Era Of Combination Antiretroviral Therapy Research Articles

CD4 nadir and neurocognitive trajectories in people living with HIV

AbstractHuman immunodeficiency virus-associated neurocognitive disorders persist in the combination antiretroviral therapy era. CD4 nadir is a well-established predictor of cognition cross-sectionally, but its impact on longitudinal neurocognitive (NC) trajectories is unclear. The few studies on this topic examined trajectories of global cognition, rather than specific NC domains. The current study examined CD4 nadir in relation to domain-specific NC decline. 132 HIV + adults from the Temple/Drexel Comprehensive NeuroHIV Center, Clinical and Translational Research Support Core Cohort were administered comprehensive NC assessments longitudinally, with last visit occurring an average of 12 years after CD4 nadir. Linear mixed models were used to examine CD4 nadir in relation to longitudinal NC trajectories in three empirically identified NC domains: speed/executive function (S/EF), visuospatial memory (VM), and verbal fluency (VF). CD4 nadir was associated with change in VF (p = 0.020), but not with S/EF or VM. Specifically, those with CD4 nadir < 200 demonstrated increasing VF over time (p = .002), whereas those with CD4 nadir > 200 demonstrated stable VF (p = .568), though these differing trajectories may partly reflect regression to the mean or differential practice effect. CD4 dynamics over time were analyzed as potential mechanisms for the identified associations, with mixed findings. While low CD4 nadir has been associated with weaker neurocognition among people living with HIV, the results of this study suggest that low CD4 nadir is not associated with ongoing decline a decade later. Nadir-related deficits in VF may be stable or even improve over time, possibly reflecting the beneficial cognitive effects of long-term treatment and immune reconstitution.

Outcome in patients with HIV-associated Hodgkin lymphoma treated with chemotherapy using Doxorubicin, Bleomycin, Vinblastine, and Dacarbazine in the combination antiretroviral therapy (cART) era: results of a multicenter study from China

Little is known about the outcome for HIV-associated Hodgkin lymphoma (HIV-HL) as this is less common than HIV-negative lymphoma. Therefore, we performed a multi-center study to analyze the clinical characteristics and outcomes of HIV-HL patients in China. Nineteen cases of HIV-HL were diagnosed and treated at three center and including the sixth people’s hospital of Zhengzhou, Peking union medical college hospital, and Chongqing university cancer hospital, between December 2013 and June 2022. Data on the clinical features, laboratory results, response, and prognosis were collected and analyzed. The median age at diagnosis was 43(22–74) years. All patients were infected with HIV through sexual transmission, with ten cases transmitted through man having sex with man (MSM) and nine cases transmitted through heterosexual transmission. Seven patients were diagnosed with lymphoma and found to be infected with HIV. Four cases were in stage III, and fifteen cases were in stage IV. After a median follow up of 46.8(4.0-112.9) months, 17 cases were alive after ABVD regimen chemotherapy combined with combination antiretroviral therapy (cART). The 5-year progression-free survival (PFS) and overall survival (OS) rate were 83.9% and 89.5%,respectively. HIV-HL exhibits an invasive process in clinical practice, and cART combined with ABVD regimen chemotherapy can achieve long-term survival for patients.

HIV and COVID-19: two pandemics with significant (but different) central nervous system complications.

Human immunodeficiency virus (HIV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cause significant neurologic disease. Central nervous system (CNS) involvement of HIV has been extensively studied, with well-documented invasion of HIV into the brain in the initial stage of infection, while the acute effects of SARS-CoV-2 in the brain are unclear. Neuropathologic features of active HIV infection in the brain are well characterized whereas neuropathologic findings in acute COVID-19 are largely non-specific. On the other hand, neuropathologic substrates of chronic dysfunction in both infections, as HIV-associated neurocognitive disorders (HAND) and post-COVID conditions (PCC)/long COVID are unknown. Thus far, neuropathologic studies on patients with HAND in the era of combined antiretroviral therapy have been inconclusive, and autopsy studies on patients diagnosed with PCC have yet to be published. Further longitudinal, multidisciplinary studies on patients with HAND and PCC and neuropathologic studies in comparison to controls are warranted to help elucidate the mechanisms of CNS dysfunction in both conditions.

