Modern Antiretroviral Therapy Research Articles

Managing Modern Antiretroviral Therapy in the Intensive Care Unit: Overcoming Challenges for Critically Ill People With Human Immunodeficiency Virus.

People with human immunodeficiency virus (HIV) have a 50% excess risk for intensive care unit (ICU) admission, often for non-HIV-related conditions. Despite this, clear guidance for managing antiretroviral therapy (ART) in this setting is lacking. Selecting appropriate ART in the ICU is complex due to drug interactions, absorption issues, and dosing adjustments. Continuing ART in the ICU can be challenging due to organ dysfunction, drug interactions, and formulary limitations. However, with careful consideration, continuation is often feasible through dose adjustments or alternative administration methods. Temporary discontinuation of ART may be beneficial depending on the clinical scenario. Clinicians should actively seek resources and support to mitigate adverse events and drug interactions in critically ill people with HIV. Navigating challenges in the ICU can optimize ART and improve care and outcomes for critically ill people with HIV. This review aims to identify strategies for addressing the challenges associated with the use of modern ART in the ICU.

Incident HIV-Associated Wasting/Low Weight Is Associated with Nearly Doubled Mortality Risk in the Modern ART Era.

HIV-associated wasting (HIVAW) is an underappreciated AIDS-defining illness, despite highly effective antiretroviral therapy (ART). We (a) assessed the association between incident HIVAW/low weight and all-cause mortality and (b) described virologic outcomes after people with HIV (PWH) experienced HIVAW/low weight while on ART. In the Observational Pharmaco-Epidemiology Research & Analysis (OPERA®) cohort, PWH without prior HIVAW/low weight who were active in care in 2016-2020 were followed through the first of the following censoring events: death, loss to follow-up, or study end (October 31, 2021). HIVAW/low weight was a diagnosis of wasting or low body mass index (BMI)/underweight or a BMI measurement <20 kg/m2. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between time-dependent HIVAW/low weight and mortality were estimated with extended Cox regression models. Over a median follow-up of 45 months (interquartile range: 27, 65), there were 4,755 (8%) cases of HIVAW/low weight and 1,354 (2%) deaths among 62,314 PWH. PWH who experienced HIVAW/low weight had a significantly higher risk of death than those who did not (HR: 1.96; 95% CI: 1.68, 2.27) after adjusting for age, race, ethnicity, and changes in viral load (VL) and Veterans Aging Cohort Study Mortality Index scores over follow-up. Among 4,572 PWH on ART at HIVAW/low weight, 68% were suppressed (VL of <200 copies/mL); subsequent virologic failure was uncommon (7%). Among viremic PWH, 70% and 60% achieved suppression and undetectability (VL of <50 copies/mL), respectively, over follow-up. HIVAW remains a challenge for some PWH. Particular attention needs to be paid to HIVAW/low weight and virologic control to restore health and potentially reduce the risk of death.

Prevention and infection control of HIV infection and AIDS

Background: Although the global incidence of human immunodeficiency virus (HIV) has decreased significantly since modern antiretroviral therapy (ART), new HIV infections steadily occur, in the Republic of Korea. Based on the understanding of the risk factors for HIV infection, combined strategic behavioral and biomedical interventions should be implemented to reduce HIV infection. This paper reviews the strategies for the prevention of HIV infection.Current Concepts: While the consistent use of latex condoms is effective for the prevention of HIV transmission, consistent use of condoms is low among sexually active individuals. ART can be initiated, after exposure, to prevent HIV infection (post-exposure prophylaxis) after occupational or sexual exposure, injection drug use, and other nonoccupational exposures to HIV. There is a negligible risk of sexual transmission of HIV when the HIV-infected sexual partner has durably suppressed viral replication with ART. Antiretroviral agents have been shown to be highly effective when administered prophylactically to HIV-uninfected but at-risk individuals (preexposure prophylaxis). A high-risk group, such as men who have sex with men, is required to be included in health insurance care benefits for pre-exposure prophylaxis, in addition to the current partners of HIV-infected individuals, to ensure its efficacy.Discussion and Conclusion: HIV-related deaths are rapidly decreasing, but new HIV infections continue to occur. In an environment where a cure or the development of vaccines is unlikely, a multifaceted and proactive approach is required to minimize new HIV infections.

