-eight studies in 5 230 189 individuals were included. Incidence per 100 person-years ranged from 0.03 (blood donors) to 3.82 (people who inject drugs). Using the number needed to treat to benefit for each strategy, a mean incidence of 2.6 per 100 person-years in at-risk populations, and a 100 000 target population, current-price continuous CAB-LA cost $949 487 per HIV infection successfully prevented, followed by target-price CAB-LA ($11 453), continuous TDF/FTC ($4231), and event-driven TDF/FTC ($1923). CONCLUSIONS: High prices of CAB-LA limit numbers treatable within fixed budgets. Low-cost event-driven TDF/FTC consistently prevents the most HIV infections within fixed budgets.

Recent HIV-1 infection in Israel 2017-2021: Evaluation of geenius and HIV-1/2 combo assays for identifying recent infection detected by Sedia assay and assessment of factors related to recent infection: Recent HIV-1 infection in Israel.

BACKGROUND: Estimating HIV-1 recency of infection for incidence and local outbreaks detection usually involves specifically designed assays. Here, we established an approach to identify recent infections, estimate their rate, and assess potential risk factors. METHODS: Randomly selected HIV-1 positive samples (n = 382) collected in 2017-2021 were tested by Sedia and compared to the results of Geenius recency algorithm and the S/CO values of the HIV-1/2 Combo assay. Using Geenius and Combo recency verdict, we assessed all cases diagnosed in 2017-2021. Related factors were further assessed. RESULTS: While Geenius and Combo had a sensitivity of 65.9 % and 89.30 %, respectively, and specificity of 96 % and 90 %, respectively, compared to Sedia, higher concordance (97.2 %) and kappa (>0.9) were observed when the verdict of both assays together was compared to Sedia. Using this approach, 15.3 % (238/1548) of individuals diagnosed in 2017-2021 were defined as recently infected. In multivariate analysis, recent diagnosis was mainly associated with men who have sex with men (MSM) and with birthplace in Israel, Western/Central Europe, or North America. CONCLUSIONS: Only 15.3 % of infections in 2017-2021, mainly in MSM and Israeli/Western countries-born individuals, were diagnosed early. Regular diagnostic assays have a potential to identify and monitor trends in recent infections.

Assessment of pain-related behaviors in HIV-1 transgenic rats as a model of HIV-associated chronic pain.

Human immunodeficiency virus-1 (HIV)-associated chronic pain is a debilitating comorbid condition that affects 25-85% of people with HIV. The use of opioids to alleviate pain has given rise to opioid dependency in this cohort. Therefore, there is an urgent need to understand mechanisms and identify novel therapeutics for HIV-associated chronic pain. Several animal models have been developed to study HIV-related comorbidities. HIV-1 transgenic (Tg) rats have been shown to serve as a reliable model that mimic the deficits observed in people with HIV, such as neurological and immune system alterations. However, pain-related behavior in these animals has not been extensively evaluated. In this study, we measured evoked and spontaneous behavior in HIV-1Tg male and female rats. The results indicated that HIV-1Tg rats exhibit similar behavior to those with HIV-1-related neuropathy, specifically, cold sensitivity. Consequently, HIV-1Tg rats can serve as a model of neuropathy to study pain-related mechanisms and therapeutics targeted toward individuals living with HIV-1.

Texas Developmental Center for AIDS Research CFAR Diversity, Equity, and Inclusion Pathway Initiative Program.

BACKGROUND: The Texas Developmental Center for AIDS Research (D-CFAR) diversity program, termed the CFAR Diversity, Equity, and Inclusion Pathway Initiative (CDEIPI), was created in 2021 to engage high school students and graduate students from Underrepresented Minorities/Black, Indigenous, and People of Color populations. SETTING: The Texas D-CFAR CDEIPI has partnered with 2 Texas high schools with predominantly economically disadvantaged and minority student populations-Michael E. DeBakey High School for Health Professions in Houston, TX, and the South Texas Independent School District Medical Professions High School in Olmito, TX in the Rio Grande Valley. METHODS: A total of 370 high school student learners at both partner schools participated in presentations of research and career paths related to HIV-1 and SARS-CoV-2 during the 2021-2022 academic year. Afterward, learners completed anonymous surveys to share their self-reported interest in research degrees and careers. RESULTS: Learners reported increased knowledge of related science content and interest in research careers, including HIV-1 research, after each of the sessions. CONCLUSIONS: The programming has been of interest to student learners, and future additions intend to build upon the Texas D-CFAR CDEIPI.