Clinical markers of HIV predict redox-regulated neural and behavioral function in the sensorimotor system

Even in the modern era of combination antiretroviral therapy, aberrations in motor control remain a predominant symptom contributing to age-related functional dependencies (e.g., neurocognitive impairment) in people with HIV (PWH). While recent evidence implicates aberrant mitochondrial redox environments in the modulation of neural oscillatory activity serving motor control in PWH, the contribution of important clinical and demographic factors on this bioenergetic-neural-behavioral pathway is unknown. Herein, we evaluate the predictive capacity of clinical metrics pertinent to HIV (e.g., CD4 nadir, time with viremia) and age on mitochondrial redox-regulated sensorimotor brain-behavior dynamics in 69 virally-suppressed PWH. We used state-of-the-art systems biology and neuroscience approaches, including Seahorse analyzer of mitochondrial energetics, EPR spectroscopy of intracellular oxidant levels, antioxidant activity assays pertinent to superoxide and hydrogen peroxide (H2O2) redox environments, and magnetoencephalographic (MEG) imaging to quantify sensorimotor oscillatory dynamics. Our results demonstrate differential effects of redox systems on the neural dynamics serving motor function in PWH. In addition, measures of immune stability and duration of compromise due to HIV had dissociable effects on this pathway, above and beyond the effects of age alone. Moreover, peripheral measures of antioxidant activity (i.e., superoxide dismutase) fully mediated the relationship between immune stability and current behavioral performance, indicative of persistent oxidative environments serving motor control in the presence of virologic suppression. Taken together, our data suggest that disease-related factors, in particular, are stronger predictors of current redox, neural and behavioral profiles serving motor function, which may serve as effective targets for alleviating HIV-specific alterations in cognitive-motor function in the future.

Ocular Manifestations of Human Immunodeficiency Virus Infection in the Combination Antiretroviral Therapy Era.

Since the introduction of combination antiretroviral therapy (cART) in Japan in 2008, the spectrum of ocular manifestations in patients with human immunodeficiency virus (HIV) has changed. This study, conducted at Tokyo Medical and Dental University Hospital between January 2012 and August 2023, aimed to understand the epidemiology and clinical features of ocular manifestations in patients with HIV during the cART era. Of the 218 patients diagnosed with HIV, 23 (10.55%) exhibited ocular manifestations; all were male, aged 32-73. The most prevalent ocular complication was uveitis (60.67%). Notably, the prevalence of uveitis in this cART era has surged compared to earlier Japanese studies. Our data also suggest a potential direct link between uveitis and HIV, particularly in patients who have not yet undergone cART. However, cytomegalovirus retinitis, another prevalent ocular disease in our study, appeared more strongly associated with patients who commenced cART. Neither ocular condition was significantly correlated with CD4+ T-cell count. Importantly, our observed ocular manifestation prevalence (10.55%) was lower than that in previous studies, emphasizing the potential influence of cART and national healthcare support. These findings provide unique insights into the evolution of ocular manifestations in patients with HIV in Japan amidst cART availability.

Selinexor in Combination with R-EPOCH for Patients with Previously Untreated HIV-Associated Diffuse Large B Cell Lymphoma(DLBCL)

Introduction : The incidence of HIV-positive lymphoma remains significantly higher than HIV-negative patients in the era of combined antiretroviral therapy(cART). DLBCL is the most common histological type of HIV-positive non-Hodgkin's lymphoma(NHL). Exportin 1 protein(XPO1) inhibitor has demonstrated preliminary anti-HIV activity and synergy with anti-lymphoma drug(e.g. etoposide, doxorubicin, prednisone). Methods: The study was designed to evaluate safety and efficacy of selinexor (60mg Days 1, 8, 15) combined with R-EPOCH(rituximab 375 mg/m2d1, etoposide 50 mg/m2 d1-d4, doxorubicin 10mg/m2 d1-d4, vinblastine 0.4mg/m2 d1-d4, prednisone 60mg/m2 d1-d5 and cyclophosphamide 750mg/m2 d5) every 3 weeks (4-6 cycles), followed by selinexor maintenance (60 mg weekly) or transplantation as per physician's choice in patients with untreated HIV-positive DLBCL. All patients received cART concomitantly during chemotherapy. This study was registered at Chictr.org.cn(ChiCTR2300069941). Results: From Feb 24, 2023 to July 17, 2023, 6 patients were enrolled and received at least one cycles of study treatment. Median age was 55 years (range 43-67) with four patients(66.7%) was male. All six patients were in advanced stage according to Ann Arbor staging system, with aaIPI intermediate to high risk or IPI low to intermediate risk. Four patients(66.7%) were germinal center B-cell-like lymphoma (GCB) subtype and three patients(50%) had an Elevated lactate dehydrogenase level. Median HIV RNA load was 74450(10000-100000) copies/mL and Median CD4 cell count was 233 cells/μL (233 cells/mm3) with one patient having a CD4 cell count less than 200 cells/μL (200 cells/mm3). Two patients were HBV-positive and one was EB virus(EBV) coinfection at baseline. Three patients achieved PR after two treatment cycles, one patient of which had completed five treatment cycles and achieved complete response at the end of the fourth cycle (Figure 1). One patients after interim evaluation with PR stopped treatment because of loss to follow-up. The EBV DNA load of the patient with EBV coinfection at baseline turned to normal level after one treatment cycle. Similar result was observed in two HBV-positive patients, the one achieved HBV-negative after two cycles and the other's HBV DNA load level declined from 7.96×10^4 IU/mL to 1.12×10^3 after completing first cycle. HIV RNA load of the patient with CR had declined to <20 copies/mL from 58300 copies/mL after the fourth cycle, another patient likewise became HIV-negative before the initiation of the third cycle. The change of CD4+T cell count during treatment was presented in Figure 2. All patients experienced at least one treatment-emergent adverse event (TEAE), 3 (50%) patients with at least one Grade≥3 TEAE. The most common grade 3 or 4 adverse events were hematological toxicities including lymphopenia(83.3%), neutropenia (50%), leukopenia(33.3%), thrombocytopenia (33.3%). Two patients experienced Febrile neutropenia. The non-hematological toxicities were grade 1 or 2, including nausea(66.7%), vomit(50%), constipation(33.3%), cough(33%). One patient stopped treatment for one month due to pulmonary infection. All toxicities were manageable by supportive care. Conclusion: Selinexor plus R-EPOCH regimen demonstrated a favorable Interim efficacy and manageable safety profile in patients with HIV-associated DLBCL. The change of HIV RNA load and CD4+ cell count still requires further evaluation.