Efficacy of Lamivudine and Dolutegravir simplification therapy compared with triple therapy in Northeast Brazil (LAMDO Study)

Background: Modern antiretroviral therapy provides numerous effective and well-tolerated treatment options for individuals living with HIV. However, due to medication tolerability, toxicity, and cost optimization associated with the emergence of highly potent drugs, dual therapy has emerged as a new therapeutic alternative for patients with viral suppression. Observational studies worldwide are being conducted to assess the effectiveness of dual therapy in people living with HIV/AIDS. A real-world study is important to validate the findings obtained in controlled studies. Objective: Assess the effectiveness of dual therapy with lamivudine and dolutegravir compared to triple therapy in real-life settings. Methods: The study was conducted at São José Infectious Diseases Hospital, a tertiary referral hospital in the state of Ceará, northeast Brazil, for the treatment of PLWHA. Results: A total of 521 patients were taking double therapy with lamivudine plus dolutegravir and 450 patients were in triple therapy, mostly in the use of association with dolutegravir, were analyzed. Patients on dual therapy had a higher median age compared to those on triple therapy. A statistically significant higher viral suppression was observed in patients on dual therapy compared to triple therapy (p &lt; 0,001). Viral suppression on dual therapy under 200 copies was 97.2%. There was a statistically significant higher percentage of patients with higher CD4/CD8 ratio using triple therapy compared to dual therapy. Conclusion: The current study suggests a higher effective response to dual therapy compared to triple therapy in PLWHA in the real-world, supporting therapy simplification as a sustainable option to maintain virological suppression in patients experiencing toxicity or comorbidities.

Demographic and clinical characteristics of HIV-infected patients in Ekaterinburg

Aim. To study the demographic and clinical characteristics of patients with HIV infection during registration in the period from 2016 to 2020 in the city of Ekaterinburg.Materials and methods. The study was conducted on the basis of the Sverdlovsk Regional Center for the Prevention and Control of AIDS, Ekaterinburg. The data of 4222 patients with HIV infection registered in the period from 2016 to 2020 were analyzed retrospectively.Results and discussion. This study included a large number of patients with HIV infection registered for 5 years, which made it possible to comprehensively assess the portrait of a patient with HIV infection at the present stage, reflecting the demographic and clinical parameters of the cohort. A downward trend in the detection of HIV infection from 2016 to 2020 was noted; reducing the time from the detection of HIV infection to the start of dispensary observation and the appointment of antiretroviral therapy (ART); increase in the proportion of patients of older age groups. The maximum terms of registration were noted in the group of injecting drug users. The proportion of patients with comorbidities is 75–86%, which requires expanding the possibilities for choosing an ART regimen. Most of naïve patients receive «non-nucleoside reverse transcriptase inhibitor (NNRTI) and two nucleoside reverse transcriptase inhibitors (NIOT)» and «protease inhibitor (PI) and two NIOT», as a first line treatment, integrase inhibitors account for 6.9%.Conclusion. Despite the positive dynamics of indicators regarding the start of medical examination and treatment of patients with HIV infection in the period from 2016 to 2020, in order to reduce the time for involving patients, additional research and subsequent interventions are required in the identified gender, age and clinical risk groups, as well as ensuring accessibility modern ART and an increase in the proportion of fixed combinations of ARV drugs in it. The increase in the average age of patients, high polypharmacy and the need to reduce the risk of possible drug interactions argue in favor of the need to increase the proportion of integrase inhibitors.In order to determine the patient’s responsibility for monitoring and treating their disease, the Federal Law of March 30, 1995 No. 38-FL «On the Prevention of the Spread in the Russian Federation of a Disease Caused by the Human Immunodeficiency Virus (HIV)» needs to be brought into line with the Federal Law dated November 21, 2011 No. 323-FL «On the fundamentals of the health of citizens in the Russian Federation».

Alzheimer’s pathology in older people with HIV in South Africa: protocol of a case‐control study examining mechanisms of inflammation and infection

AbstractBackgroundDue to the success of modern antiretroviral therapy, people with HIV in South Africa are now living into older age. This provides an opportunity to study Alzheimer’s pathology in the context of chronic inflammation and infection. Here we present the protocol of a large case‐control study examining Alzheimer’s pathogenesis.Method250 South African people over 70 years of age will be recruited from a low‐income area of Cape Town with high HIV prevalence. Half will be living with HIV and half will be HIV‐negative and sociodemographically similar. Our primary outcome is CSF biomarkers of amyloidopathy. We have power to detect a 1.5‐fold increase in CSF amyloid positivity from 40% to 60%. Secondary analyses will compare clinical diagnoses of Alzheimer’s disease, and correlate indicators of HIV‐related neuroinflammation with degree of amyloidopathy.ResultProtocol presentation only. Funding is from the Race Against Dementia.ConclusionThis unique cohort will provide a valuable resource for mechanistic studies of Alzheimer’s pathogenesis.

Survival and prognostic factors of progressive multifocal leukoencephalopathy in people living with HIV in modern ART era.

