Combination Antiretroviral Treatment Research Articles

Multimodal Approach to Neurocognitive Function in People Living with HIV in the cART Era: A Comprehensive Review.

Combination antiretroviral treatment (cART) has revolutionized the management of human immunodeficiency virus (HIV) and has markedly improved the disease burden and life expectancy of people living with HIV. HIV enters the central nervous system (CNS) early in the course of infection, establishes latency, and produces a pro-inflammatory milieu that may affect cognitive functions, even in the cART era. Whereas severe forms of neurocognitive impairment (NCI) such as HIV-associated dementia have declined over the last decades, milder forms have become more prevalent, are commonly multifactorial, and are associated with comorbidity burdens, mental health, cART neurotoxicity, and ageing. Since 2007, the Frascati criteria have been used to characterize and classify HIV-associated neurocognitive disorders (HAND) into three stages, namely asymptomatic neurocognitive impairment (ANI), mild neurocognitive disorder (MND), and HIV-associated dementia (HAD). These criteria are based on a comprehensive neuropsychological assessment that presupposes the availability of validated, demographically adjusted, and normative population data. Novel neuroimaging modalities and biomarkers have been proposed in order to complement NCI assessments, elucidate neuropathogenic mechanisms, and support HIV-associated NCI diagnosis, monitoring, and prognosis. By integrating neuropsychological assessments with biomarkers and neuroimaging into a holistic care approach, clinicians can enhance diagnostic accuracy, prognosis, and patient outcomes. This review interrogates the value of these modes of assessment and proposes a unified approach to NCI diagnosis.

Acceptability and tolerability of long-acting injectable cabotegravir or rilpivirine in the first cohort of virologically suppressed adolescents living with HIV (IMPAACT 2017/MOCHA): a secondary analysis of a phase 1/2, multicentre, open-label, non-comparative dose-finding study

Long-acting injectable cabotegravir and rilpivirine have demonstrated safety, acceptability, and efficacy in adults living with HIV-1. The IMPAACT 2017 study (MOCHA study) was the first to use these injectable formulations in adolescents (aged 12-17 years) living with HIV-1. Herein, we report acceptability and tolerability outcomes in cohort 1 of the study. In this a secondary analysis of a phase 1/2, multicentre, open-label, non-comparative dose-finding study, with continuation of pre-study oral combination antiretroviral treatment (ART), 55 adolescents living with HIV-1 were enrolled to receive sequential doses of either long-acting cabotegravir or rilpivirine and 52 received at least two injections. Participants had a body weight greater than 35 kg and BMI less than 31·5 kg/m2 and had been on stable ART for at least 90 consecutive days with an HIV-1 viral load of less than 50 copies per mL at a participating IMPAACT study site. Participants had to be willing to continue their pre-study ART during cohort 1. The primary objectives of the study were to confirm doses for oral and injectable cabotegravir and for injectable rilpivirine in adolescents living with HIV. This analysis of participant-reported outcomes included a face scale assessment of pain at each injection and a Pediatric Quality of Life Inventory (PedsQL) at baseline and week 16 for participants in the USA, South Africa, Botswana, and Thailand. A subset of 11 adolescents and 11 parents or caregivers in the USA underwent in-depth interviews after receipt of one or two injections. This trial is registered at ClinicalTrials.gov, NCT03497676. Between March 19, 2019, and Nov 25, 2021, 55 participants were enrolled into cohort 1. Using the six-point face scale, 43 (83%) of participants at week 4 and 38 (73%) at week 8 reported that the injection caused "no hurt" or "hurts little bit", while only a single (2%) participant for each week rated the pain as one of the two highest pain levels. Quality of life was not diminished by the addition of one injectable antiretroviral. In-depth interviews revealed that parents and caregivers in the USA frequently had more hesitancy than adolescents about use of long-acting formulations, but parental acceptance was higher after their children received injections. High acceptability and tolerability of long-acting cabotegravir or rilpivirine injections suggests that these are likely to be favoured treatment options for some adolescents living with HIV. National Institutes of Health and ViiV Healthcare.

Impact of Combination Antiretroviral Treatment on Liver Metabolic Health in HIV-Infected Persons.