Association of combination antiretroviral therapy with risk of neurological diseases in patients with HIV/AIDS in Taiwan: a nested case-control study.

Heterogeneous neurocognitive impairment remains an important issue, even in the era of combination antiretroviral therapy (cART), with an incidence ranging from 15% to 65%. Although ART drugs with higher penetration scores to the central nervous system (CNS) show better HIV replication control in the CNS, the association between CNS penetration effectiveness (CPE) scores and neurocognitive impairment remains inconclusive. To explore whether ART exposure is associated with the risk of neurological diseases among patients with HIV/AIDS, this study in Taiwan involved 2,571 patients with neurological diseases and 10,284 matched, randomly selected patients without neurological diseases between 2010 and 2017. A conditional logistic regression model was used in this study. The parameters for ART exposure included ART usage, timing of exposure, cumulative defined daily dose (DDD), adherence, and cumulative CPE score. Incident cases of neurological diseases, including CNS infections, cognitive disorders, vasculopathy, and peripheral neuropathy, were obtained from the National Health Insurance Research Database in Taiwan. Odds ratios (ORs) for the risk of neurological diseases were conducted using a multivariate conditional logistic regression model. Patients with a history of past exposure (OR: 1.68, 95% confidence interval [CI]:1.22-2.32), low cumulative DDDs (< 2,500) (OR: 1.28, 95% CI: 1.15-1.42), low adherence (0 < adherence (ADH) ≤ 0.8) (OR: 1.46, 95% CI: 1.30-1.64), or high cumulative CPE scores (>14) (OR: 1.34, 95% CI: 1.14-1.57) had a high risk of neurological diseases. When stratified by classes of ART drugs, patients with low cumulative DDDs or low adherence had a high risk of neurological diseases, including NRTIs, PIs, NNRTIs, INSTIs, and multi-drug tablets. Subgroup analyses also suggested that patients with low cumulative DDDs or low adherence had a high risk of neurological diseases when they had high cumulative CPE scores. Patients with high cumulative DDDs or medication adherence were protected against neurological diseases only when they had low cumulative CPE scores (≤ 14). Patients may be at risk for neurological diseases when they have low cumulative DDDs, low adherence, or usage with high cumulative CPE scores. Continuous usage and low cumulative CPE scores of ART drugs may benefit neurocognitive health in patients with HIV/AIDS.

The Impact of COVID-19 on People Living with HIV-1 and HIV-1-Associated Neurological Complications.