The incidence of progressive multifocal leukoencephalopathy (PML) in people living with HIV (PLWH) is 2%-4%. Currently, there is no effective therapeutic strategy for the treatment of PML in PLWH, resulting in a mortality of up to 50%. This study aimed to identify risk factors of death and prognostic markers in people living with HIV with PML. A retrospective cohort study of AIDS-related PML individuals was conducted from January 1, 2015, to October 1, 2022, in Shanghai, China. PLWH who were diagnosed with PML for the first time were included. Kaplan-Meier curve and Cox regression were used to analyze the survival and its predictors. Levels of inflammatory markers and immune checkpoint inhibitors in blood and cerebrospinal fluid (CSF) were measured in the prestored samples using bead-based multiplex assay Indolamine 2,3-dioxygenase was determined using ELISA. Twenty of 71 subjects had initiated antiretroviral therapy (ART) before PML onset and no patients discontinued ART during this period. In total, 34 patients (47.9%) had opportunistic infections (OIs), the median CD4+ T cell count was 73.0 (33.0-149.0) cells/μL. The estimated probability of survival at six months was 78% (95% confidential intervals [CIs]:0.63-0.85). OIs, low CD4+ T cell count were associated with lower estimated six-month survival (hazard ratio 8.01, 95% CIs: 1.80-35.00, P=0.006 and 5.01, 95% CIs:1.57-16.03, p=0.007). Indolamine 2,3-dioxygenase activity in CSF of non-survivors group were higher than survivors group (p<0.05). The survival rate of AIDS-related PML in the modern ART era was higher than the survival rate a decade ago. Low CD4+T cell count, OIs, were all associated with death of individuals with AIDS-related PML. The role of IDO in AIDS-related PML warrant further investigation.

HIV Infection and 90-Day Stroke Outcomes in Uganda: A Prospective Observational Cohort Study.

Little is known about the impact of HIV infection on the clinical presentation and outcomes after stroke in the modern antiretroviral therapy (ART) era. We aimed to compare stroke characteristics and outcomes between persons with HIV (PWH) and without HIV (PWOH) presenting with stroke in Uganda. We conducted a matched cohort study at Mulago National Referral Hospital and Mbarara Regional Referral Hospital between January 2018 and November 2020. We enrolled consecutive PWH presenting with CT-confirmed acute or subacute stroke (symptom onset ≤14 days) and matched them by sex and stroke type to 2 consecutive available PWOH admitted to the same hospital. We obtained baseline clinical data and followed participants for 90 days from the day of clinical presentation. We compared stroke severity (defined by the NIH stroke scale [NIHSS]) and 90-day all-cause mortality and morbidity (using the modified Rankin Scale [mRS]) by HIV serostatus with and without adjustment for confounders. We enrolled 105 PWH and 157 PWOH with stroke. PWH were younger (mean [SD] age 49 [14] vs 59 [16] years, p < 0.001), and nearly 80% (82/105) were on ART for a median of 5 years and a median CD4 count of 214 cells/uL (interquartile range 140, 337). Compared with PWOH, PWH presented with a 3-point lower median NIHSS (16 vs 19, p = 0.011), a 20% lower proportion of all-cause mortality at 90 days (p = 0.001), and had less disability at 90 days (median mRS 4 vs 5, p = 0.004). Age and NIHSS-adjusted odds ratio of 90-day all-cause mortality in PWH compared with PWOH was 0.45 (95% CI 0.22-0.96, p = 0.037). In the modern ART era, PWH with acute stroke in Uganda present with modest stroke and are significantly less likely to die within 90 days than PWOH. This potentially reflects the protective effects of ART, enhanced health care access, and their younger age at stroke presentation.

Prediction of incidence of neurological disorders in HIV-infected persons in Taiwan: a nested case–control study

BackgroundNeurological disorders are still prevalent in HIV-infected people. We aimed to determine the prevalence of neurological disorders and identify their risk factors in HIV-infected persons in Taiwan.MethodsWe identified 30,101 HIV-infected people between 2002 and 2016 from the National Health Insurance Research Database in Taiwan, and analyzed the incidence of neurological disorders. We applied a retrospective, nested case–control study design. The individuals with (case group) and without (control group) a neurological disorder were then matched by age, sex and time. Factors associated with neurological disorders were analyzed using a conditional logistic regression model, and a nomogram was generated to estimate the risk of developing a neurological disorder.ResultsThe incidence of neurological disorders was 13.67 per 1000 person-years. The incidence remained stable during the observation period despite the use of early treatment and more tolerable modern anti-retroviral therapy. The conditional logistic regression model identified nine clinical factors and comorbidities that were associated with neurological disorders, namely age, substance use, traumatic brain injury, psychiatric illness, HIV-associated opportunistic infections, frequency of emergency department visits, cART adherence, urbanization, and monthly income. These factors were used to establish the nomogram.ConclusionNeurological disorders are still prevalent in HIV-infected people in Taiwan. To efficiently identify those at risk, we established a nomogram with nine risk factors. This nomogram could prompt clinicians to initiate further evaluations and management of neurological disorders in this population.