In the last three decades, there has been a considerable improvement in human immunodeficiency virus (HIV) therapy. Acquired immunodeficiency syndrome (AIDS) is no longer a common cause of death for people living with HIV (PLWH) in developed countries, and co-infections with hepatitis viruses can be effectively managed. However, metabolic syndrome and metabolic dysfunction-associated steatotic liver disease (MASLD) are emerging threats these days, especially as the HIV-positive population gets older. The factors for MASLD development in PLWH are numerous, including non-specific (common for both HIV-positive and negative) and virus-specific. We focus on what is known for both, and in particular, on the burden of antiretroviral therapy (ART) for metabolic health and liver damage. We review data on contemporary drugs, including different groups and some particular agents in those groups. Among current ART regimens, the switch from tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide fumarate (TAF) and particularly its combination with integrase inhibitors (INSTIs) appear to have the most significant impact on metabolic disturbances by increasing insulin resistance, which over the years promotes the evolution of the cascade leading to metabolic syndrome (MetS), MASLD, and eventually metabolic dysfunction-associated steatohepatitis (MASH).

Frailty in Aging HIV-Positive Individuals: An Evolving Healthcare Landscape.

The life expectancy of people living with HIV (PLWH) has greatly increased due to advancements in combination antiretroviral treatment (cART). However, this longer life has also increased the prevalence of age-related comorbidities, such as frailty, which now manifest sooner in this group. Frailty, a term coined by the insurance industry, has been broadened to include physical, cognitive, and emotional elements and has been recognized as a critical predictor of negative health outcomes. With the median age of PLWH now in the mid-50s, treating frailty is critical given its link to chronic diseases, cognitive decline, and even death. Frailty assessment tools, such as the Frailty Phenotype (FP) and the Frailty Index (FI), are used to identify vulnerable people. Understanding the pathophysiology of frailty in PLWH indicates the role of immunological mechanisms. Frailty screening and management in this group have progressed, with specialized clinics and programs concentrating on multidisciplinary care. Potential pharmacotherapeutic solutions, as well as novel e-health programs and sensors, are in the future of frailty treatment, but it is critical to ensure that frailty evaluation is not exploited to perpetuate ageist healthcare practices. This narrative review investigates the changing healthcare environment for older people living with HIV (OPLWH), notably in high-income countries. It emphasizes the significance of identifying and managing frailty as a crucial feature of OPLWH's holistic care and well-being.

Immune checkpoint inhibitors as potential therapy for reverting T-cell exhaustion and reverting HIV latency in people living with HIV.

The immune system of people living with HIV (PLWH) is persistently exposed to antigens leading to systemic inflammation despite combination antiretroviral treatment (cART). This inflammatory milieu promotes T-cell activation and exhaustion. Furthermore, it produces diminished effector functions including loss of cytokine production, cytotoxicity, and proliferation, leading to disease progression. Exhausted T cells show overexpression of immune checkpoint molecules (ICs) on the cell surface, including programmed cell death protein 1 (PD-1), cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT), and lymphocyte activation gene-3 (LAG-3). The ICs also play a crucial role in T-cell exhaustion by reducing the immune response to cancer antigens. Immunotherapy based on immune checkpoint inhibitors (ICIs) has changed the management of a diversity of cancers. Additionally, the interest in exploring this approach in the setting of HIV infection has increased, including AIDS-defining cancers and non-AIDS-defining cancers in PLWH. To date, research on this topic suggests that ICI-based therapies in PLWH could be a safe and effective approach. In this review, we provide an overview of the current literature on the potential role of ICI-based immunotherapy not only in cancer remission in PLWH but also as a therapeutic intervention to restore immune response against HIV, revert HIV latency, and attain a functional cure for HIV infection.