Model-Based Dose Selection of Fostemsavir for Pediatric Populations With Multidrug-Resistant HIV-1 and Relative Bioavailability Assessment in Healthy Adults.

Fostemsavir, a prodrug of the first-in-class HIV-1 attachment inhibitor temsavir, is approved for the treatment of multidrug-resistant HIV-1 in adults; its use in pediatric populations is currently being studied. Population pharmacokinetic modeling across pediatric weight bands was used to guide pediatric fostemsavir dose selection. Dosing simulations demonstrated that twice-daily fostemsavir 600-mg (adult dose) and 400-mg doses met safety and efficacy criteria for 35 kg or greater and 20 or greater to less than 35 kg pediatric weight bands, respectively. Temsavir relative bioavailability of 2 low-dose fostemsavir extended-release formulations (3 × 200 mg; formulations A and B) and reference formulation (600 mg extended release) was assessed in a 2-part, open-label, randomized, crossover study in healthy adults. Part 1 (N = 32) compared single-dose temsavir relative bioavailability, and Part 2 (N = 16) evaluated the impact of fed versus fasted conditions using the selected low-dose formulation. Temsavir geometric mean ratios for the area under the plasma concentration-time curve from time zero to infinity and maximum concentration for formulation B were bioequivalent to the reference formulation. Temsavir maximum concentration for formulation B was similar in fed and fasted states, but area under the plasma concentration-time curve from time zero to infinity geometric mean ratio was increased under fed conditions, consistent with previous results in adults. These analyses demonstrated efficient pediatric dose selection using a model-based approach.

The Burden of Neuropsychiatric Disorders in Medicaid Patients Living With HIV-1 Treated With Integrase Inhibitor or Protease Inhibitor Antiretroviral Therapies.

Objective: Data are scarce regarding the incidence of neuropsychiatric events (NPEs) in people living with human immunodeficiency virus (HIV)-1 taking integrase inhibitor (INI)- or protease inhibitor (PI)-based regimens. This study evaluated the prevalence, incidence, and economic burden of NPEs among people living with HIV-1 who were newly treated with INI- or PI-based regimens in a Medicaid population.Methods: A retrospective cohort study was conducted using administrative claims from the IBM MarketScan Multi-State Medicaid Database (January 1, 2014-December 31, 2018). Treatment-naive and treatment-experienced adults with HIV-1 newly treated with an INI- or PI-based regimen were included. Outcomes included NPE prevalence during the 12-month baseline period, prevalence of existing and incidence of new-onset NPEs during the 6-month post-index period, and total all-cause and NPE-related costs between treatment cohorts. Baseline characteristics between the 2 cohorts were balanced using inverse probability treatment weighting.Results: In the INI (n = 3,929) and PI (n = 3,916) cohorts, mean (SD) ages were 44.87 (12.81) and 44.36 (11.85) years, and 41.7% and 41.3% were female, respectively. High proportions of patients in both cohorts had NPEs during the 12-month baseline period. Among patients with no baseline NPEs, adjusted NPE incident rate ratios (95% CIs) during the post-index period were as follows: any, 1.15 (1.00-1.33); chronic, 1.18 (0.98-1.42); and acute, 1.16 (0.96-1.39). Mean all-cause and NPE-related costs were similar between cohorts.Conclusions: In this study of the Medicaid population, the prevalence and incidence of NPEs, as well as health care costs, were similar among people living with HIV-1 newly treated with an INI- or PI-based regimen.

