Bridging the gap: addressing real-life challenges to the implementation of DTG/3TC in treatment-naive people living with HIV

Effectiveness of COVID-19 primary and booster vaccination in HIV-infected individuals

Despite improved access to antiretroviral therapy (ART) for people with HIV (PWH), HIV continues to contribute considerably to morbidity and mortality. Increasingly, advanced HIV disease (AHD) is found among PWH who are ART-experienced. Using a multi-state model we examined associations between engagement with care and AHD on ART in South Africa. Using data from IeDEA Southern Africa, we included PWH from South Africa, initiating ART from 2004 to 2017 aged more than 5 years with a CD4+ cell count at ART start and at least one subsequent measure. We defined a gap as no visit for at least 18 months. Five states were defined: 'AHD on ART' (CD4+ cell count <200 cells/μl), 'Clinically Stable on ART' (CD4+ cell count ≥200 or if no CD4+ cell count, viral load <1000 copies/ml), 'Early Gap' (commencing ≤18 months from ART start), 'Late Gap' (commencing >18 months from ART start) and 'Death'. Among 32 452 PWH, men and those aged 15-25 years were more likely to progress to unfavourable states. Later years of ART start were associated with a lower probability of transitioning from AHD to clinically stable, increasing the risk of death following AHD. In stratified analyses, those starting ART with AHD in later years were more likely to re-engage in care with AHD following a gap and to die following AHD on ART. In more recent years, those with AHD on ART were more likely to die, and AHD at re-engagement in care increased. To further reduce HIV-related mortality, efforts to address the challenges facing these more vulnerable patients are needed.

Background Previous studies demonstrated that integrase strand transfer inhibitor (INSTI)-based two-drug regimens (2DRs) reliably maintain HIV suppression. Corresponding data in older people with HIV (PWH) remain limited. This retrospective study compared the real-world maintenance outcomes of INSTI-based 2DRs between PWH aged 50 or above (PWH &amp;gt;=50) and those below 50 years (PWH&amp;lt; 50). It was approved by the Research and Ethics Committee, Kowloon Central/Kowloon East Cluster, Hospital Authority (KC/KE-23-0195/ER-4). Methods PWH who switched from suppressive standard three-drug antiretroviral therapy (ART) to oral INSTI-based 2DRs at the HIV Clinic of the Queen Elizabeth Hospital, Hong Kong, China were identified through electronic records. The formulations of 2DRs and outcomes of those who reached 96 weeks after switch, before 1 March 2024 were retrieved. HIV suppression and virologic failure (VF) were defined as plasma HIV-1 RNA &amp;lt; 50 copies/mL and &amp;gt;200 copies/mL respectively. Results Since January 2014, 237 PWH switched to INSTI-based 2DRs. Their pre-switch characteristics are summarized in Table 1. On 29 February 2024, 96 weeks has lapsed from their 2DR switch dates in 87 PWH&amp;lt; 50 and 101 PWH &amp;gt;=50. Eight (4.3%) of them died due to causes unrelated to HIV. Twenty-two of them (11.7%) discontinued 2DRs during the 96-week period: six (6.9%) were PWH&amp;lt; 50 and 16 (15.8%) were PWH &amp;gt;=50, with reasons summarized in Table 2. By log-rank test, PWH &amp;gt;=50 trended toward significance for a higher risk of 2DR discontinuation when compared to PWH&amp;lt; 50 (p=0.058) (Figure 1). VF occurred in only 3 (1.6%) users, with similar rates between both groups (p=1). One PWH&amp;lt; 50 developed VF due to non-adherence, continued 2DR and achieved subsequent viral suppression. Another two had negative drug resistance mutation tests afterwards. 2DRs discontinuation due to non-VF causes was numerically higher in the PWH &amp;gt;=50 group without statistical significance (p=0.06).Figure 1.Kaplan-Meier estimator for the cumulative risk of 2DR discontinuation Conclusion In this real-world study comparing the maintenance outcomes of virally suppressed PWH who switched to INSTI-based 2DRs, occurrence of VF was uncommon in both older and younger PWH. However, discontinuation due to non-VF causes was more common in older PWH above 50 years old than those below, with a majority contributed by intolerance and non-HIV deaths. Disclosures Wilson Lam, n/a, Gilead: Advisor/Consultant|Gilead: Honoraria|GSK: Advisor/Consultant|GSK: Honoraria|Moderna: Honoraria|Pfizer: Conference sponsor

The 2022 global outbreak of mpox disproportionally affected people with HIV (PWH). We review the data on the presentation, treatment, and prevention of mpox in PWH. Most PWH with mpox had a mild and self-limiting illness, no different to people without HIV. A higher rate of rectal symptoms has been reported among PWH and those with advanced HIV disease were at higher risk of severe disease, hospitalization, and death. Treatment with antivirals was widely used in hospitalized patients without any randomized control trial data to support its use and without any data specifically in PWH. Use of smallpox vaccines to prevent mpox is safe in PWH regardless of CD4+ cell count. There is limited data on efficacy in those with lower CD4+ cell count and on long-term protective efficacy. PWH should be offered vaccination against mpox in line with national guidelines. PWH should be individually risk-assessed for severe mpox, based on their CD4+ cell count and co-morbidities and ideally recruited into treatment trials to build an evidence base on efficacy. HIV and other sexually transmitted infection testing should be offered to all people diagnosed with mpox.