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the causative pathogen of the coronavirus disease 2019 (COVID-19) pandemic, a fatal respiratory illness. The associated risk factors for COVID-19 are old age and medical comorbidities. In the current combined antiretroviral therapy (cART) era, a significant portion of people living with HIV-1 (PLWH) with controlled viremia is older and with comorbidities, making these people vulnerable to SARS-CoV-2 infection and COVID-19-associated severe outcomes. Additionally, SARS-CoV-2 is neurotropic and causes neurological complications, resulting in a health burden and an adverse impact on PLWH and exacerbating HIV-1-associated neurocognitive disorder (HAND). The impact of SARS-CoV-2 infection and COVID-19 severity on neuroinflammation, the development of HAND and preexisting HAND is poorly explored. In the present review, we compiled the current knowledge of differences and similarities between SARS-CoV-2 and HIV-1, the conditions of the SARS-CoV-2/COVID-19 and HIV-1/AIDS syndemic and their impact on the central nervous system (CNS). Risk factors of COVID-19 on PLWH and neurological manifestations, inflammatory mechanisms leading to the neurological syndrome, the development of HAND, and its influence on preexisting HAND are also discussed. Finally, we have reviewed the challenges of the present syndemic on the world population, with a particular emphasis on PLWH.

Cesarean delivery and risk of HIV vertical transmission in Southern Brazil, 2008-2018

Childbirth via cesarean delivery can prevent intrapartum vertical transmission for women who are not virally suppressed at the time of delivery. Few studies have compared cesarean delivery trends between women living with HIV and women without HIV and have examined the role of cesarean delivery in the prevention of vertical transmission in the era of potent combination antiretroviral therapy. We hypothesized that the cesarean delivery rate is high in women living with HIV compared with women without HIV and that cesarean delivery usage decreases over time among women living with HIV with advances in combined antiretroviral therapy in a country with a high national cesarean delivery rate. This study aimed (1) to evaluate cesarean delivery trends in women with and without HIV and (2) to examine its role in preventing vertical transmission among women living with HIV in a setting of free, universal combined antiretroviral therapy coverage in a retrospective cohort of nearly 56,000 deliveries at a major referral institution in a city with the highest prevalence of maternal HIV in Brazil. Data from maternal-infant pairs from January 1, 2008, to December 31, 2018, were extracted. Cesarean delivery rates were compared using the Pearson chi-square test. Cesarean delivery predictors were evaluated by multivariate log-linear Poisson regression using a generalized estimating equations approach. HIV viral suppression was defined as a viral load of <1000 copies/ml at delivery. HIV vertical transmission was determined following national guidelines. Over 11 years, 48,688 pregnancies occurred in 40,375 women; HIV seroprevalence was 2.7%; 18,886 cesarean deliveries (38.8%) were performed; 47.7% of women living with HIV and 38.6% of women without HIV underwent cesarean delivery (P<.001). Although HIV was associated with cesarean delivery (adjusted relative risk, 1.17 [95% confidence interval, 1.05-1.29]), women living with HIV with vertical transmission achieved similar cesarean delivery rates (36.7%) as women without HIV (39.8%) in 2018. Cesarean delivery in women living with HIV with an unknown viral load at delivery (42.6%) did not increase over time. HIV vertical transmission rate was 2.2%, the highest in women living with HIV with an unknown viral load (8.4%) vs women living with HIV without vertical transmission (4.1%) and women living with HIV with vertical transmission (0.5%) (P<.001). In the HIV epicenter of Brazil, women living with HIV with vertical transmission had fewer surgical deliveries, likely because of the use of potent combination antiretroviral therapy. Nearly half of the women living with HIV with an unknown viral load did not undergo cesarean delivery, a potential missed opportunity for the prevention of HIV vertical transmission.

English

The Human Immunodeficiency Virus (HIV) is a neurotropic virus that is associated with cognitive, behavioral and motor deficits known as HIV Associated Neurocognitive Disorder (HAND). This was a prospective study aimed at determining the prevalence of cognitive impairment as well as comparing the performance of the HIV positive patients on a screening test, the International HIV Dementia Scale (IHDS), and subtests drawn from a neuropsychological test battery - WHO/UCLA. The screening test and neuropsychological test battery were administered to HIV positive patients while the HIV negative patients had only the test battery administered to determine the mean score of each test domain. Neurocognitive impairment was defined using the cut-off score of 10 for the International HIV Dementia scale and Z scores greater than 1 SD in at least two domains of the neuropsychological test battery. The mean performance on each domain of the test battery was determined after administration to the HIV negative individuals. Ninety-two HIV positive patients (57 females and 35 males) and ninety-two age, sex and education matched HIV negative subjects (46 females and 46 males) were enrolled into the study. The median age and interquartile range were 33(26-39) and 35(27-46) for the HIV positive and negative participants respectively. The prevalence estimates of cognitive impairment determined by the IHDS and the test battery were 42.4 and 76.1%, respectively. The IHDS in this study was found to have a sensitivity of 50% and a specificity of 81% for HAND. Neurocognitive impairment still persists in the combination anti-retroviral therapy (CART) era and is better accessed using neuropsychological testing than with screening tests although the former is cumbersome and require expertise and patience on the part of the subjects. Key words: HIV, neurocognitive disorder, sub-Saharan Africa, dementia tests, neuropsychology.