Alerta monitoramento do horizonte tecnológico: Lenacapavir para o tratamento de HIV-1 multirresistente / Technological horizon monitoring alert: Lenacapavir for the treatment of multidrug resistant HIV-1

A TECNOLOGIA: Condição clínica: O vírus da imunodeficiência humana (HIV) é o causador da Síndrome da Imunodeficiência Adquirida (Aids), estágio avançado da infecção que debilita o sistema imunológico e deixa o organismo suscetível a doenças oportunistas. A infecção não possui cura, porém, sua progressão pode ser evitada com o uso de tratamento farmacológico antiretroviral. Dois subtipos de vírus podem causar a infecção, HIV-1 e HIV-2. O subtipo mais virulento e disseminado em todo o mundo é o HIV-1, enquanto o HIV-2 é menos infeccioso e mais frequente em países onde a doença é endêmica (4). A transmissão de ambos os subtipos ocorre por meio de relações sexuais sem proteção, compartilhamento de perfurocortantes contaminados e de mãe para filho durante a gestação, parto ou amamentação. O diagnóstico inicial é realizado por meio de testes rápidos ou laboratoriais para a identificação da presença do vírus ou detecção de anticorpos, a exemplo da Imunocromatografia e o imunoensaio de ELISA (do Inglês, Enzyme-Linked Immunosorbent Assay). Caso seja detectada a infecção, exames como o Western Blot (WB), Imunoblot (IB), Imunoblot Rápido (IBR) são utilizados como confirmatórios para o diagnóstico. DESCRIÇÃO DA TECNOLOGIA: Lenacapavir (Sunlenca®), desenvolvido pelo laboratório Gilead Sciences, é um inibidor de longa duração da função do capsídeo do HIV-1, o primeiro da classe. Esse antirretroviral impede a replicação do vírus a partir de múltiplos mecanismos de ação, afetando as principais etapas necessárias para o ciclo de vida do vírus, tais como: a captação nuclear que é mediada pela cápside do DNA viral, a montagem e libertação do vírus, e a formação do núcleo da cápside, gerando capsídeos malformados (20). Ademais, confere importante vantagem em não apresentar resistência cruzada com outros antirretrovirais. O medicamento está indicado em combinação com outros antirretrovirais para adultos com infeção por HIV-1 multirresistente e que apresentaram falha terapêutica devido à resistência, intolerância ou impossibilidade de uso por questões de segurança. INFORMAÇÕES REGULATÓRIAS: Informações sobre registro: O lenacapavir não possui registro sanitário na Agência Nacional de Vigilância Sanitária (Anvisa). Estratégia de busca: A busca teve dois objetivos, sendo que o primeiro foi recuperar registros de ensaios clínicos de fase 3 envolvendo lenacapavir no tratamento do HIV-1 e o segundo identificar resultados publicados desses estudos. Resultados de eficácia e segurança: Os resultados relatados são referentes ao estudo CAPELLA (NCT04150068), exceto os desfechos medidos em chances, que são provenientes de um estudo de comparação indireta. estudo de comparação indireta, conduzido por Chatzidaki I e colaboradores, teve como objetivo comparar lenacapavir + regime de base otimizado (RBO) versus fostemsavir + RBO e ibalizumabe + RBO versus RBO sozinho considerando os desfechos supressão virológica e alteração na contagem de células CD4+. Para tanto, uma revisão sistemática (RS) foi conduzida e os estudos identificados foram ponderados quanto à adequação para integrar análises comparativas. Tal avaliação tomou por base os seguintes critérios: desenho do estudo, semelhança das características basais dos participantes com as da coorte aleatória do estudo CAPELLA, intervenções investigadas, desfechos e pontos de tempo relatados. Assim, dados de participantes individuais da coorte aleatória do estudo CAPELLA e dados agregados dos estudos identificados na RS foram usados para conduzir comparações indiretas usando a metodologia de comparação de tratamento simulado não ancorada para ajuste da população. CONSIDERAÇÕES FINAIS: Um dos desafios do tratamento da infecção por HIV é uma adesão subótima ao tratamento e a ocorrência de resistência aos antirretrovirais. PVHIV com histórico de falhas e resistência significativa aos antirretrovirais têm opções terapêuticas limitadas e necessidade de um regime de tratamento altamente individualizado. Esses indivíduos podem não obter supressão viral sustentada do HIV. Nesse cenário em que são necessárias terapias capazes de garantir a preservação e restauração da função imunológica, evitando a progressão para Aids, o lenacapavir apresenta-se como o primeiro antirretroviral da classe inibidor do capsídeo do HIV-1, com um mecanismo de ação que interfere em múltiplos estágios do ciclo de vida do vírus. Além disso, o medicamento apresenta ação prolongada, com regime posológico de manutenção mais conveniente (duas vezes ao ano) em relação às terapias atuais, o que pode contribuir para uma melhor adesão ao tratamento e, consequentemente, com a obtenção de melhores resultados terapêuticos. O antirretroviral também parece não apresentar resistência cruzada com as outras classes disponíveis. Lenacapavir é indicado como adjuvante no tratamento de adultos com infecção HIV-1 multirresistente e falha à terapia atual e possui registro sanitário nos EUA, Canadá e países da União Europeia. A tecnologia apresentou um balanço positivo com relação à eficácia e segurança no estudo CAPELLA, uma vez que se mostrou capaz de promover redução de carga viral e supressão virológica sustentada até a semana 52, sem registro de eventos adversos graves. Adicionalmente, houve aumento na contagem de células CD4+ e redução na proporção de indivíduos com contagens inferiores a 50 células/mm3. Apesar do estudo CAPELLA apresentar algumas limitações, como tamanho amostral pequeno, diferenças nas características basais dos grupos randomizados, período de acompanhamento limitado e inclusão de indivíduos com terapias antirretrovirais muito variada, os resultados parecem promissores para uma população de difícil manejo clínico. O perfil de segurança do lenacapavir no estudo pivotal mostrou-se favorável, com registro de eventos adversos leves a moderados. Apenas um participante descontinuou a terapia em consequência de evento adverso No entanto, uma limitação do uso de lenacapavir é seu potencial de interação medicamentosa com outros antirretrovirais já utilizados no tratamento do HIV, a exemplo de atazanavir, efavirenz, nevirapina e etravirina Ademais, foi identificada resistência em cenários nos quais o lenacapavir estava em monoterapia funcional devido à ausência de antirretrovirais totalmente ativos no RBO ou adesão inadequada a esse regime. O lenacapavir também está sendo estudado para uso em associação de dose fixa oral com bictegravir no tratamento de indivíduos com supressão virológica. A despeito das evidências aqui apresentadas, para que ocorra a oferta desse medicamento no SUS, é necessária sua análise pela Comissão Nacional de Incorporação de Tecnologias no SUS (Conitec), conforme disposto na Lei nº 12.401/2011, que alterou a Lei nº 8.080/1990. Os relatórios de recomendação da Conitec levam em consideração as evidências científicas sobre eficácia, acurácia, efetividade e a segurança, além da avaliação econômica comparativa dos benefícios e dos custos em relação às tecnologias já incorporadas e o impacto da incorporação da tecnologia no SUS.