Characterization and outcomes of difficult-to-treat patients starting modern first-line ART regimens: Data from the ICONA cohort

ObjectivesTreatment failures to modern antiretroviral therapy (ART) raise concerns, as they could reduce future options. Evaluations of occurrence of multiple failures to modern ART are missing and their significance in the long run is unclear. MethodsPeople with HIV (PWH) in the ICONA cohort who started a modern first-line ART were defined as ‘difficult to treat’ (DTT) if they experienced ≥1 among: i) ≥2 VF (2 viral loads, VL>200 copies/mL or 1 VL>1000 copies/mL) with or without ART change; ii) ≥2 treatment discontinuations (TD) due to toxicity/intolerance/failure; iii) ≥1 VF followed by ART change plus ≥1 TD due to toxicity/intolerance/failure. A subgroup of the DTT participants were matched to PWH that, after the same time, were non-DTT. Treatment response, analysing VF, TD, treatment failure, AIDS/death, and SNAE (Serious non-AIDS event)/death, were compared. Survival analysis by KM curves and Cox regression models were employed. ResultsAmong 8061 PWH, 320 (4%) became DTT. Estimates of becoming DTT was 6.5% (95% CI: 5.8–7.4%) by 6 years. DTT PWH were significantly older, with a higher prevalence of AIDS and lower CD4+ at nadir than the non-DTT. In the prospective analysis, DTT demonstrated a higher unadjusted risk for all the outcomes. Once controlled for confounders, significant associations were confirmed for VF (aHR 2.23, 1.33–3.73), treatment failure (aHR 1.70, 1.03–2.78), and SNAE/death (aHR 2.79, 1.18–6.61). ConclusionA total of 6.5% of PWH satisfied our definition of DTT by 6 years from ART starting. This appears to be a more fragile group who may have higher risk of failure.

Common antiretroviral combinations are associated with somatic depressive symptoms in women with HIV.

While modern antiretroviral therapy (ART) is highly effective and safe, depressive symptoms have been associated with certain ART drugs. We examined the association between common ART regimens and depressive symptoms in women with HIV (WWH) with a focus on somatic vs. nonsomatic symptoms. Analysis of longitudinal data from the Women's Interagency HIV Study. Participants were classified into three groups based on the frequency of positive depression screening (CES-D ≥16): chronic depression (≥50% of visits since study enrollment), infrequent depression (<50% of visits), and never depressed (no visits). Novel Bayesian machine learning methods building upon a subset-tree kernel approach were developed to estimate the combined effects of ART regimens on depressive symptoms in each group after covariate adjustment. The analysis included 1538 WWH who participated in 12 924 (mean = 8.4) visits. The mean age was 49.9 years, 72% were Black, and 14% Hispanic. In the chronic depression group, combinations including tenofovir alafenamide and cobicistat-boosted elvitegravir and/or darunavir were associated with greater somatic symptoms of depression, whereas those combinations containing tenofovir disoproxil fumarate and efavirenz or rilpivirine were associated with less somatic depressive symptoms. ART was not associated with somatic symptoms in the infrequent depression or never depressed groups. ART regimens were not associated with nonsomatic symptoms in any group. Specific ART combinations are associated with somatic depressive symptoms in WWH with chronic depression. Future studies should consider specific depressive symptoms domains as well as complete drug combinations when assessing the relationship between ART and depression.

Viral protein R (Vpr)-induced neuroinflammation and its potential contribution to neuronal dysfunction: a scoping review

HIV-associated neurocognitive disorders (HAND) are the result of the activity of HIV-1 within the central nervous system (CNS). While the introduction of antiretroviral therapy (ART) has significantly reduced the occurrence of severe cases of HAND, milder cases still persist. The persistence of HAND in the modern ART era has been linked to a chronic dysregulated inflammatory profile. There is increasing evidence suggesting a potential role of Viral protein R (Vpr) in dysregulating the neuroinflammatory processes in people living with HIV (PLHIV), which may contribute to the development of HAND. Since the role of Vpr in neuroinflammatory mechanisms has not been clearly defined, we conducted a scoping review of fundamental research studies on this topic. The review aimed to assess the size and scope of available research literature on this topic and provide commentary on whether Vpr contributes to neuroinflammation, as highlighted in fundamental studies. Based on the specified selection criteria, 10 studies (6 of which were cell culture-based and 4 that included both animal and cell culture experiments) were eligible for inclusion. The main findings were that (1) Vpr can increase neuroinflammatory markers, with studies consistently reporting higher levels of TNF-α and IL-8, (2) Vpr induces (neuro)inflammation via specific pathways, including the PI3K/AKT, p38-MAPk, JNK-SAPK and Sur1-Trpm4 channels in astrocytes and the p38 and JNK-SAPK in myeloid cells, and (3) Vpr-specific protein amino acid signatures (73R, 77R and 80A) may play an important role in exacerbating neuroinflammation and the neuropathophysiology of HAND. Therefore, Vpr should be investigated for its potential contribution to neuroinflammation in the development of HAND.