Dolutegravir-induced growth and lifespan effects in Caenorhabditis elegans

BackgroundIntegrase strand transfer inhibitor (INSTIs)-based combination antiretroviral treatment in people living with HIV (PLWH) has been reportedly correlated with several adverse effects, such as weight gain, fetal defects or psychiatric disorders.MethodsTo comprehensively understand the adverse effect of INSTIs, our study utilized Caenorhabditis Elegans (C. elegans) as a model to investigate how dolutegravir (DTG) affected its life cycle, growth, reproduction and lifespan.ResultsOur results indicated that DTG enhanced body growth at the early stage of treatment, but no change was detected for long-term treatment. The treatment also influenced the reproductive system, decreased egg-hatching but had no effect on egg-laying. Besides, DTG resulted in lifespan reduction, which is dependent on increased levels of reactive oxidative species (ROS) accumulation. Treatment with N-acetyl-cysteine (NAC) in worms restrained intracellular ROS accumulation and improved DTG-induced lifespan reduction.ConclusionsOur study demonstrates for the first time the effect of DTG treatment on life cycle. DTG-induced adverse effects are potentially associated with intracellular ROS accumulation. Quenching ROS accumulation might provide a novel strategy for dealing with the adverse effects of INSTIs.

Clinical Utility of Soluble CD163 and its Diagnostic and Prognostic Value in a Variety of Neurological Disorders.

Nowadays, many people suffer from Neurological Diseases (NDs), particularly neurodegenerative diseases. Hence, there is an urgent need to discover new and more effective diagnostic and prognostic biomarkers as well as therapeutic strategies for the treatment of NDs. In this context, detecting biomarkers can provide helpful information on various levels of NDs. Up to now, there has been a lot of progress in recognizing these diseases, but they are not completely clear yet. NDs are associated with inflammatory conditions and there are several differences in NDs' immune biomarkers compared to normal conditions. Among these biomarkers, soluble CD163 (sCD163) levels (as a new biomarker) increase in biofluids, relating to the activation of macrophage/microglia and inflammation levels in NDs. ADAM17/TACE and ADAM10 are the responsible enzymes for producing sCD163 from macrophages. Increased shedding of CD163 is caused by inflammatory stimuli, and a function has been hypothesized for sCD163 in immunological suppression. When the body confronts an inflammation or infection, the concentration of sCD163 drives up. sCD163 is stable and can be easily quantified in the serum. In addition to its role as a biomarker, sCD163 can be a good modulator of adaptive immune suppression after stroke. sCD163, with a long half-life, has been proposed to be a surrogate for some critical markers such as Tumor Necrosis Factor-α (TNF- α). Furthermore, sCD163 production can be regulated by some regents/approaches such as zidovudine, nanotechnology, combination antiretroviral treatment, and aprepitant. Considering the importance of the issue, the critical role of sCD163 in NDs was highlighted for novel diagnostic and prognostic purposes.

Initiation of combined antiretroviral therapy confers suboptimal beneficial effects on neurovascular function in people with HIV.

Due to advances in combined anti-retroviral treatment (cART), there is an increased burden of age-related cerebrovascular disease (CBVD), in people living with HIV (PWH). The underlying CNS injury can be assessed by measuring cerebral blood flow (CBF) and cerebrovascular reactivity (CVR). 35 treatment-naïve PWH and 53 HIV negative controls (HC) were enrolled in this study. Study participants underwent T1-weighted anatomical, pseudo-continuous arterial spin labeling, and resting-state functional MRI to obtain measures of CBF and CVR prior to starting cART treatment and at two-time points (12 weeks and 2 years) post-cART initiation. Controls were scanned at the baseline and 2-year visits. We also measured plasma levels of microparticles of endothelial and glial origin and well-known endothelial inflammation markers, ICAM-1 and VCAM-1, to assess HIV-associated endothelial inflammation and the interaction of these peripheral markers with brain neurovascular function. HIV infection was found to be associated with reduced CVR and increased levels of endothelial and glial microparticles (MPs) prior to initiation of cART. Further, CVR correlated negatively with peripheral MP levels in PWH. Our results suggest that while cART treatment has a beneficial effect on the neurovascular function after initiation, these benefits are suboptimal over time.

Time trends in perinatal outcomes among HIV-positive pregnant women in Northern Tanzania: A registry-based study.