Assessment of HIV viral load monitoring in remote settings in Vietnam - comparing people who inject drugs to the other patients.

INTRODUCTION: Increasing access to viral load (VL) monitoring is essential to fight HIV epidemics. In remote settings in Vietnam, using dried blood spot (DBS) sampling for specimen collection could improve the situation. Here, people who inject drugs (PWID) represent many newly antiretroviral therapy (ART)-initiated patients. The goals of this evaluation were to evaluate if access to VL monitoring and the rate of virological failure differed between PWID and non-PWID. METHODS: Prospective cohort study of patients newly initiated on ART in remote settings in Vietnam. DBS coverage at 6, 12 and 24 months of ART was investigated. Factors associated with DBS coverage were identified through logistic regression, as were factors associated with virological failure (VL ≥1,000 copies/mL) at 6, 12 and 24 months of ART. RESULTS: Overall 578 patients were enrolled in the cohort, of whom 261 (45%) were PWID. DBS coverage improved from 74.7% to 82.9% between 6 and 24 months of ART (p = 0.001). PWID status was not associated with DBS coverage (p = 0.74), but DBS coverage was lower in patients who were late to clinical visits and in those in WHO stage 4 (p = 0.023 and p = 0.001, respectively). The virological failure rate decreased from 15.8% to 6.6% between 6 and 24 months of ART (p<0.001). In multivariate analysis, PWID were more at risk of failure (p = 0.001), as were patients who were late to clinical visits (p<0.001) and not fully adherent (p<0.001). CONCLUSIONS: Despite training and simple procedures, DBS coverage was not perfect. DBS coverage was not associated with PWID status. Close management is required for effective routine HIV VL monitoring. PWID were more at risk of failure, as were patients who were not fully adherent and patients who were late to clinical visits. Specific interventions targeting these patients are needed to improve their outcomes. Overall, efforts in coordination and communication are essential to improve global HIV care. TRIAL REGISTRATION: Clinical Trial Number: NCT03249493.

Long-term evolution of comorbidities and their disease burden in individuals with and without HIV as they age: analysis of the prospective AGEhIV cohort study.

BACKGROUND: People with HIV generally have more ageing-associated comorbidities than those without HIV. We aimed to establish whether the difference in comorbidities and their disease burden changes with ageing. METHODS: In this prospective, longitudinal cohort study, we assessed comorbidities commonly associated with ageing every 2 years in 596 HIV-positive and 550 HIV-negative participants. HIV-positive participants were recruited from the HIV outpatient clinic of the Amsterdam University Medical Centres (Amsterdam, Netherlands). HIV-negative participants were recruited from the sexual health clinic and the Amsterdam Cohort Studies at the Public Health Service of Amsterdam (Amsterdam, Netherlands). Inclusion criteria were participants aged 45 years or older and, for HIV-negative participants, a documented HIV-negative antibody test. The mean number of comorbidities present over time was compared between groups by use of Poisson regression, accounting for dropout and death through joint survival models. Mean disability-adjusted life-years (DALYs) accrued during 2-year intervals were compared between groups by use of an exponential hurdle model. FINDINGS: Between Oct 29, 2010, and Oct 9, 2012, participants were enrolled and then prospectively followed up until their last visit before Oct 1, 2018. 1146 participants were followed up for a median 5·9 years (IQR 5·7-6·0), during which 231 participants (20·2%) dropped out: 145 (24·3%) of 596 HIV-positive and 86 (15·6%) of 550 HIV-negative. 38 (3·3%) of 1146 participants died: 31 (5·2%) of 596 HIV-positive and seven (1·3%) of 550 HIV-negative. 24 HIV-positive and two HIV-negative participants died from ageing-associated comorbidities. 15 HIV-positive participants versus one HIV-negative participant died from non-AIDS malignancies. At inclusion, mean number of comorbidities was higher in HIV-positive participants (0·65) than in HIV-negative participants (0·32; p<0·0001). Mean number of comorbidities increased at similar rates over time: rate ratio (RR) per year for HIV-positive participants 1·04 (95% CI 1·00-1·08), RR per year for HIV-negative participants 1·05 (1·01-1·08; pinteraction=0·78). Number of comorbidities was associated with an increased risk of death (hazard ratio 3·33 per additional comorbidity, 95% CI 2·27-4·88; p<0·0001). HIV-positive participants had higher increases in mean DALYs than HIV-negative participants (0·209 per year, 95% CI 0·162-0·256 vs 0·091 per year, 0·025-0·157; pinteraction=0·0045). This difference was reduced when deaths were excluded in establishing DALYs (0·127, 0·083-0·171 vs 0·066, 0·005-0·127; pinteraction =0·11). INTERPRETATION: The larger comorbidity prevalence in HIV-positive participants aged 50-55 years on effective antiretroviral treatment than in HIV-negative participants increased similarly as participants aged and was associated with an increased risk of death, particularly of non-AIDS malignancies. Our findings reinforce the need for strategies to optimise prevention, screening, and early intervention. FUNDING: Netherlands Organization for Health Research and Development, Aidsfonds, Gilead Sciences, ViiV Healthcare, Janssen Pharmaceuticals, and Merck & Co. TRANSLATION: For the Dutch translation of the abstract see Supplementary Materials section.

Stability of APOBEC3F in the Presence of the APOBEC3 Antagonist HIV-1 Vif Increases at the Expense of Co-Expressed APOBEC3H Haplotype I.

The seven human APOBEC3 enzymes (APOBEC3A through H, excluding E) are host restriction factors. Most of the APOBEC3 enzymes can restrict HIV-1 replication with different efficiencies. The HIV-1 Vif protein combats APOBEC3-mediated restriction by inducing ubiquitination and degradation in the proteasome. APOBEC3F and APOBEC3G can hetero-oligomerize, which increases their restriction capacity and resistance to Vif. Here we determined if APOBEC3C, APOBEC3F, or APOBEC3G could hetero-oligomerize with APOBEC3H haplotype I. APOBEC3H haplotype I has a short half-life in cells due to ubiquitination and degradation by host proteins, but is also resistant to Vif. We hypothesized that hetero-oligomerization with APOBEC3H haplotype I may result in less Vif-mediated degradation of the interacting APOBEC3 and stabilize APOBEC3H haplotype I, resulting in more efficient HIV-1 restriction. Although we found that all three APOBEC3s could interact with APOBEC3H haplotype I, only APOBEC3F affected APOBEC3H haplotype I by surprisingly accelerating its proteasomal degradation. However, this increased APOBEC3F levels in cells and virions in the absence or presence of Vif and enabled APOBEC3F-mediated restriction of HIV-1 in the presence of Vif. Altogether, the data suggest that APOBEC3 enzymes can co-regulate each other at the protein level and that they cooperate to ensure HIV-1 inactivation rather than evolution.

From Capillary Electrophoresis to Deep Sequencing: An Improved HIV-1 Drug Resistance Assessment Solution Using In Vitro Diagnostic (IVD) Assays and Software.

BACKGROUND: Drug-resistance mutations were mostly detected using capillary electrophoresis sequencing, which does not detect minor variants with a frequency below 20%. Next-Generation Sequencing (NGS) can now detect additional mutations which can be useful for HIV-1 drug resistance interpretation. The objective of this study was to evaluate the performances of CE-IVD assays for HIV-1 drug-resistance assessment both for target-specific and whole-genome sequencing, using standardized end-to-end solution platforms. METHODS: A total of 301 clinical samples were prepared, extracted, and amplified for the three HIV-1 genomic targets, Protease (PR), Reverse Transcriptase (RT), and Integrase (INT), using the CE-IVD DeepChek® Assays; and then 19 clinical samples, using the CE-IVD DeepChek® HIV Whole Genome Assay, were sequenced on the NGS iSeq100 and MiSeq (Illumina, San Diego, CA, USA). Sequences were compared to those obtained by capillary electrophoresis. Quality control for Molecular Diagnostics (QCMD) samples was added to validate the clinical accuracy of these in vitro diagnostics (IVDs). Nineteen clinical samples were then tested with the same sample collection, handling, and measurement procedure for evaluating the use of NGS for whole-genome HIV-1. Sequencing analyzer outputs were submitted to a downstream CE-IVD standalone software tailored for HIV-1 analysis and interpretation. RESULTS: The limits of range detection were 1000 to 106 cp/mL for the HIV-1 target-specific sequencing. The median coverage per sample for the three amplicons (PR/RT and INT) was 13,237 reads. High analytical reproducibility and repeatability were evidenced by a positive percent agreement of 100%. Duplicated samples in two distinct NGS runs were 100% homologous. NGS detected all the mutations found by capillary electrophoresis and identified additional resistance variants. A perfect accuracy score with the QCMD panel detection of drug-resistance mutations was obtained. CONCLUSIONS: This study is the first evaluation of the DeepChek® Assays for targets specific (PR/RT and INT) and whole genome. A cutoff of 3% allowed for a better characterization of the viral population by identifying additional resistance mutations and improving the HIV-1 drug-resistance interpretation. The use of whole-genome sequencing is an additional and complementary tool to detect mutations in newly infected untreated patients and heavily experienced patients, both with higher HIV-1 viral-load profiles, to offer new insight and treatment strategies, especially using the new HIV-1 capsid/maturation inhibitors and to assess the potential clinical impact of mutations in the HIV-1 genome outside of the usual HIV-1 targets (RT/PR and INT).

Estimation of HIV-1 Incidence Using a Testing History-Based Method; Analysis From the Population-Based HIV Impact Assessment Survey Data in 12 African Countries.

BACKGROUND: Estimating HIV incidence is essential to monitoring progress in sub-Saharan African nations toward global epidemic control. One method for incidence estimation is to test nationally representative samples using laboratory-based incidence assays. An alternative method based on reported HIV testing history and the proportion of undiagnosed infections has recently been described. METHODS: We applied an HIV incidence estimation method which uses history of testing to nationally representative cross-sectional survey data from 12 sub-Saharan African nations with varying country-specific HIV prevalence. We compared these estimates with those derived from laboratory-based incidence assays. Participants were tested for HIV using the national rapid test algorithm and asked about prior HIV testing, date and result of their most recent test, and date of antiretroviral therapy initiation. RESULTS: The testing history-based method consistently produced results that are comparable and strongly correlated with estimates produced using a laboratory-based HIV incidence assay (ρ = 0.85). The testing history-based method produced incidence estimates that were more precise compared with the biomarker-based method. The testing history-based method identified sex-, age-, and geographic location-specific differences in incidence that were not detected using the biomarker-based method. CONCLUSIONS: The testing history-based method estimates are more precise and can produce age-specific and sex-specific incidence estimates that are informative for programmatic decisions. The method also allows for comparisons of the HIV transmission rate and other components of HIV incidence among and within countries. The testing history-based method is a useful tool for estimating and validating HIV incidence from cross-sectional survey data.

Cost-effectiveness of broadly neutralizing antibody prophylaxis for HIV-exposed infants in sub-Saharan African settings.

INTRODUCTION: Infant HIV prophylaxis with broadly neutralizing anti-HIV antibodies (bNAbs) could provide long-acting protection against vertical transmission. We sought to estimate the potential clinical impact and cost-effectiveness of hypothetical bNAb prophylaxis programmes for children known to be HIV exposed at birth in three sub-Saharan African settings. METHODS: We conducted a cost-effectiveness analysis using the CEPAC-Pediatric model, simulating cohorts of infants from birth through death in Côte d'Ivoire, South Africa and Zimbabwe. These settings were selected to reflect a broad range of HIV care cascade characteristics, antenatal HIV prevalence and budgetary constraints. We modelled strategies targeting bNAbs to only WHO-designated "high-risk" HIV-exposed infants (HR-HIVE) or to all HIV-exposed infants (HIVE). We compared four prophylaxis approaches within each target population: standard of care oral antiretroviral prophylaxis (SOC), and SOC plus bNAbs at birth (1-dose), at birth and 3 months (2-doses), or every 3 months throughout breastfeeding (Extended). Base-case model inputs included bNAb efficacy (60%/dose), effect duration (3 months/dose) and costs ($60/dose), based on published literature. Outcomes included paediatric HIV incidence and incremental cost-effectiveness ratios (ICERs) calculated from discounted life expectancy and lifetime HIV-related costs. RESULTS: The model projects that bNAbs would reduce absolute infant HIV incidence by 0.3-2.2% (9.6-34.9% relative reduction), varying by country, prophylaxis approach and target population. In all three settings, HR-HIVE-1-dose would be cost-saving compared to SOC. Using a 50% GDP per capita ICER threshold, HIVE-Extended would be cost-effective in all three settings with ICERs of $497/YLS in Côte d'Ivoire, $464/YLS in South Africa and $455/YLS in Zimbabwe. In all three settings, bNAb strategies would remain cost-effective at costs up to $200/dose if efficacy is ≥30%. If the bNAb effect duration were reduced to 1 month, the cost-effective strategy would become HR-HIVE-1-dose in Côte d'Ivoire and Zimbabwe and HR-HIVE-2-doses in South Africa. Findings regarding the cost-effectiveness of bNAb implementation strategies remained robust in sensitivity analyses regarding breastfeeding duration, maternal engagement in postpartum care, early infant diagnosis uptake and antiretroviral treatment costs. CONCLUSIONS: At current efficacy and cost estimates, bNAb prophylaxis for HIV-exposed children in sub-Saharan African settings would be a cost-effective intervention to reduce vertical HIV transmission.

Assessment of a diverse panel of transmitted/founder HIV-1 infectious molecular clones in a luciferase based CD8 T-cell mediated viral inhibition assay.

Introduction: Immunological protection against human immunodeficiency virus-1 (HIV-1) infection is likely to require both humoral and cell-mediated immune responses, the latter involving cytotoxic CD8 T-cells. Characterisation of CD8 T-cell mediated direct anti-viral activity would provide understanding of potential correlates of immune protection and identification of critical epitopes associated with HIV-1 control. Methods: The present report describes a functional viral inhibition assay (VIA) to assess CD8 T-cell-mediated inhibition of replication of a large and diverse panel of 45 HIV-1 infectious molecular clones (IMC) engineered with a Renilla reniformis luciferase reporter gene (LucR), referred to as IMC-LucR. HIV-1 IMC replication in CD4 T-cells and CD8 T-cell mediated inhibition was characterised in both ART naive subjects living with HIV-1 covering a broad human leukocyte antigen (HLA) distribution and compared with uninfected subjects. Results & discussion: CD4 and CD8 T-cell lines were established from subjects vaccinated with a candidate HIV-1 vaccine and provided standard positive controls for both assay quality control and facilitating training and technology transfer. The assay was successfully established across 3 clinical research centres in Kenya, Uganda and the United Kingdom and shown to be reproducible. This IMC-LucR VIA enables characterisation of functional CD8 T-cell responses providing a tool for rational T-cell immunogen design of HIV-1 vaccine candidates and evaluation of vaccine-induced T-cell responses in HIV-1 clinical trials.

Evaluation of plasma viral-load monitoring and the prevention of mother-to-child transmission of HIV-1 in three health facilities of the Littoral region of Cameroon.

BACKGROUND: Prevention of mother-to-child transmission (PMTCT) has reduced HIV incidence among new-borns. However, PMTCT remains concerning in sub-Saharan Africa due to bottlenecks including viral load (VL) monitoring during pregnancy. We assessed VL coverage and materno-foetal outcomes of pregnancy among HIV-infected women within the Cameroonian context. METHODS: A hospital-based study was conducted among HIV-infected mothers and their babies in three facilities of the Littoral region of Cameroon from January 2019 to May 2021. Maternal VL-coverage was monitored during pregnancy (VL>1000 copies/ml or unknown were classified as MTCT high-risk group); HIV early infant diagnosis (EID) was evaluated by PCR at six-weeks after birth, and EID results were analysed according to maternal VL; p<0.05 was considered statistically significant. RESULTS: Of 135 HIV-infected pregnant women enrolled (median [IQR] age 39 [27-37] years), VL-coverage during antenatal care (ANC) was 50.4% (68/135), with a lower VL-coverage in 2019 (37.5% vs. 61.9%, p = 0.0069). Married women vs. single (61.8% vs. 42.5%, p = 0.0275) and those on treatment before vs. during pregnancy (56.7% vs. 5.8%, p = 0.0043) had a higher VL-coverage, respectively. Among those with known VL, 10.3% (7/68) had high (VL>1000 copies/mL), 22.1% (15/68) had low (50-1000 copies/mL), and 67.6% (46/68) had undetectable (<50 copies/mL) VL, suggesting an overall viral suppression (<1000copies/mL) of 89.7% (61/68). Vaginal delivery was 80.75% (109/135) regardless of VL, including 81.1% (59/74) women in the high-risk group. EID coverage was 88.1% (119/135) and the rate of HIV-1 MTCT was 1.68% (2/119). Both HIV-positive infants were from the high-risk group, had prolonged labour, had vaginal delivery and were breastfed. CONCLUSION: In these Cameroonian settings, VL-coverage remains suboptimal (below 90%) among ANC attendees, and women at high-risk of MTCT mainly have vaginal delivery. Viral suppression rate remains below the target (below 90%) for accelerating the elimination of MTCT. HIV-MTCT persists, and might be driven essentially by poor VL monitoring. Thus, achieving an optimal PMTCT performance requires a thorough compliance to virologic assessment during ANC.

Determinants of Direct Costs of HIV-1 Outpatient Care in Israel.

HIV-1 patients place an economic burden on the health system. The objectives of this study were to estimate the direct HIV-1 costs and cost-related factors of HIV-1 patients in Israel and identify cost predictors. We conducted a retrospective study of randomly selected HIV-1 patients aged ≥18 who visited a large outpatient clinic in 2015 and/or 2019. Yearly costs of physician and nurse visits, antiretroviral therapy (ART) and laboratory tests were calculated in USD using the 2020 purchasing power parities. Associations between disease characteristics and costs were analyzed using univariate and multivariable analysis. The median (IQR) total direct costs per patient per year were USD 12,387 (9813-14,124) and USD 12,835 (11,651-13,970) in 2015 (n = 284) and 2019 (n = 290), respectively. ART accounted for approximately 77% of all direct costs, followed by laboratory tests (20%) and medical visits (3%) in both studied years. Being female (USD +710), first yearly viral load <50 c/mL (+$1984) and ≥20 years with HIV-1 (USD +1056) were independently associated with higher costs. In conclusion, HIV-1 cost was stable in the studied period. Viral load and time since diagnosis were the major determinants associated with HIV-1 costs. ART and laboratory tests accounted for 97% of the costs. Therefore, these factors should be considered when planning future expenditures.