Involvement of lncRNA TUG1 in HIV-1 Tat-Induced Astrocyte Senescence.

HIV-1 infection in the era of combined antiretroviral therapy has been associated with premature aging. Among the various features of HIV-1 associated neurocognitive disorders, astrocyte senescence has been surmised as a potential cause contributing to HIV-1-induced brain aging and neurocognitive impairments. Recently, lncRNAs have also been implicated to play essential roles in the onset of cellular senescence. Herein, using human primary astrocytes (HPAs), we investigated the role of lncRNA TUG1 in HIV-1 Tat-mediated onset of astrocyte senescence. We found that HPAs exposed to HIV-1 Tat resulted in significant upregulation of lncRNA TUG1 expression that was accompanied by elevated expression of p16 and p21, respectively. Additionally, HIV-1 Tat-exposed HPAs demonstrated increased expression of senescence-associated (SA) markers-SA-β-galactosidase (SA-β-gal) activity and SA-heterochromatin foci-cell-cycle arrest, and increased production of reactive oxygen species and proinflammatory cytokines. Intriguingly, gene silencing of lncRNA TUG1 in HPAs also reversed HIV-1 Tat-induced upregulation of p21, p16, SA-β gal activity, cellular activation, and proinflammatory cytokines. Furthermore, increased expression of astrocytic p16 and p21, lncRNA TUG1, and proinflammatory cytokines were observed in the prefrontal cortices of HIV-1 transgenic rats, thereby suggesting the occurrence of senescence activation in vivo. Overall, our data indicate that HIV-1 Tat-induced astrocyte senescence involves the lncRNA TUG1 and could serve as a potential therapeutic target for dampening accelerated aging associated with HIV-1/HIV-1 proteins.

Healthcare utilization and outcomes in testicular cancer with and without HIV.

411 Background: Risk of testicular cancer (TC) was higher in HIV patients before combined antiretroviral therapy (cART) era. However the risk has decreased and outcomes reported to be similar since cART (PMID 17548695, 34592009). We evaluated the characteristics, outcomes, and healthcare utilization of patients with TC with and without HIV from a national sample. Methods: Healthcare Cost and Utilization Project-Nationwide Inpatient Sample database was queried to identify all TC patients with and without HIV from 2016-2019. The groups were compared for socio-demographic differences, medical comorbidities, inpatient mortality, length of stay (LOS), and total hospital charges (THC). Secondary outcomes included rates of orchiectomy, sepsis, septic shock, acute kidney injury, UTI, anemia, and protein energy malnutrition. Statistics were performed using t-test, univariate and multinomial logistic regression. Results: A total 265 admissions of HIV-TC and 29,450 non-HIV-TC were identified. HIV-TC patients were more likely to be in middle age group (45-65yrs) (38 vs 19% 40, p = 0.08) than non-HIV-TC who were younger &lt;45yrs (76 vs 62%, p = 0.08). Compared to non-HIV-TC, HIV-TC patients were more likely to be Black (36% vs 5%, p&lt;0.001), on Medicaid (47% vs 33%, p=0.002) or uninsured (12% vs 8%, p=0.002), treated at a teaching hospital (94% vs 84%, p=0.036). HIV-TC had a significantly higher comorbidity burden, prevalence of CKD and coinfection with Hepatitis B/C (all p&lt;0.05). Other comorbidities and secondary outcomes were not significantly different. The overall adjusted all-cause mortality was not significantly different between groups (aOR = 0.6, 95% CI 0.08-4.24, p = 0.61), however on subgroup analysis mortality was significantly increased for blacks (aOR = 1.98, 95% CI 1.07-3.66, p = 0.02) and Asians (aOR = 1.84, 95% CI 1.05-3.21, p = 0.03) compared to Caucasians. Mean LOS (7 vs 6 days, p = 0.49) and THC ($68,766 vs $69,371, p = 0.17) were similar between cohorts. Conclusions: HIV-TC patients were older, in the middle age compared to more younger (&lt;45 years) for non-HIV-TC patients. Although overall mortality and outcomes were similar between the groups, a racial disparity was seen with higher mortality in African American patients, the cause of which should be investigated in future studies.