Maternal HIV infection is associated with increased risk of having a preterm delivery, low birth weight baby, small for gestational age baby and stillbirth. Maternal use of combination antiretroviral treatment is also associated with preterm delivery and low birth weight, although the effects vary by the type of drugs and timing of initiation. To examine time trends in adverse perinatal outcomes among HIV-positive compared with HIV-negative women. Registry-based cohort study. Northern Tanzania, 2000-2018. Mother-baby pairs of singleton deliveries (n = 41 156). Perinatal outcomes of HIV-positive women were compared with HIV-negative women during time periods representing shifts in prevention of mother-to-child transmission guidelines. Monotherapy was used as first-line therapy before 2007 while combination antiretroviral treatment was routinely used from 2007. Log binomial and quantile regression were used to analyze the data. Preterm delivery, low birth weight, perinatal death, stillbirth, low Apgar score, transfer to neonatal care unit and small for gestational age. Overall, maternal HIV infection was associated with a higher risk of low birth weight and small for gestational age. Moreover, this pattern became more pronounced over time for low birth weight, the last time period being an exception. For other outcomes we found none or only a small overall association with maternal HIV infection, although a trend towards higher risk over time in HIV-positive compared with HIV-negative women was observed for preterm delivery and perinatal death. Quantile regression showed an increase in birth weight in babies born to HIV-negative women over time and a corresponding decline in birth weight in babies born to HIV-positive women. Unfavourable trends in some of the selected perinatal outcomes were seen for HIV-positive compared with HIV-negative women. Potential side-effects of combination antiretroviral treatment in pregnancy should be further explored.

Neurocognitive Impairment in Patients with HIV and Depression in Nigeria

HIV has been associated with neurocognitive impairment which may be due to the direct effect of the virus, indirect effect or due to medications side effects or due to a combination of factors. HIV and depression have been shown separately to have neurocognitive deficits.
 Aim: Determine the prevalence of NCI and factors associated with it among depressed and non-depressed patients with HIV on combined antiretroviral treatment (cART).
 Methodology. A descriptive comparative cross-sectional study was conducted among People living with HIV (PLHIV) at Aminu Kano Teaching Hospital in Kano State, northern Nigeria. Participants were grouped into HIV with depression and HIV without depression groups based on current diagnosis using the depression module of the MINI International Neuropsychiatric Interview (MINI)-7th edition. A multi-domain neuropsychological battery (MDNPT) of 5 tests (assessed 5 cognitive domains) was used to diagnose Neurocognitive impairment.
 Results: Fifty-seven percent of the study sample were females, and the mean age of the participants was 37.54 (±10.04) years with an age range of 18-65 years.
 The prevalence of NCI was 74% among the depressed 68.3% among the non-depressed group (p=0.484). Years of education and IHDS score were significantly associated with NCI in the depressed group (p < 0.05 respectively). While among the non-depressed group, Years of education, average monthly income and IHDS score were significantly associated with NCI (p < 0.05 respectively).
 Conclusion: Neurocognitive impairment occurs in HIV-positive patients but is worsened by a depressive disorder. There is a need to adequately assess and treat HIV patients with depression. Treatment may improve neurocognitive impairment in depressed HIV patients.

Cerebral abnormalities in HIV-infected individuals with neurocognitive impairment revealed by fMRI

Although the combination antiretroviral treatment (cART) has considerably lowered the risk of HIV associated dementia (HAD), the incidence of neurocognitive impairments (NCI) has not decreased likely due to the insidious and slow progressive nature of HIV infection. Recent studies showed that the resting-state functional magnetic resonance imaging (rs-fMRI) is a prominent technique in helping the non-invasive analysis of neucognitive impairment. Our study is to explore the neuroimaging characteristics among people living with HIV (PLWH) with or without NCI in terms of cerebral regional and neural network by rs-fMRI, based on the hypothesis that HIV patients with and without NCI have independent brain imaging characteristics. 33 PLWH with NCI and 33 PLWH without NCI, recruited from the Cohort of HIV-infected associated Chronic Diseases and Health Outcomes, Shanghai, China (CHCDO) which was established in 2018, were categorized into the HIV-NCI and HIV-control groups, respectively, based on Mini-Mental State Examination (MMSE) results. The two groups were matched in terms of sex, education and age. Resting-state fMRI data were collected from all participants to analyze the fraction amplitude of low-frequency fluctuation (fALFF) and functional connectivity (FC) to assess regional and neural network alterations in the brain. Correlations between fALFF/FC values in specific brain regions and clinical characteristics were also examined. The results showed increased fALFF values in the bilateral calcarine gyrus, bilateral superior occipital gyrus, left middle occipital gyrus, and left cuneus in the HIV-NCI group compared to the HIV-control group. Additionally, increased FC values were observed between the right superior occipital gyrus and right olfactory cortex, bilateral gyrus rectus, and right orbital part of the middle frontal gyrus in the HIV-NCI group. Conversely, decreased FC values were found between the left hippocampus and bilateral medial prefrontal gyrus, as well as bilateral superior frontal gyrus. The study concluded that abnormal spontaneous activity in PLWH with NCI primarily occurred in the occipital cortex, while defects in brain networks were mostly associated with the prefrontal cortex. The observed changes in fALFF and FC in specific brain regions provide visual evidence to enhance our understanding of the central mechanisms underlying the development of cognitive impairment in HIV patients.