Cerebrospinal fluid HIV-1 escape in patients with neurocognitive symptoms: pooled data from a neuro-HIV platform and the NAMACO study.

Despite modern antiretroviral therapy, HIV-1 RNA escape into the cerebrospinal fluid (CSF) may occur. We examined the prevalence of and factors associated with CSF HIV-1 escape among people living with HIV (PLWH) in Switzerland. The Neurocognitive Assessment in the Metabolic and Aging Cohort (NAMACO) study is an ongoing, prospective, longitudinal, multicenter study within the Swiss HIV Cohort Study. The neuro-HIV platform is a multi-disciplinary, single-day outpatient consultation at Lausanne University Hospital. We pooled data from the NAMACO study and the neuro-HIV platform participants who underwent lumbar puncture (LP) between 2011 and 2019. Both patient groups had neurocognitive symptoms. CSF HIV-1 escape was defined as the presence of quantifiable CSF HIV-1 RNA when plasma HIV-1 RNA was suppressed or CSF HIV-1 RNA greater than plasma HIV-1 RNA when the latter was detectable. Of 1166 PLWH assessed, 288 underwent LP. CSF HIV-1 escape was observed in 25 PLWH (8.7%) of whom 19 (76%) had supressed plasma HIV-1 RNA. Characteristics of PLWH were comparable whether they had CSF HIV-1 escape or not, including comorbidities, time since HIV diagnosis (15 vs 16 years, p=0.9), median CD4 nadir (158.5/mm3 vs 171/mm3, p=0.6), antiretroviral CSF-Penetration-Effectiveness score (7 vs 7 points, p=0.8), neurocognitive diagnosis based on Frascati criteria and radiological findings. In this large pooled sample of PLWH with neurocognitive symptoms, CSF HIV-1 escape occurred in 8.7% of PLWH. PLWH with CSF HIV-1 escape presented no distinctive clinical or paraclinical characteristics. We conclude that LP is unavoidable in confirming CSF HIV-1 escape.

Pilot imaging of the colony stimulating factor 1 receptor in the brains of virally-suppressed individuals with HIV.

Neuroimmune activation is a putative driver of cognitive impairment in people with HIV (PWH), even in the age of modern antiretroviral therapy. Nevertheless, imaging of the microglial marker, the 18kDa translocator protein (TSPO), with positron emission tomography (PET) in treated PWH has yielded inconclusive findings. One potential reason for the varied TSPO results is a lack of cell-type specificity of the TSPO target. [11C]CPPC is a radiotracer for use with PET to image the colony stimulating factor 1 receptor (CSF1R). The CSF1R is expressed on microglia and central nervous system macrophages, with little expression on other cell types. We used [11C]CPPC PET in virally-suppressed- (VS)-PWH and HIV-uninfected individuals to estimate the effect sizes of higher CSF1R in the brains of VS-PWH. Sixteen VS-PWH and 15 HIV-uninfected individuals completed [11C]CPPC PET. [11C]CPPC binding (VT) in nine regions was estimated using a one-tissue compartmental model with a metabolite-corrected arterial input function, and compared between groups. Regional [11C]CPPC VT did not significantly differ between groups after age- and sex- adjustment (unstandardized beta coefficient [B] = 1.84, standard error [SE] = 1.18, P = 0.13). The effect size was moderate (Cohen's d = 0.56, 95%confidence interval [CI] -0.16, 1.28), with strongest trend of higher VT in VS-PWH in striatum and parietal cortex (each P = 0.04; Cohen's d = 0.71 and 0.72 respectively). Group difference in [11C]CPPC VT was not observed between VS-PWH and HIV-uninfected individuals in this pilot, although the observed effect sizes suggest the study was underpowered to detect regional group differences in binding.

A Camptothetin Analog, Topotecan, Promotes HIV Latency via Interference with HIV Transcription and RNA Splicing.

Low level HIV transcription during modern antiretroviral therapy (ART) in persons with HIV is linked to residual inflammation and associated diseases, like cardiovascular disease and cancer. The "block and lock" approach to hold HIV in a state of deep latency may help decrease residual inflammation in a person with HIV on ART and thus improve health. A camptothecin analog topotecan (TPT) was previously implicated as an inhibitor of active HIV replication. Using an in vitro primary T cell model of HIV latency, we demonstrated that (i) TPT reduces HIV transcriptional activity in latently infected cells; (ii) downregulation of HIV RNA by TPT cannot be reversed by latency reversing agents; (iii) several primary and secondary mechanism of action of TPT may be involved in control of HIV replication; (iv) regulation of HIV RNA by TPT is dependent on splicing complexity; (v) increase in proportion of unspliced HIV transcripts was facilitated by intron retention and upregulation of splicing factors, specifically SRSF6, by TPT. Although high TPT dosing (10 μM) was needed to achieve the observed effects, viability of primary CD4+ T cells was not greatly affected. Because toxicity can be observed with TPT in persons with cancer, TPT is unlikely to be used as an anti-HIV agent in clinic, but our study provides proof that camptothetin has "block and lock" activity. Other camptothetin analogs, which are less toxic than TPT, should be designed and tested as HIV "block and lock" agents. IMPORTANCE HIV survives in a state of very low activity, called latency, for long periods in persons with HIV on antiretroviral therapy. This low activity of HIV is linked to residual inflammation and associated diseases, such as heart disease and cancer. New strategies are being explored to further silence the HIV provirus and suppress residual inflammation. This study provides strong evidence that the camptothetin analog, Topotecan, can reduce residual activity of HIV in an experimental model of HIV latency. While Topotecan itself is likely not suitable for use in the clinic due to its toxicity, other camptothetin analogs should be designed and investigated as "block and lock" agents.

Roadmap for Achieving Universal Antiretroviral Treatment.

Modern antiretroviral therapy safely, potently, and durably suppresses human immunodeficiency virus (HIV) that, if left untreated, predictably causes acquired immunodeficiency syndrome (AIDS), which has been responsible for tens of millions of deaths globally since it was described in 1981. In one of the most extraordinary medical success stories in modern times, a combination of pioneering basic science, innovative drug development, and ambitious public health programming resulted in access to lifesaving, safe drugs, taken as an oral tablet daily, for most of the world. However, substantial challenges remain in the fields of prevention, timely access to diagnosis, and treatment, especially in pediatric and adolescent patients. As HIV-positive adults age, treating their comorbidities will require understanding the course of different chronic diseases complicated by HIV-related and antiretroviral toxicities and finding potential treatments. Finally, new long-acting antiretrovirals on the horizon promise exciting new options in both the prevention and treatment fields.

CD4+ T lymphocyte recovery in the modern antiretroviral therapy era: Toward a new threshold for defining immunological non-responders

IntroductionDespite the high level of efficacy of modern antiretroviral therapy (ART) in reducing HIV viremia and the control of viral replication, some people living with HIV (PLWH) do not recover their CD4+ T cell count.MethodsTo evaluate the frequency and predictive factors of discordant immune responses, we performed a retrospective cohort study of 324 antiretroviral-naïve PLWH who initiated first-line ART between 2008 and 2018 and maintained HIV RNA &amp;lt; 50 copies/ml during 36 months of follow-up. PLWH were defined as immunological non-responders (INRs) when CD4+ T cell count was &amp;lt; 20% compared with baseline (INR20%), or &amp;lt; 500 cells/mm3 (INR500) or &amp;lt; 200 cells/mm3 (INR200) at 36 months.ResultsThe prevalence of INR20%, INR500, and INR200 was 12.5%, 34.6%, and 1.5%, respectively. After adjustment for possible confounders, CD4 nadir showed a significant association with all INR definitions, with lower values predicting INR500 (aOR 0.98, 95% CI 0.98–0.99, p &amp;lt; 0.001) and INR200 (aOR 0.98, 95% CI 0.95–1.01, p = 0.096). Moreover, a higher baseline CD4/CD8 ratio was inversely related to the probability of being INR500 (OR 0.03, 95% CI 0.01–0.12, p &amp;lt; 0.001) and INR200 (OR 0.002, 95% CI 18–7–67.72, p = 0.255). By contrast, INR20% had a higher CD4 nadir and CD4/CD8 ratio than other INRs, suggesting the identification of an heterogenous population with such definition.DiscussionThe present study highlights how INR200 has become rare in the contemporary ART era, and about one-third of PLWH meet the criteria for INR500. Overcoming the threshold of 500 CD4/mm3 could be an appropriate definition of immune response, in contrast with the older definitions of INR200 and INR20%. Early diagnosis and rapid treatment initiation, before CD4 counts and the CD4/CD8 ratio begin to decline, are critical for achieving an optimal immune response.

Palliative care considerations for the older adults with HIV/AIDS: a clinical practice review.

Human immunodeficiency virus (HIV) has historically been viewed as a terminal condition affecting younger populations, however, with advancements in antiretroviral therapy (ART) and better healthcare provisions, people with HIV are now living longer than ever before. This shift has highlighted the need to readdress the end-of-life care needs of patients aging with HIV. People aging with HIV face a double burden. Aging itself comes with an array of health challenges, including cognitive decline, frailty, and increased susceptibility to chronic illnesses. Despite effective management with ART, HIV is associated with ongoing inflammation, and may accelerate aging processes, increasing the risk of certain cancers and comorbidities, as well as an increased risk of cardiovascular disease. The stigma surrounding HIV, though diminished over the years, still lingers. People living with HIV have experienced decades of intersecting stigmatized identities in the context of social isolation, leading to potential psychological challenges like depression, anxiety, and loneliness, all of which may be amplified by aging. Addressing these emotional and social needs is as crucial as managing their physical health. The integration of primary palliative care into geriatric practice is crucial, as it improves the quality of life for older patients with chronic illnesses, lifelimiting conditions. This is particularly relevant for aging individuals with HIV, who often face complex medical needs and multiple comorbidities. Primary palliative care is the basic, integrated palliative care support provided by non-specialists as part of routine care, while specialist palliative care involves more complex and specialized support from a team with specific training in palliative care. Incorporating palliative care principles enables geriatric healthcare providers to address these comprehensive needs more effectively. This approach encompasses not only physical symptom management but also the emotional well-being of patients. It aids in advanced care planning and decision-making that resonate with the patients' values and goals. Ultimately, this integrated approach leads to improved patient outcomes and a higher quality of care. This review delves into the unique considerations and challenges of providing palliative care to people aging with HIV, recognizing the interplay of age and HIV in the era of modern ART.

441. Association between Incident HIV-Associated Wasting/Low Weight and All-Cause Mortality in the OPERA® Cohort

Abstract Background HIV-associated wasting (i.e., progressive, involuntary weight loss with both fat and lean tissue loss; HIVAW) is an under-appreciated AIDS-defining illness; the 2012-2018 period prevalence was reported as 18% in a recent claims study in the United States. We aimed to assess the association between incident HIVAW/low weight and all-cause mortality in the era of modern combination antiretroviral therapy (ART). Methods In the Observational Pharmaco-Epidemiology Research &amp; Analysis (OPERA®) cohort, PWH without (a) any prior HIVAW/low weight, (b) malignancy within 3 years, and (c) opportunistic infection within 1 year who were active in care between 2016 and 2020 were followed through death, loss to follow-up, or study end (31OCT2021). HIVAW/low weight included a wasting or low BMI/underweight diagnosis (ICD codes, title search) or BMI &amp;lt; 20 kg/m2. Hazard ratios (HR) and 95% confidence intervals (CI) for the association between time-dependent incident HIVAW/low weight (exposure) and all-cause mortality (outcome) were estimated with extended Cox regression models. The adjusted model included age at baseline, race, ethnicity, and time-dependent covariates (log10 viral load, Veterans Aging Cohort Study [VACS] Mortality Index score). Viral load and VACS score were included as surrogate markers for ART use and comorbidities, respectively. Linear and quadratic terms of continuous variables were included. Results Of 67,119 PWH without prior HIVAW/low weight in OPERA®, 62,314 (93%) PWH had non-missing covariate data and were included in the models; baseline characteristics did not differ between the full and model study populations (Table 1). Over a median follow-up of 45 months (interquartile range: 27, 65), there were 4,755 (8%) cases of incident HIVAW/low weight and 1,354 (2%) deaths. In the adjusted model, PWH who experienced incident HIVAW/low weight had a significantly increased risk of death over follow-up than those who did not experience HIVAW/low weight (HR: 1.96; 95% CI: 1.68, 2.27) (Table 2). Conclusion In this analysis of 62,314 PWH in care, incident HIVAW/low weight was associated with twice the risk for all-cause mortality in the modern ART era. Particular attention needs to be paid to HIVAW/low weight among PWH to restore health and potentially reduce the risk of death. Disclosures Rachel P. Weber, PhD, AIDS Healthcare Foundation: Client of my employer|EMD Serono: Client of my employer|Gilead Sciences: Client of my employer|Janssen: Client of my employer|Merck &amp; Co.: Client of my employer|TheraTechnologies: Client of my employer|ViiV Healthcare: Client of my employer Laurence Brunet, PhD, AIDS Healthcare Foundation: Client of my employer|EMD Serono: Client of my employer|Gilead Sciences: Client of my employer|Janssen: Client of my employer|Merck &amp; Co: Client of my employer|TheraTechnologies: Client of my employer|ViiV Healthcare: Client of my employer Javeed Siddiqui, MD, MPH, Abbvie: Advisor/Consultant|Abbvie: Honoraria|Cumberland pharmaceuticals: Advisor/Consultant|Cumberland pharmaceuticals: Honoraria|EMD serono: Advisor/Consultant|EMD serono: Honoraria|Merck: Advisor/Consultant|Merck: Honoraria Javeed Siddiqui, MD, MPH, Abbvie: Advisor/Consultant|Abbvie: Honoraria|Cumberland pharmaceuticals: Advisor/Consultant|Cumberland pharmaceuticals: Honoraria|EMD serono: Advisor/Consultant|EMD serono: Honoraria|Merck: Advisor/Consultant|Merck: Honoraria Michael Harbour, MD, MPH, FACP, EMD Serono: Employee Amy L. Phillips, PharmD, EMD Serono, Inc.: Employment Brooke Hayward, SM, MBA, EMD Serono, Inc.: Employee Jennifer S. Fusco, BS, AIDS Healthcare Foundation: Client of my employer|EMD Serono: Client of my employer|Gilead Sciences: Client of my employer|Janssen: Client of my employer|Merck &amp; Co.: Client of my employer|TheraTechnologies: Client of my employer|ViiV Healthcare: Client of my employer Ricky K. Hsu, MD, Gilead: Honoraria|Merck: Honoraria|ViiV: Advisor/Consultant|ViiV: Grant/Research Support|ViiV: Honoraria Gregory P. Fusco, MD, MPH, AIDS Healthcare Foundation: Client of employer|EMD: Grant/Research Support|Gilead Sciences: Client of employer|Janssen: Client of employer|Merck &amp; Co.: Client of employer|Theratechnologies: Client of employer|ViiV Healthcare: Client of employer.

446. Hyperlactatemia and Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTI): Still present even with modern antiretroviral therapy (ART)

Abstract Background Hyperlactatemia and lactic acidosis represent a rare but dangerous manifestation of mitochondrial toxicity associated with NRTIs. Although mitochondrial toxicity has been linked to the NRTI class, it is more prevalent with older agents such as zidovudine (AZT), didanosine (ddI) and stavudine (d4t). Methods Prompted by the diagnosis of symptomatic hyperlactatemia in 4 people with HIV on newer NRTIs between September 2019 and December 2021, we present a single-center case series to illustrate its subtle presentation and management. Hyperlactatemia was defined as a serum lactate of 1.6-4 mmol/L and lactic acidosis was defined as a serum lactate of &amp;gt; 4mmol/L. Results 75% of the patients were male, the mean age was 57.8 years, and 100% were Caucasian. 75% (3/4) were either overweight or obese (body mass index &amp;gt; 25 kg/m2). 75% had a CD4 lymphocyte count &amp;lt; 200 cells/mm3 at the time of human immunodeficiency virus (HIV) diagnosis and 50% had the diagnosis for &amp;gt;10 years. The most common symptom reported was non-specific fatigue (100%), followed by widespread myalgias (75%). 1 patient reported severe peripheral neuropathy affecting activities of daily living and 1 patient reported palpitations and night sweats. The mean duration of symptoms prior to reporting was 27.5 months. At the time of diagnosis of symptomatic hyperlactatemia, 75% had a CD4 lymphocyte count &amp;gt; 200 cells/mm3, the mean serum lactate was 2.7 mmol/L (1.9 mmol/L - 3.9 mmol/L), 50% were on abacavir (ABC) and lamivudine (3TC), and 50% were on tenofovir alafenamide (TAF) and emtricitabine (FTC). After stopping ART for 2 weeks, mean serum lactate decreased to 0.6 mmol/L (0.4 mmol/L – 1.1 mmol/L). 100% reported an improvement in quality of life after NRTI cessation and were managed with an NRTI-sparing regimen. Clinical characteristics are noted in Table 1. Conclusion This case series highlights the insidious nature of symptoms related to NRTI-associated mitochondrial toxicity including hyperlactatemia. Management strategies are not well defined for hyperlactatemia; however, NRTI-sparing regimens may offer improvement in quality of life. Despite improved tolerability of modern ART, clinicians should be aware of and monitor for symptoms of this potentially life-threatening side effect. Disclosures Carlos Malvestutto, MD MPH, Gilead Sciences: Advisor/Consultant|Viiv Healthcare: Advisor/Consultant.