Early diagnosis of HIV infection is important for the individual and for disease control. A consensus was recently reached among European countries on definitions of timing of presentation for care: 'Late presentation' refers to entering care with a CD4 count <350 cells/μL or an AIDS-defining event, regardless of the CD4 count. Presentation with 'advanced HIV disease' is a subset having a CD4 count <200 cells/μL and also includes all who have an AIDS-defining event regardless of CD4 count. This study examines timing of presentation in New Zealand from 2005 to 2010. Since 2005, information on the initial CD4 cell count has been requested on all people newly diagnosed with HIV infection through antibody testing in New Zealand. Excluded in this analysis were those previously diagnosed overseas or for an immigration medical. A CD4 cell count was provided for 606 (80.3%) of the 755 newly diagnosed adults. Overall, 50.0% were 'late presenters' and 32.0% had 'advanced HIV disease'. Compared with men who have sex with men (MSM), people heterosexually infected were more likely to present late. 'Late presentation' and presentation with 'advanced HIV disease' were significantly more common among older MSM. Māori and Pacific MSM were more likely to present with 'advanced HIV disease'. Compared with European MSM, the age-adjusted relative risks for Māori and Pacific MSM were 2.1 [95% confidence interval (CI) 1.4-3.2] and 2.5 (95% CI 1.2-5.0), respectively. The high proportion of people presenting late reflects inadequate levels of HIV testing. The lower proportion of late presentations among MSM compared with those heterosexually infected may be explained by a higher proportion of recent locally acquired infections together with different testing patterns.

How we treat Nocardia infections in transplant recipients and people with HIV.

HIV infection is a significant independent risk factor for severe coronavirus disease 2019 (COVID-19) disease and death. We summarize COVID-19 vaccine responses in people with HIV (PWH). A systematic literature review of studies from January 1, 2020, to March 31, 2022, of COVID-19 vaccine immunogenicity in PWH from multiple databases was performed. Twenty-eight studies from 12 countries were reviewed. While 22 (73%) studies reported high COVID-19 vaccine seroconversion rates in PWH, PWH with lower baseline CD4 counts, CD4/CD8 ratios, or higher baseline viral loads had lower seroconversion rates and immunologic titers. Data on vaccine-induced seroconversion in PWH are reassuring, but more research is needed to evaluate the durability of COVID-19 vaccine responses in PWH.

Purpose of ReviewWe reviewed the available literature on mpox in People with HIV (PWH). We highlight special considerations of mpox infection related to epidemiology, clinical presentation, diagnostic and treatment considerations, prevention, and public health messaging in PWH.Recent FindingsDuring the 2022 mpox outbreak, PWH were disproportionally impacted worldwide. Recent reports suggest that the disease presentation, management, and prognosis of these patients, especially those with advanced HIV disease, can widely differ from those without HIV-associated immunodeficiency.SummaryMpox can often be mild and resolve on its own in PWH with controlled viremia and higher CD4 counts. However, it can be severe, with necrotic skin lesions and protracted healing; anogenital, rectal, and other mucosal lesions; and disseminated organ systems involvement. Higher rates of healthcare utilization are seen in PWH. Supportive, symptomatic care and single or combination mpox-directed antiviral drugs are commonly used in PWH with severe mpox disease. Data from randomized clinical control trials on the efficacy of therapeutic and preventive tools against mpox among PWH are needed to better guide clinical decisions.

Burden of advanced HIV disease among antiretroviral therapy-experienced persons with HIV in Italy over the past 20 years.