Clinical characteristics of cervical cancer in patients infected with human immunodeficiency virus

Background. Infection caused by human immunodeficiency virus (HIV) is a slowly developing anthroponosis with a long course and a variety of clinical manifestations, which finally results in acquired immunodeficiency syndrome (AIDS). Over the past 4 decades, the HIV / AIDS pandemic has been considered as one of the world’s most serious public health problems. Globally, there were approximately 38 million people living with HIV in 2022; 53 % of them were women. The number of HIV-infected patients living in Russia reaches 1,168,000. The incidence and prevalence of HIV infectionvaries across different regions of Russia. High prevalence of cervical cancer usually correlates with HIV prevalence, which is associated with the long-term and aggressive persistence of human papillomavirus (HPV) in HIV patients. HIV co-infection is believed to be the main risk factor for HPV-related precancerous lesions to the cervical epithelium and their rapid progression to invasive cancer. Aim. To analyze risk factors for poor prognosis in HIV-infected patients with HPV. Materials and methods. This study included 15 HIV-infected patients with cervical cancer treated in Novosibirsk Regional Clinical Oncology Dispensary or Federal Research and Clinical Center for Specialized Medical Care and Medical Technologies, Federal Biomedical Agency of Russia between 2016 and 2021. Results. Median age of the patients was 38 years; all of them were HPV-positive. Their viral load was >400 copies / mL and baseline CD4+ cell count ≥350 cells / mL. All patients were diagnosed with AIDS, given the presence of HPV infection. During the therapy for cervical cancer, patients also received combination antiretroviral treatment, including Lamivudine Advanced at a dose of 300 mg / day. Ten patients received comprehensive treatment, while 8 patients received chemoradiotherapy. Conclusion. Given the more aggressive course of cervical cancer in HIV-infected patients, their treatment plan should be developed by a multidisciplinary team, including an infectious disease specialist, clinical pharmacologist, radiotherapist, and gynecological oncologist. Such patients should receive maximal antitumor treatment, as well as intensive antiretroviral therapy. HIV-positive women with cervical cancer require special attention to ensure treatment completion and to optimize long-term outcomes.

HIV/AIDS Treatment & Prevention with Nano-Technology: A Review

Abstract: The HIV/AIDS epidemic remains unabated due to the lack of a cure or vaccine. Combination antiretroviral treatment has significantly improved patient outcomes, but it must be taken continuously,may have severe side effects, and is no longer effective for those whose viruses have developed resistance. Nanomedicine is a cutting-edge illustration of how nanotechnology, a multidisciplinary new science, is influencing healthcare in the twenty-first century. It might dramatically enhance HIV/AIDS treatment and prevention overtime. In this paper, the challenges ofthe current HIV/AIDS treatment are examined, followed by a discussion of the amazing potential ofnanotechnology to increase the effectiveness of antiretroviral therapy, and gene therapy.

Cohort profile: a longitudinal study of HIV infection in the central nervous system with focus on cerebrospinal fluid – the Gothenburg HIV CSF Study Cohort

PurposeIn order to enable long-term follow-up of the natural course of HIV infection in the central nervous system, a longitudinal cohort study with repeated cerebrospinal fluid (CSF) analyses at intervals...

Prognostic Factors in Children and Adolescents with Lymphomas and Vertical Transmission of HIV in Rio de Janeiro, Brazil: A Multicentric Hospital-Based Survival Analysis Study.

Lymphomas related to HIV are generally aggressive and have a poor prognosis, despite the use of combined antiretroviral therapy (cART) and effective chemotherapy treatment. To determine survival and prognostic factors in children and adolescents living with HIV (CLWH) in Rio de Janeiro (RJ), Brazil, who developed lymphomas, we performed a retrospective and observational study of vertically infected CLWH aged from 0 to 20 incomplete years during1995 to 2018 at five reference centers for cancer and HIV/AIDS treatment. Of the 25 lymphomas, 19 were AIDS-defining malignancies (ADM) and 6 were non-AIDS-defining malignancies (NADM). The 5-year overall survival (OS) and 5-year event-free survival (EFS) probabilities were both 32.00% (95% CI = 13.72-50.23%), and the 5-year disease-free survival (DFS) probability was 53.30% (95% CI = 28.02-78.58%). In the multivariate Cox regression analysis, performance status 4 (PS 4) was considered a poor prognostic factor for OS (HR 4.85, 95% CI = 1.81-12.97, p = 0.002) and EFS (HR 4.95, 95% CI = 1.84-13.34, p = 0.002). For the DFS, higher CD4+ T-cell counts were considered a better prognostic factor (HR 0.86, 95% CI = 0.76-0.97, p = 0.017) in the multivariate Cox regression analysis. This study demonstrates, for the first time, survival and prognostic factors for CLWH who developed lymphomas in RJ, Brazil.

Efficacy, Convenience, Safety and Durability of DTG-Based Antiretroviral Therapies: Evidence from a Prospective Study by the Italian MaSTER Cohort.

Background: Dolutegravir (DTG) is recommended by international guidelines as a main component of an optimal initial regimen of cART (combination antiretroviral treatment) in people living with HIV (PLWH) and in case of switching for failure or optimization strategies. However, studies on the performance of DTG-containing regimens and indications for switching therapies in the long term are sparse. The purpose of this study was to evaluate prospectively the performance of DTG-based regimens, using the metrics of "efficacy", "safety", "convenience" and ''durability'', among a nationally representative cohort of PLWH in Italy. Methods: We selected all PLWH in four centers of the MaSTER cohort who initiated a DTG-based regimen either when naïve or following a regimen switch between 11 July 2018 and 2 July 2021. Participants were followed until the outcomes were recorded or until the end of the study on 4 August 2022, whichever occurred first. Interruption was reported even when a participant switched to another DTG-containing regimen. Survival regression models were fitted to evaluate associations between therapy performance and age, sex, nationality, risk of HIV transmission, HIV RNA suppression status, CD4+ T-cell count, year of HIV diagnosis, cART status (naïve or experienced), cART backbone and viral hepatitis coinfection. Results: There were 371 participants in our cohort who initiated a DTG-based cART regimen in the time frame of the study. The population was predominantly male (75.2%), of Italian nationality (83.3%), with a history of cART use (80.9%), and the majority initiated a DTG-based regimen following a switch strategy in 2019 (80.1%). Median age was 53 years (interquartile range (IQR): 45-58). Prior cART regimen was based mostly on a combination of NRTI drugs plus a PI-boosted drug (34.2%), followed by a combination of NRTIs plus an NNRTI (23.5%). Concerning the NRTI backbone, the majority comprised 3TC plus ABC (34.5%), followed by 3TC alone (28.6%). The most reported transmission risk factor was heterosexual intercourse (44.2%). Total interruptions of the first DTG-based regimen were registered in 58 (15.6%) participants. The most frequent reason for interruption was due to cART simplification strategies, which accounted for 52%. Only 1 death was reported during the study period. The median time of total follow-up was 556 days (IQR: 316.5-722.5). Risk factors for poor performance of DTG-containing-regimens were found to be: a backbone regimen containing tenofovir, being cART naïve, having detectable HIV RNA at baseline, FIB-4 score above 3.25 and having a cancer diagnosis. By contrast, protective factors were found to be: higher CD4+ T-cell counts and higher CD4/CD8 ratio at baseline. Conclusion: DTG-based regimens were used mainly as a switching therapy in our cohort of PLWH who had undetectable HIV RNA and a good immune status. In this type of population, the durability of DTG-based regimens was maintained in 84.4% of participants with a modest incidence of interruptions mostly due to cART simplification strategies. The results of this prospective real-life study confirm the apparent low risk of changing DTG-containing regimens due to virological failure. They may also help physicians to identify people with increased risk of interruption for different reasons, suggesting targeted medical interventions.