Longitudinal impact of compliance with routine CD4 monitoring on all cause deaths among treated people with HIV in China.

Keeping adherence to the continuous and standardized CD4 follow-up monitoring service is of great significance to the control of disease progression and the reduction of avoidable mortality for HIV-infected patients. As non-communicable diseases (NCDs) have become main causes of deaths for people with HIV (PWH) in the era of combination antiretroviral therapy (cART), how and to what extent does adherence to routine CD4 monitoring differentially impact on AIDS-related versus NCDs-related deaths in low- and middle-income countries (LMIC) remains elucidated. A CD4 test index was developed by dividing the actual number of received CD4 tests by the theoretical number of CD4 tests that should have been performed according to national treatment guidelines during the study period, with an index value of 0.8-1.2 reflecting compliance. From 1989 to 2020, 14,571 adults were diagnosed with HIV infection in Dehong Prefecture of Yunnan province in Southwestern China, 6,683 (45.9%) PWH had died with the all-cause mortality of 550.13 per 10,000 person-years, including 3,250 (48.6%) AIDS-related deaths (267.53 per 10,000 person-years). Among patients on cART, the median CD4 test index was 1.0 (IQR 0.6-1.3), and 35.2% had a CD4 test index less than 0.8. Cox proportional hazards regression analysis indicated that PWH with CD4 test index at 0.8-1.2 were at the lowest risk of both AIDS-related (aHR = 0.06; 95%CI: 0.05-0.07) and NCDs-related (aHR = 0.13; 95%CI: 0.11-0.16)deaths. Adherence to routine CD4 monitoring is critical for reducing both AIDS-related and NCDs-related mortality of PWH. An appropriate (once or twice a year) rather than an unnecessarily higher frequency of routine CD4 testing could be most cost-effective in reducing mortality in LMIC.

HIV-associated Burkitt lymphoma in the combination antiretroviral therapy era: Real-world outcomes and prognostication.

We performed a retrospective study to analyze the clinical characteristics and outcomes of human immunodeficiency virus-associated Burkitt's lymphoma in Chongqing University Cancer Hospital, southwest China, from March 2012 to February 2022. In the entire cohort, the median age was 36 years (range, 28-60 years), and more patients were male (82.4%). The median CD4+ T cell count was 214/μl (range, 54-601), of whom 47.1% had a CD4+ T cell count below 200/μl. Most patients had elevated lactate dehydrogenase (LDH), elevated β2-MG, extranodal involvement and advanced Ann Arbor stage at diagnosis. With a median follow-up of 11.5 months (range, 1.6-94.9 months), the overall 1-year progression-free survival and overall survival (OS) rates were 27.6% and 47.6%, respectively. The 1-year OS times in the LDH<3 upper limit of normal and LDH≥3 upper limit of normal groups were 62.5% and 31.3%, respectively (p=0.008). The 1-year OS times in the received <4 cycles and ≥4 cycles groups were 0% and 77.8%, respectively (p<0.001). These results demonstrated that LDH<3 upper limit of normal and received ≥4 cycles of chemotherapy were significantly associated with improved outcomes. However, rituximab administration was not significantly associated with improved outcomes.

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.

Patterns of pregnancy loss among women living with and without HIV in Brazil, 2008–2018

Pregnancy loss is poorly understood, but infection may be a risk factor. Few studies have evaluated pregnancy loss among women living with HIV in the era of potent combination antiretroviral therapy. We hypothesize that maternal HIV and syphilis infection lead to increased risk of pregnancy loss, including both miscarriage and stillbirth. This study aimed to assess trends and possible predictors of spontaneous miscarriage and stillbirth among women living with HIV in a cohort of nearly 56,000 deliveries at a major referral institution in a city with the highest prevalence of HIV in Brazil. Data from hospital records for women delivering from January 1, 2008 to December 31, 2018 were reviewed. Rates of stillbirth, miscarriage, and any pregnancy loss were compared using the Pearson chi-square test. Predictors of pregnancy loss were evaluated by robust univariate log-linear Poisson regression using a generalized estimating equations approach. A total of 55,844 pregnancies were included in the analysis, with 54,308 pregnancies from 43,502 women without HIV and 1536 pregnancies from 1186 women living with HIV (seroprevalence of maternal HIV: 2.7%). Overall, 1130 stillbirths (2.0%) and 6558 miscarriages (11.7%) occurred. Any pregnancy loss was similar in both groups (13.8% in women without and 14.1% in women with HIV; P=.733). Stillbirth was higher among women living with HIV (3.4%) than among women without HIV (2.0%; P<.001), but there was no difference in overall miscarriage rates (10.7% in women with vs. 11.8% in women without HIV; P=.188). Women living with HIV had higher miscarriage rates between 12 and 20 weeks than women without HIV (34.8% vs 23.7%; P=.001), likely because of syphilis coinfection. Stillbirth rates were higher for women living with HIV from 2008 to 2014; however, a steady plateau was reached from 2014 to 2018, mirroring stillbirth rates in women without HIV. Maternal HIV infection did not increase the risk of miscarriage (relative risk, 0.90; 95% confidence interval, 0.77-1.05) or any pregnancy loss (relative risk, 1.00; 95% confidence interval, 0.88-1.15), but was associated with stillbirth (relative risk, 1.65; 95% confidence interval, 1.23-2.21). Maternal syphilis was associated with any pregnancy loss (relative risk, 1.24; 95% confidence interval, 1.11-1.38) and stillbirth (relative risk, 3.39; 95% confidence interval, 2.77-4.14), but not miscarriage (relative risk, 0.91; 95% confidence interval, 0.80-1.04). In the era of combination antiretroviral therapy, there was no difference in miscarriage rates between women with and without HIV. HIV was associated with stillbirth risk but improved over time. Maternal syphilis was significantly associated with any pregnancy loss and stillbirth in all women. Syphilis is likely the main driver of pregnancy loss in women living with HIV in Brazil.

AIDS-related cytomegalovirus encephalitis in the late ART era: A retrospective cohort study at a referral center in Brazil.

AIDS-related cytomegalovirus (CMV) encephalitis has declined in the combined antiretroviral therapy (ART) era in high-income countries. However, there is scarce information on CMV encephalitis in low- and middle-income countries. The objectives of this study were to identify the prevalence of AIDS-related CMV encephalitis and describe its main features. This was a retrospective cohort study carried out at a referral center in São Paulo, Brazil. We included adult people living with HIV/AIDS (PLWHA), hospitalized in 2019, with a CD4 cell count ≤100/mm3 and quantitation CMV DNA results in plasma. Cases with compatible neurological manifestations and detection of CMV DNA by polymerase chain reaction (PCR) in cerebrospinal fluid samples were defined as CMV encephalitis. Among 761 PLWHA hospitalized, 248 (32.5%) cases were included in this study. Prevalence of CMV encephalitis was 2.4% (6/248) among all included cases and 7.7% (6/78) among individuals with neurological opportunistic diseases. The six patients with CMV encephalitis were males and had CD4 cell count <50/mm3. Five (83%) cases had CMV encephalitis as AIDS-defining disease and showed CMV DNA detection by PCR >50,000UI/mL plasma. All six cases received anti-CMV therapy (ganciclovir, n = 4; ganciclovir plus foscarnet, n = 2) and five were discharged to home. CMV encephalitis was not uncommon among hospitalized PLWHA with neurological opportunistic diseases. The epidemiological and immunological profile of individuals with CMV encephalitis was similar to that described in the pre-ART era, but in contrast, most cases were treated and discharged from the hospital.

HIV-related lymphomas.

To summarize the recent evidence on the pathology, current standard of care and recent advances in the treatment of HIV-related lymphomas. Lymphomas remain a major cause of morbidity and mortality in people living with HIV, even in the era of combination antiretroviral therapy (cART). However, treatment outcomes for these malignancies have improved in recent decades, due to full-dose chemotherapy, effective cART and supportive care. Recent advances include the identification of novel driving signaling pathways as promising molecular targets to improve lymphoma outcomes. Patients with HIV-related lymphomas who receive effective cART should be treated like the general population.

A Novel Prognostic Score Including the CD4/CD8 for AIDS-Related Lymphoma.

BackgroundA simple and clinically applicable prognostic scoring system for AIDS-related lymphoma (ARL) in the era of combination antiretroviral therapy (cART) is needed to better stratify patients’ risks and to assist in the decision-making of therapeutic strategies.MethodsWe conducted a retrospective multicenter cohort study in 138 primary ARL patients over an 8-year period from 2013 to 2020. Survival curves were estimated using the Kaplan–Meier method. Univariate and multivariate Cox proportional hazard models were performed to identify the association between patient-, lymphoma-, and HIV-specific variables with progression-free survival (PFS) and overall survival (OS). The incremental prognostic value of novel inflammatory biomarkers in the International Prognostic Index (IPI) was evaluated by comparing the receiver operating characteristic (ROC) curves, the concordance index (C-index), and the integrated Brier score (IBS).ResultsThe median age was 49.14 ± 14.20 (range 18–79) years, 81.9% were men, and the median follow-up was 44.94 (95% CI = 37.05–52.84) months. The 3-year OS and PFS were 39.4% (95% CI = 16.3–21.2) and 38.7% (95% CI = 14.5–19.7), respectively. We found that age, extranodal sites, bulky mass, CD4 T-cell counts, CD4/CD8 ratio, and hypoalbuminemia were associated with OS (all P < 0.05) at both univariate and multivariate analyses. Of the new inflammatory markers, only the CD4/CD8 ratio was an independent prognostic parameter of OS and PFS. A lower CD4/CD8 ratio was strongly associated with adverse clinical factors, including older age, advanced Ann Arbor stage, more extranodal sites, elevated erythrocyte sedimentation rate, prior history of HIV, higher red cell distribution width ratio, hypoproteinemia, and emaciation. When the CD4/CD8 ratio was added to the IPI, the composite HIV-IPI score showed significantly better discrimination than IPI alone [AUC (95% CI): HIV-IPI, 0.83 (0.77–0.89) vs. IPI, 0.72 (0.70–0.85)]. The HIV-IPI model provided good predictive performance [C-index (95% CI): HIV-IPI, 0.82 (0.81–0.83) vs. IPI, 0.75 (0.73–0.77), P < 0.001] and a satisfactory calibration function.ConclusionsThe CD4/CD8 ratio, an inexpensive and readily available marker, is a powerful independent prognostic parameter in patients with ARL. Furthermore, when the CD4/CD8 ratio is used in combination with IPI, it increases prognostic ability. The useful prediction of expected outcomes in ARL can inform treatment decisions.

Impact of HIV infection on clinical outcomes among people diagnosed with head and neck cancer.

e18080 Background: Incidence of non-AIDS-defining cancers, including head and neck cancer (HNC), is rising among people with HIV (PWH) in the combination antiretroviral therapy (cART) era. The following study compares demographics, clinical outcomes, and the tumor microenvironment of HIV+ and Uninfected HNC patients at a single institution. Methods: Yale Tumor Registry query identified 3,356 HNC patients from 2002 to 2018 for analysis, including 50 PWH. In addition, quantitative immunofluorescence (QIF) was performed on tumor tissue from 22 PWH and 75 matched Uninfected patients. HPV status was based on p16 staining done universally among oropharyngeal squamous cell carcinomas (OPSCC) after 2010. Results: PWH were younger at cancer presentation compared to Uninfected patients (55.5 vs. 62.0, p &lt; 0.001), with differences in race/ethnicity and insurance status (p &lt; 0.001 for both). Biologic sex, tobacco use, alcohol consumption, anatomic site, stage at presentation, stage-specific treatment, and time to initiation of treatment were comparable between HIV+ and Uninfected cohorts. 89% of the PWH were on cART, with 79% achieving viral loads ≤200 copies/mL and a median CD4 count of 341 cells/mm³. Median survival among PWH was 39.1 months, compared to 100.8 months among Uninfected patients (p &lt; 0.001). In a multivariate (MV) analysis that included age, sex, race/ethnicity, tobacco use, anatomic site, stage, time to treatment initiation and insurance status, HIV was an independent predictor of poor outcome (HR 1.88 with 95% CI: 1.25-2.81). Difference in survival was noted particularly in early stage (stages 0, I, II) cancer, with a median survival of 73.8 months in PWH compared to 141.9 months in Uninfected patients (p = 0.001). Survival was comparable among late stage (stages III, IV) HNC patients. Among PWH, increased HIV viral load was associated with poor outcome in a MV analysis (p = 0.03). Among HPV-associated OPSCC, PWH had decreased survival compared to Uninfected patients (p &lt; 0.001). In our study of the tumor microenvironment by QIF, tumors of PWH had lower tumoral CD8 T cell infiltration (p = 0.04) and lower PD-L1 expression in tumor, stroma, and combined compartments (CPS) (p = 0.01, p = 0.03, and p = 0.01, respectively) compared to Uninfected patients. Conclusions: In our single institution study, HNC patients living with HIV experienced decreased overall survival, with HIV serving as an independent predictor of poor outcome in a multivariate analysis which included insurance status and treatment approaches. Difference in outcome was significant among early stage tumors and among HPV+ OPSCC. CD8 T cell infiltration and PD-L1 expression, both associated with improved outcomes in the general population, are decreased within the TME of PWH. Our data suggest that HIV-associated HNC is associated with poorer outcomes and highlight differences in tumor biology that require further detailed characterization in large cohorts.