While combination antiretroviral therapy (cART) has dramatically increased the life expectancy of people with HIV (PWH), nearly 50% develop HIV-associated neurocognitive disorders. This may be due to previously uncontrolled HIV viral replication, immune activation maintained by residual viral replication or activation from other sources, or cART-associated neurotoxicity. The aim of this study was to determine the effect of cART on cognition and neuroimaging biomarkers in PWH before and after initiation of cART compared with that in HIV-negative controls (HCs) and HIV elite controllers (ECs) who remain untreated. We recruited 3 groups of participants from the University of Rochester, McGovern Medical School, and SUNY Upstate Medical University: (1) ART treatment-naive PWH; (2) age-matched HCs; and (3) ECs. Participants underwent brain MRI and clinical and neuropsychological assessments at baseline, 1 year, and 2 years. PWH were also assessed 12 weeks after initiating cART. Volumetric analysis and fractal dimensionality (FD) were calculated for cortical and subcortical regions. Mixed effect regressions examined the effect of group and imaging variables on cognition. We enrolled 47 PWH, 58 HCs, and 10 ECs. At baseline, PWH had worse cognition and lower cortical volumes than HCs. Cognition improved after initiation of cART and remained stable over time. Greater cortical thickness was associated with better cognition at baseline; greater FD of parietal, temporal, and occipital lobes was associated with better cognition at baseline and longitudinally. At baseline, ECs had worse cognition, lower cortical thickness, and lower FD in all 4 lobes and caudate than PWH and HCs. Greater cortical thickness, hippocampal volumes, and FD of frontal, temporal, and occipital lobes were associated with better cognition longitudinally. Initiation of cART in PWH is associated with improvement in brain structure and cognition. However, significant differences persist over time when compared with HCs. Similar trends in ECs suggest that results are due to HIV infection rather than treatment. Stronger associations between cognition and FD suggest this imaging metric may be a more sensitive marker of neuronal injury than cortical thickness and volumetric measures.

Currently, AIDS or severe immunodeficiency remains as a challenge for people with HIV (PWHIV) and healthcare providers. Our purpose was to analyze the impact of advanced HIV disease (AHD) on mortality, life expectancy and health-related quality of life (HRQoL). We reviewed cohort studies and meta-analyses conducted in middle- and high-income countries. To analyze HRQoL, we selected studies that reported overall health and/or physical/mental health scores on a validated HRQoL instrument. AIDS diagnosis supposes a higher risk of mortality during the first six months, remaining higher for 48 months. It has been reported that cancer and cardiovascular disease persist as frequent causes of mortality in PWHIV, especially those with previous or current AHD. PWHIV who initiate combination antiretroviral therapy (cART) with CD4 < 200 cells/µL have significantly lower estimated life expectancy than those with higher counts. AHD is associated with lower HRQoL, and a worse physical health or mental health status. AIDS and non-AIDS defining events are significant predictors of a lower HRQoL, especially physical health status. AHD survivors are in risk of mortality and serious comorbidities, needing special clinical attention and preventive programs for associated comorbidities. Their specific needs should be reflected in HIV guidelines.

Doravirine (DOR) is an attractive new option both for ART-naïve people with HIV (PWH) and those with suppressed HIV-RNA who seek treatment simplification. We used real-world data to examine the pattern of use of DOR-containing regimens in these settings. All PWH enrolled in the Icona cohort after January 2020 who initiated a three-drug regimen (3-DR) with DOR or an integrase inhibitor (INSTI)-based regimen as first antiretroviral therapy (ART) or when switching ART, with HIV-RNA ≤50 copies/mL, were included. We used univariate and multivariable logistic regression models to identify demographic factors, immuno-virological and laboratory markers associated with the prescription of 3-DR DOR instead of INSTI-based regimens. A total of 5803 PWH were included; 1958 were in the first regimen (80 DOR, 1,878 INSTI) and 3854 (387 DOR, 3,458 INSTI) were ART-experienced virologically suppressed. In the first line, 3-DR DOR was more frequently started in people who inject drugs, and its use was also associated with higher body mass index, higher low-density lipoprotein levels, and less advanced HIV disease compared with PWH initiating an INSTI-based regimen. In the switch setting, older age, Italian origin, higher estimated glomerular filtration rate and aspartate aminotransferase levels were all strongly associated with 3-DR DOR use, as well as higher a CD4/CD8 ratio (only vs. 3-DR INSTI), while the association with lipid abnormalities was attenuated. Our analysis shows that among PWH in care in Italy, those with less advanced HIV disease but with other fragilities and potential risk factors for comorbidities are more likely to use DOR- than INSTI-based regimens, regardless of prior treatment history.