Maternal ART throughout gestation prevents caudate volume reductions in neonates who are HIV exposed but uninfected.

Successful programmes for prevention of vertical HIV transmission have reduced the risk of infant HIV infection in South Africa from 8% in 2008 to below 1% in 2018/2019, resulting in an increasing population of children exposed to HIV perinatally but who are uninfected (HEU). However, the long-term effects of HIV and antiretroviral treatment (ART) exposure on the developing brain are not well understood. Whereas children who are HEU perform better than their HIV-infected counterparts, they demonstrate greater neurodevelopmental delay than children who are HIV unexposed and uninfected (HUU), especially in resource-poor settings. Here we investigate subcortical volumetric differences related to HIV and ART exposure in neonates. We included 120 infants (59 girls; 79 HEU) born to healthy women with and without HIV infection in Cape Town, South Africa, where HIV sero-prevalence approaches 30%. Of the 79 HEU infants, 40 were exposed to ART throughout gestation (i.e., mothers initiated ART pre conception; HEU-pre), and 39 were exposed to ART for part of gestation (i.e., mothers initiated ART post conception; HEU-post). Post-conception mothers had a mean (± SD) gestational age (GA) of 15.4 (± 5.7) weeks at ART initiation. Mothers with HIV received standard care fixed drug combination ART (Tenofovir/Efavirenz/Emtricitabine). Infants were imaged unsedated on a 3T Skyra (Siemens, Erlangen, Germany) at mean GA equivalent of 41.5 (± 1.0) weeks. Selected regions (caudate, putamen, pallidum, thalamus, cerebellar hemispheres and vermis, and corpus callosum) were manually traced on T1-weighted images using Freeview. HEU neonates had smaller left putamen volumes than HUU [β (SE) = -90.3 (45.3), p = 0.05] and caudate volume reductions that depended on ART exposure duration in utero. While the HEU-pre group demonstrated no caudate volume reductions compared to HUU, the HEU-post group had smaller caudate volumes bilaterally [β (SE) = -145.5 (45.1), p = 0.002, and -135.7 (49.7), p = 0.008 for left and right caudate, respectively]. These findings from the first postnatal month suggest that maternal ART throughout gestation is protective to the caudate nuclei. In contrast, left putamens were smaller across all HEU newborns, despite maternal ART.

The Evolving Pediatric HIV Epidemic in Rural Southern Zambia: The Beneficial Impact of Advances in Prevention and Treatment at a District Hospital From 2007 to 2019.

Remarkable progress has been made in expanding access to services addressing the pediatric HIV epidemic, including programs to prevent mother-to-child transmission, early diagnosis and treatment for children living with HIV. Few long-term data are available from rural sub-Saharan Africa to assess implementation and impact of national guidelines. Results from 3 cross-sectional studies and 1 cohort study conducted at Macha Hospital in Southern Province, Zambia from 2007 to 2019 were summarized. For infant diagnosis, maternal antiretroviral treatment, infant test results and turnaround times for results were evaluated by year. For pediatric HIV care, the number and age of children initiating care and treatment, and treatment outcomes within 12 months were evaluated by year. Receipt of maternal combination antiretroviral treatment increased from 51.6% in 2010-2012 to 93.4% in 2019, and the proportion of infants testing positive decreased from 12.4% to 4.0%. Turnaround times for results returning to clinic varied but were shorter when labs consistently used a text messaging system. The proportion of mothers receiving results was higher when a text message intervention was piloted. The number of children living with HIV enrolled into care and the proportion initiating treatment with severe immunosuppression and dying within 12 months decreased over time. These studies demonstrate the long-term beneficial impact of implementing a strong HIV prevention and treatment program. While expansion and decentralization brought challenges, the program succeeded in decreasing the rate of mother-to-child transmission and ensuring that children living with HIV benefit from access to life-saving treatment.

Sirtuin-2, NAD-Dependent Deacetylase, Is a New Potential Therapeutic Target for HIV-1 Infection and HIV-Related Neurological Dysfunction.

The implementation and access to combined antiretroviral treatment (cART) have dramatically improved the quality of life of people living with HIV (PLWH). However, some comorbidities, such as neurological disorders associated with HIV infection still represent a serious clinical challenge. Soluble factors in plasma that are associated with control of HIV replication and neurological dysfunction could serve as early biomarkers and as new therapeutic targets for this comorbidity. We used a customized antibody array for determination of blood plasma factors in 40 untreated PLWH with different levels of viremia and found sirtuin-2 (SIRT2), an NAD-dependent deacetylase, to be strongly associated with elevated viral loads and HIV provirus levels, as well as with markers of neurological damage (a-synuclein [SNCA], brain-derived neurotrophic factor [BDNF], microtubule-associated protein tau [MAPT], and neurofilament light protein [NFL]). Also, longitudinal analysis in HIV-infected individuals with immediate (n = 9) or delayed initiation (n = 10) of cART revealed that after 1 year on cART, SIRT2 plasma levels differed between both groups and correlated inversely with brain orbitofrontal cortex involution. Furthermore, targeting SIRT2 with specific small-molecule inhibitors in in vitro systems using J-LAT A2 and primary glial cells led to diminished HIV replication and virus reactivation from latency. Our data thus identify SIRT2 as a novel biomarker of uncontrolled HIV infection, with potential impact on neurological dysfunction and offers a new therapeutic target for HIV treatment and cure. IMPORTANCE Neurocognitive disorders are frequently reported in people living with HIV (PLWH) even with the introduction of combined antiretroviral treatment (cART). To identify biomarkers and potential therapeutic tools to target HIV infection in peripheral blood and in the central nervous system (CNS), plasma proteomics were applied in untreated chronic HIV-infected individuals with different levels of virus control. High plasma levels of sirtuin-2 (SIRT2), an NAD+ deacetylase, were detected in uncontrolled HIV infection and were strongly associated with plasma viral load and proviral levels. In parallel, SIRT2 levels in the peripheral blood and CNS were associated with markers of neurological damage and brain involution and were more pronounced in individuals who initiated cART later in infection. In vitro infection experiments using specific SIRT2 inhibitors suggest that specific targeting of SIRT2 could offer new therapeutic treatment options for HIV infections and their associated neurological dysfunction.

Assessment and Diagnosis of HIV-Associated Dementia.

The modern combined antiretroviral treatment (cART) for human immunodeficiency virus (HIV) infection has substantially lowered the incidence of HIV-associated dementia (HAD). The dominant clinical features include deficits in cognitive processing speed, concentration, attention, and memory. As people living with HIV become older, with high rates of comorbidities and concomitant treatments, the prevalence and complexity of cognitive impairment are expected to increase. Currently, the management of HAD and milder forms of HAND is grounded on the best clinical practice, as there is no specific, evidence-based, proven intervention for managing cognitive impairment. The present article acknowledges the multifactorial nature of the cognitive impairments found in HIV patients, outlining the current concepts in the field of HAD. Major areas of interest include neuropsychological testing and neuroimaging to evaluate CNS status, focusing on greater reliability in the exclusion of associated diseases and allowing for earlier diagnosis. Additionally, we considered the evidence for neurological involvement in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the impact of the coronavirus (COVID-19) pandemic, with wider consequences to population health than can be attributed to the virus itself. The indirect effects of COVID-19, including the increased adoption of telehealth, decreased access to community resources, and social isolation, represent a significant health burden, disproportionately affecting older adults with dementia who have limited social networks and increased functional dependence on the community and health system. This synopsis reviews these aspects in greater detail, identifying key gaps and opportunities for researchers and clinicians; we provide an overview of the current concepts in the field of HAD, with suggestions for diagnosing and managing this important neurological complication, which is intended to be applicable across diverse populations, in line with clinical observations, and closely representative of HIV brain pathology.