Advanced HIV disease at diagnosis among newly diagnosed people with HIV in rural eastern Uganda: a retrospective cohort study

Background:Despite expanded access to antiretroviral therapy (ART) and the rollout of the World Health Organization’s (WHO) ‘test-and-treat’ strategy, the proportion of people with HIV (PWH) presenting with advanced HIV disease (AHD) remains unchanged at approximately 30%. Fifty percent of persons with AHD report prior engagement to care. ART failure and insufficient retention in HIV care are major causes of AHD. People living with AHD are at high risk for opportunistic infections and death. In 2017, the WHO published guidelines for the management of AHD that included a comprehensive package of care for screening and prophylaxis of major opportunistic infections (OIs). In the interim, ART regimens have evolved: integrase inhibitors are first-line therapy globally, and the diagnostic landscape is evolving. The objective of this review is to highlight novel point-of-care (POC) diagnostics and treatment strategies that can facilitate OI screening and prophylaxis for persons with AHD.Methods:We reviewed the WHO guidelines for recommendations for persons with AHD. We summarized the scientific literature on current and emerging diagnostics, along with emerging treatment strategies for persons with AHD. We also highlight the key research and implementation gaps together with potential solutions.Results:While POC CD4 testing is being rolled out in order to identify persons with AHD, this alone is insufficient; implementation of the Visitect CD4 platform has been challenging given operational and test interpretation issues. Numerous non-sputum POC TB diagnostics are being evaluated, many with limited sensitivity. Though imperfect, these tests are designed to provide rapid results (within hours) and are relatively affordable for resource-poor settings. While novel POC diagnostics are being developed for cryptococcal infection, histoplasmosis and talaromycosis, implementation science studies are urgently needed to understand the clinical benefit of these tests in the routine care.Conclusions:Despite progress with HIV treatment and prevention, a persistent 20%–30% of PWH present to care with AHD. Unfortunately, these persons with AHD continue to carry the burden of HIV-related morbidity and mortality. Investment in the development of additional POC or near-bedside CD4 platforms is urgently needed. Implementation of POC diagnostics theoretically could improve HIV retention in care and thereby reduce mortality by overcoming delays in laboratory testing and providing patients and healthcare workers with timely same-day results. However, in real-world scenarios, people with AHD have multiple comorbidities and imperfect follow-up. Pragmatic clinical trials are needed to understand whether these POC diagnostics can facilitate timely diagnosis and treatment, thereby improving clinical outcomes such as HIV retention in care.

Background: Individuals with immune dysfunction, including people with HIV (PWH) or solid organ transplant recipients (SOT), might have worse outcomes from COVID-19. We compared odds of COVID-19 outcomes between patients with and without immune dysfunction.Methods: We evaluated data from the National COVID-19 Cohort Collaborative (N3C), a multicenter retrospective cohort of electronic medical record (EMR) data from across the United States, on. 1,446,913 adult patients with laboratory-confirmed SARS-CoV-2 infection. HIV, SOT, comorbidity, and HIV markers were identified from EMR data prior to SARS-CoV-2 infection. COVID-19 disease severity within 45 days of SARS-CoV-2 infection was classified into 5 categories: asymptomatic/mild disease with outpatient care; mild disease with emergency department (ED) visit; moderate disease requiring hospitalization; severe disease requiring ventilation or extracorporeal membrane oxygenation (ECMO); and death. We used multivariable, multinomial logistic regression models to compare odds of COVID-19 outcomes between patients with and without immune dysfunction.Findings: Compared to patients without immune dysfunction, PWH and SOT had a greater likelihood of having ED visits (adjusted odds ratio [aOR]: 1.28, 95% confidence interval [CI] 1.27-1.29; aOR: 2.61, CI: 2.58-2.65, respectively), requiring ventilation or ECMO (aOR: 1.43, CI: 1.43-1.43; aOR: 4.82, CI: 4.78-4.86, respectively), and death (aOR: 1.20, CI: 1.19-1.20; aOR: 3.38, CI: 3.35-3.41, respectively). Associations were independent of sociodemographic and comorbidity burden. Compared to PWH with CD4>500 cells/mm 3 , PWH with CD4Interpretation: Individuals with immune dysfunction have greater risk for severe COVID-19 outcomes. More advanced HIV disease (greater immunosuppression and HIV viremia) was associated with higher odds of severe COVID-19 outcomes. Appropriate prevention and treatment strategies should be investigated to reduce the higher morbidity and mortality associated with COVID-19 among PWH and SOT.Funding Information: NCATS U24 TR002306. ALO was supported by CTSA award No. UL1TR002649 from the National Center for Advancing Translational Sciences. Dr. Gregory Kirk is supported in part by NIAID K24AI118591. Dr. Rena C. Patel’s effort was supported by NIAID of the NIH (K23AI120855). Ms. Andersen received doctoral training support from the National Heart, Lung and Blood Institute Pharmacoepidemiology T32 Training Program (T32HL139426). Dr. Todd Brown is supported in part by NIAID K24AI120834.Declaration of Interests: None to declare. Ethics Approval Statement: The N3C Data Enclave is approved under the authority of the NIH Institutional Review Board (IRB, IRB00249128) with Johns Hopkins University School of Medicine as a central IRB for data transfer. Institutional IRB at each study site approved the study protocol or ceded to this single IRB. The current study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines.