Human Immunodeficiency Virus RNA Levels Research Articles

Broadly neutralizing antibodies for HIV prevention: a comprehensive review and future perspectives.

SUMMARYThe human immunodeficiency virus (HIV) epidemic remains a formidable global health concern, with 39 million people living with the virus and 1.3 million new infections reported in 2022. Despite anti-retroviral therapy's effectiveness in pre-exposure prophylaxis, its global adoption is limited. Broadly neutralizing antibodies (bNAbs) offer an alternative strategy for HIV prevention through passive immunization. Historically, passive immunization has been efficacious in the treatment of various diseases ranging from oncology to infectious diseases. Early clinical trials suggest bNAbs are safe, tolerable, and capable of reducing HIV RNA levels. Although challenges such as bNAb resistance have been noted in phase I trials, ongoing research aims to assess the additive or synergistic benefits of combining multiple bNAbs. Researchers are exploring bispecific and trispecific antibodies, and fragment crystallizable region modifications to augment antibody efficacy and half-life. Moreover, the potential of other antibody isotypes like IgG3 and IgA is under investigation. While promising, the application of bNAbs faces economic and logistical barriers. High manufacturing costs, particularly in resource-limited settings, and logistical challenges like cold-chain requirements pose obstacles. Preliminary studies suggest cost-effectiveness, although this is contingent on various factors like efficacy and distribution. Technological advancements and strategic partnerships may mitigate some challenges, but issues like molecular aggregation remain. The World Health Organization has provided preferred product characteristics for bNAbs, focusing on optimizing their efficacy, safety, and accessibility. The integration of bNAbs in HIV prophylaxis necessitates a multi-faceted approach, considering economic, logistical, and scientific variables. This review comprehensively covers the historical context, current advancements, and future avenues of bNAbs in HIV prevention.

HIV-1 Tat is present in the serum of people living with HIV-1 despite viral suppression

ObjectivesDespite successful human immunodeficiency virus (HIV) control with combination antiretroviral therapy (cART), individuals with HIV still face health risks, including cancers, cardiovascular and neurocognitive diseases. An HIV protein, Tat, is potentially involved in these HIV-related diseases. Previous studies demonstrated circulating Tat in the blood of untreated people with HIV. Here, we measured Tat levels in the serum of cART-treated people with HIV to examine the effect of cART on Tat production. MethodsSerum samples from 63 HIV-positive and 20 HIV-seronegative individuals were analyzed using an ELISA assay that detected Tat concentrations above 2.5 ng/mL. ResultsAmong HIV-positive individuals, the Tat level ranged from 0 to 14 ng/mL. 25.4% (16 out of 63) exceeded the 2.5 ng/mL cut-off, with a median HIV Tat level of 4.518 [3.329-8.120] ng/mL. No correlation was revealed between Tat levels and CD4+ T cell counts, serum HIV RNA, p24 antigen, or anti-Tat levels. ConclusionsDespite cART, circulating HIV Tat persists and may contribute to HIV-related diseases. This emphasizes the need for further research on the mechanisms of Tat action in non-infected cells where it can penetrate upon circulation in the blood.

HIV-1 proviral DNA in purified peripheral blood CD34+ stem and progenitor cells in individuals with long-term HAART; paving the way to HIV gene therapy

Human immunodeficiency virus (HIV)-1 infection is an important public health problem worldwide. After primary HIV-1 infection, transcribed HIV-1 DNA is integrated into the host genome, serving as a reservoir of the virus and hindering a definite cure. Although highly active antiretroviral therapy suppresses active viral replication, resulting in undetectable levels of HIV RNA in the blood, a viral rebound can be detected after a few weeks of treatment interruption. This supports the concept that there is a stable HIV-1 reservoir in people living with HIV-1. Recently, a few individuals with HIV infection were reported to be probably cured by hematopoietic stem transplantation (HSCT). The underlying mechanism for this success involved transfusion of uninfected hematopoietic stem and progenitor cells (HSPCs) from CCR5-mutated donors who were naturally resistant to HIV infection. Thus, gene editing technology to provide HIV-resistant HSPC has promise in the treatment of HIV infections by HSCT. In this study, we aimed to find HIV-infected individuals likely to achieve a definite cure via gene editing HSCT. We screened for total HIV proviral DNA by Alu PCR in peripheral blood mononuclear cells (PBMCs) of 20 HIV-infected individuals with prolonged viral suppression. We assessed the amount of intact proviral DNA via a modified intact proviral DNA assay (IPDA) in purified peripheral CD34+ HSPCs. PBMCs from all 20 individuals were positive for the gag gene in Alu PCR, and peripheral CD34+ HSPCs were IPDA-negative for six individuals. Our results suggested that these six HIV-infected individuals could be candidates for further studies into the ability of gene editing HSCT to lead to a definite HIV cure.

Distribution of the Prevalence of Human Leukocyte Antigen (HLA)-B*57:01 Positivity in HIV-1 Infected Individuals and Its Effects on Treatment: Türkiye Map-Buhasder Working Group

Human immunodeficiency virus (HIV)/acquired immundeficiency syndrome (AIDS) is a critical global public health problem that significantly affects both life expectancy and the overall quality of life of individuals in all age groups. The landscape of HIV infection has changed significantly in recent years due to the introduction of effective combination antiretroviral therapies (ART). A key component of first-line ART regimens for HIV treatment is abacavir, a nucleoside HIV reverse transcriptase inhibitor. Although abacavir is effective in suppressing viral replication and managing disease, its clinical utility is overshadowed by the potential for life-threatening hypersensitivity reactions in HLA-B*57:01-positive patients. In our country, local data obtained from various centers regarding the prevalence of HLA-B*57:01 in HIV-1-infected patients are available. In this study, it was aimed to determine the prevalence of the HLA-B*57:01 genotype in HIV-infected patients who were followed up and treated in many regions of our country. This retrospective study consists of the data of the patients aged 18 years and over diagnosed with HIV-1 infection between 01.01.2019 and 31.07.2022. Age, gender, place of birth, mode of transmission of the disease, death status, CD4+ T cell count and HIV RNA levels at the first clinical presentation, HLA-B*57:01 positivity, and the method used, clinical stage of the disease, virological response time with the treatment they received were recorded from the patient files. Data were collected from 16 centers and each center used different methods to detect HLA-B*57:01. These methods were sequence-specific oligonucleotide probe hybridization (SSOP), DNA sequence-based typing (SBT), single-specific primer-polymerase chain reaction (SSP-PCR), allele-specific PCR (AS-PCR) and quantitative PCR (Q-PCR). A total of 608 HIV-infected individuals, 523 males (86%) and 85 females (14%), were included in the study. The mean age of the patients was 36.9 ± 11.9 (18-73) years. The prevalence of HLA-B*57:01 allele was found to be 3.6% (22 patients). The number of CD4+ T lymphocytes in HLA-B*57:01 allele-positive patients was > 500/ mm3 in 10 patients (45.5%), while the number of CD4+ T lymphocytes in HLA-B*57:01 negative patients was > 500/mm3 in 216 patients (36.9%) (p> 0.05). Viral load at the time of diagnosis was found to be lower in patients with positive HLA-B*57:01 allele but it was not statistically significant (p> 0.05). Although different treatment algorithms were used in the centers following the patients, it was observed that the duration of virological response was shorter in HLA-B*57:01 positive patients (p= 0.006). Although the presence of the HLA-B*57:01 allele has a negative impact due to its association with hypersensitivity, it is likely to continue to attract interest due to its association with slower progression of HIV infection and reduced risk of developing AIDS. In addition, although the answer to the question of whether it is cost-effective to screen patients for HLA-B*57:01 before starting an abacavir-containing ART regimen for the treatment of HIV infection is being sought, it seems that HIV treatment guidelines will continue to recommend screening to identify patients at risk in this regard.

Evaluation of peripheral and central olfactory pathways in HIV-infected patients by MRI

To investigate peripheral and central olfactory pathways using cranial magnetic resonance imaging (MRI) in human immunodeficiency virus (HIV)-infected patients. The cranial MRI images of 37 HIV-infected adult patients and 37 adults without HIV infection having normal cranial MRI results were included in the study. In both groups, olfactory bulb (OB) volume and olfactory sulcus (OS) depth; and insular gyrus and corpus amygdala areas were measured using cranial MRI. In the HIV group, disease duration, HIV RNA, and CD4 lymphocyte count and levels as a percentage were also recorded. The HIV group had significantly lower bilateral OB volumes, insular gyrus and corpus amygdala areas compared to the control group. The HIV group showed positive correlations between OB volumes, OS depths, insular gyrus, and corpus amygdala areas bilaterally. Increases in OB volumes and OS depths were associated with an increase in the insular gyrus area. The corpus amygdala and insular gyrus areas increased similarly. There was no significant correlation between age, gender, disease duration, CD4 lymphocyte count and per cent, HIV RNA values, and the measurement values of the central and peripheral olfactory regions. A decrease in olfactory regions of OB, insular gyrus, and corpus amygdala in HIV-infected patients shows that HIV infection may cause olfactory impairment. There is no correlation between disease duration and olfactory impairment. It may be related to neuroinflammation, HIV-related brain atrophy, acquired immunodeficiency syndrome (AIDS) dementia complex, or neurocognitive impairment, which are the other explanations for the olfactory impairment in HIV. The possible toxicity from antiretroviral therapy (ART) may be another cause that should be investigated further.

Daily Oral HIV Pre-exposure Prophylaxis Among Young Men Who Have Sex With Men in the United States: Cost-saving at Generic Drug Price.

Adherence and retention concerns raise questions about the effectiveness and cost-effectiveness of oral HIV pre-exposure prophylaxis (PrEP) in young men who have sex with men (YMSM). Using an adolescent-focused simulation model, we compared annual HIV screening alone with tenofovir disoproxil fumarate/emtricitabine-based oral PrEP with every 3-month HIV screening in YMSM (aged 15-24) at increased risk of HIV. Data derived from published sources included: age-stratified HIV incidence/100 person-years (PY) on- or off-PrEP (0.6-10.1 or 0.4-6.4), PrEP retention at 6 years (28%), transmissions by HIV RNA level (0.0-78.4/100PY) and annual costs of antiretroviral therapy ($32 000-69 000), HIV care ($3100-34 600), and PrEP program/generic drug ($900/360). Outcomes included transmissions (percent of cohort infected), quality-adjusted life-years (QALYs), costs ($), and incremental cost-effectiveness ratios ($/QALY). We explored the sensitivity of findings to variation in HIV incidence and drug prices. Compared with annual screening alone, PrEP would increase QALYs (9.58 to 9.67), reduce new infections (37% to 30%), and decrease costs (by $5000) over 10 years. PrEP would remain cost-saving for HIV incidence off-PrEP ≥5.1/100PY or annual PrEP price ≤$1200. Over a lifetime horizon, PrEP would be cost-saving for HIV incidence off-PrEP ≥1.0/100PY, across all retention assumptions examined. PrEP would not be cost-effective at HIV incidence ≤0.1/100PY, regardless of drug price, due to programmatic costs. In US YMSM at increased risk of HIV, generic oral PrEP and every-3-month screening would be cost-saving compared with annual screening alone, even with high discontinuation and low adherence, over a range of HIV incidences.

A germ-free humanized mouse model shows the contribution of resident microbiota to human-specific pathogen infection.

Germ-free (GF) mice, which are depleted of their resident microbiota, are the gold standard for exploring the role of the microbiome in health and disease; however, they are of limited value in the study of human-specific pathogens because they do not support their replication. Here, we develop GF mice systemically reconstituted with human immune cells and use them to evaluate the role of the resident microbiome in the acquisition, replication and pathogenesis of two human-specific pathogens, Epstein-Barr virus (EBV) and human immunodeficiency virus (HIV). Comparison with conventional (CV) humanized mice showed that resident microbiota enhance the establishment of EBV infection and EBV-induced tumorigenesis and increase mucosal HIV acquisition and replication. HIV RNA levels were higher in plasma and tissues of CV humanized mice compared with GF humanized mice. The frequency of CCR5+ CD4+ T cells throughout the intestine was also higher in CV humanized mice, indicating that resident microbiota govern levels of HIV target cells. Thus, resident microbiota promote the acquisition and pathogenesis of two clinically relevant human-specific pathogens.

Human Immunodeficiency Virus Status, Tenofovir Exposure, and the Risk of Poor Coronavirus Disease 19 Outcomes: Real-World Analysis From 6 United States Cohorts Before Vaccine Rollout.

People with human immunodeficiency virus (HIV) (PWH) may be at increased risk for severe coronavirus disease 2019 (COVID-19) outcomes. We examined HIV status and COVID-19 severity, and whether tenofovir, used by PWH for HIV treatment and people without HIV (PWoH) for HIV prevention, was associated with protection. Within 6 cohorts of PWH and PWoH in the United States, we compared the 90-day risk of any hospitalization, COVID-19 hospitalization, and mechanical ventilation or death by HIV status and by prior exposure to tenofovir, among those with severe acute respiratory syndrome coronavirus 2 infection between 1 March and 30 November 2020. Adjusted risk ratios (aRRs) were estimated by targeted maximum likelihood estimation, with adjustment for demographics, cohort, smoking, body mass index, Charlson comorbidity index, calendar period of first infection, and CD4 cell counts and HIV RNA levels (in PWH only). Among PWH (n = 1785), 15% were hospitalized for COVID-19 and 5% received mechanical ventilation or died, compared with 6% and 2%, respectively, for PWoH (n = 189 351). Outcome prevalence was lower for PWH and PWoH with prior tenofovir use. In adjusted analyses, PWH were at increased risk compared with PWoH for any hospitalization (aRR, 1.31 [95% confidence interval, 1.20-1.44]), COVID-19 hospitalizations (1.29 [1.15-1.45]), and mechanical ventilation or death (1.51 [1.19-1.92]). Prior tenofovir use was associated with reduced hospitalizations among PWH (aRR, 0.85 [95% confidence interval, .73-.99]) and PWoH (0.71 [.62-.81]). Before COVID-19 vaccine availability, PWH were at greater risk for severe outcomes than PWoH. Tenofovir was associated with a significant reduction in clinical events for both PWH and PWoH.

Management of HBV/HIV Co-Infection

Co-infection with human immunodeficiency virus (HIV) and hepatitis B virus (HBV) represents a complex and dispassionate challenge that demands a versatile approach. This abstract specifies a survey of key strategies for the administration of HBV/ HIV co-contamination, accompanied by a devoted effort to antiretroviral healing (ART), the HBV situation, and listening. Antiretroviral therapy is the foundation for directing hepatitis B virus (HBV)/HIV contamination. The incorporation of HIVHBV drugs into ART regimens is essential. Tenofovir-located regimens containing tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) have proven to be effective against both viruses. Emtricitabine and lamivudine are frequently used in combination medicine. Monitoring drug opposition and energy abolition is achieved by guaranteeing the influence of the treatment. In HBV mono-infection, nucleotide analogs (NA) are used to restrain energetic copies. However, in cocontamination, NAs concede the possibility of ideally having a two-fold project against both HIV and HBV infection. TDF and TAF meet this necessity, making the ruling class the chosen choice. Regular listening is essential for evaluating the reaction to the situation and the progress of a liver ailment. This involves measuring the CD4 counts, HIV RNA levels, and HBV DNA levels. In addition, liver function tests and liver depictions help label cirrhosis and abnormal hepatocellular growth in animals. HBV immunization is essential for co-infected cells that are not resistant to HBV. Post-vaccination agents that negate the effect of an infection or poison titer should be restrained to ratify exemption. The prevention of broadcasting is another critical aspect of the administration. Safe sexuality practices and harm decline methods, including tease exchange programs for injecting drug use, detract from lowering the risk of transmission of the two viruses together.

Longitudinal decline of plasma neurofilament light levels after antiretroviral initiation in people living with HIV.

This retrospective follow-up study aims to investigate the dynamic longitudinal change of plasma neurofilament light (NfL) levels after antiretroviral therapy (ART) initiation in a cohort of people living with human immunodeficiency virus (HIV) (PWH). We tested a convenience sample of 116 patients from the NORTHIV study. Plasma NfL levels-measured using Single molecule array (Simoa) technology-as well as other laboratory parameters were collected at baseline, weeks 4, 48, 96, and 144. Linear mixed-effects models were estimated to evaluate longitudinal change over time. Baseline CD4+ T-cell levels, CDC classification, and HIV RNA levels were considered. Models were adjusted by age, sex, treatment regimen, and baseline serum creatinine levels. Plasma NfL levels were higher at baseline and also declined faster during the follow-up for participants with CD4+ count <100 cells/µl compared with >100 cells/µl. No significant difference was found between the CD4+ strata 100-199 and 200-499/µl. Participants with CDC classification stages B and C had higher levels of plasma NfL at baseline, as well as faster decline compared with participants with stage A. No significant main effects or change over time was found in baseline HIV RNA levels, treatment regimen, or sex. Plasma NfL is a sensitive biomarker to assess ongoing central nervous system injury in PWH. Plasma NfL concentrations decline relatively fast following ART initiation and then stabilize after 48 weeks. Plasma NfL concentrations are associated with CD4+ count and stage of HIV disease. No correlations were seen with different ART regimens.

Isolated exercise-induced pulmonary hypertension is associated with clinical worsening and poor immunological control in HIV patients

Exercise-induced pulmonary hypertension (Ex-PH), due to impaired pulmonary vascular and right ventricular (RV) contractile reserve on effort, may represent the earliest sign of pulmonary arterial hypertension (PAH), which may develop in Human immunodeficiency virus (HIV) patients with poor disease control. We investigated its association with clinical determinants of immunological status, virological control, and response to antiviral therapy in HIV patients at risk for PAH. In 31 consecutive HIV patients with either low ( n = 29) or intermediate probability ( n = 3) of PH at rest, we evaluated the association of isolated ExPH with: time to HIV diagnosis, CD4+ T cell count, clinical progression to AIDS, development of resistance to antiretroviral therapy (ART), HIV RNA levels (copies/mL), time to onset of ART, current use of protease inhibitors, combination of ART with boosters (ritonavir e cobicistat), virological response to ART, ART discontinuation. Isolated ExPH at stress echocardiography (ESE) was defined as absence of PH at rest and systolic pulmonary arterial pressure (sPAP) >45 mmHg or a raise of >20 mmHg during low-intensity exercise (while not exceeding a cardiac output of 10 l/min). 20% of the enrolled population developed ExPH. ExPH was inversely associated with CD4+ T cell count ( p = 0.047), time to HIV diagnosis ( p = 0.014) and time to onset of ART ( p = 0.041) compared to patients without ExPH. Patients with ExPH had greater worsening of functional class than patients without ExPH ( p < 0.001). ExPH and AIDS showed a non-statistically significant trend of direct association ( p = 0.093). However, AIDS patients had an increase in pulmonary vascular reserve index (PVRI) compared to patients without ExPH (p = 0.020) at rest echocardiography. We also observed an inverse correlation between the time to onset of ART with right atrium area ( r = − 0.411, p = 0.022) and indexed right atrial volume ( r = − 0.102, p = 0.009). Isolated ExPH associates with clinical worsening and poorer immunological control in HIV patients. The assessment of ExPH by ESE may help identify subgroups of HIV patients with a propensity to develop subclinical impairment of pulmonary circulation following poor control of HIV infection.

Cognitive Assessment of Young Adults Before and After Initiation of Combination Antiretroviral Therapy.

In the determination and monitoring of neurocognitive disorders in human immunodeficiency virus (HIV)-positive individuals, there is a need for significantly more practical methods which provide results in a shorter time than the tests that require challenging and specialized expertise. This study aimed to evaluate cognitive functions and the factors affecting them in naïve HIV-positive patients using by Montreal Cognitive Assessment (MoCA) test before and after the initiation of combination antiretroviral therapy. HIV-positive, treatment-naïve patients monitored between January-June 2017 were included in the study. The MoCA test was performed at the beginning and the sixth month of the treatment. Forty male patients were included in the study. The mean age was calculated as 29.1±4.0. When the factors affecting the MoCA score were examined, there was a significant relationship between the education level and the MoCA score. Smoking, using alcohol, and substance did not have a significant impact on baseline MoCA values. A significant correlation was found between cluster differentiation 4 (CD4) count and HIV RNA level and attention function. There was a significant increase in the total MoCA score and the MoCA subgroup scores at the end of the sixth month of the treatment. MoCA test is one of the most practical tests that can be applied in a short time period, and it was found useful in evaluating the changes in the cognitive functions of HIV-positive patients during antiretroviral treatment.

Low Spontaneous Clearance Rates of Recently Acquired Hepatitis C Virus in Human Immunodeficiency Virus-Positive Men Who Have Sex With Men (PROBE-C Study).

Using direct-acting antivirals (DAAs) for recently acquired hepatitis C virus (RAHCV) infections, particularly in human immunodeficiency virus (HIV)-positive men who have sex with men (MSM), dramatically reduced the incidence of hepatitis C. However, implementation into clinical practice is challenging. The aim of this study was to analyze spontaneous clearance (SC) rates of RAHCV and to identify predictors of SC. The PROBE-C study is an observational European cohort on RAHCV infections in HIV-positive MSM. Between 2007 and 2017, RAHCV infections were documented with ≥12 months of follow-up. Fisher exact, χ2, and Mann-Whitney U tests were used for statistical analysis. A total of 464 RAHCV infections were documented; 457 of 464 patients (98%) were male, and the median age (interquartile range [IQR]) was 41 (38-46) years. The main risk group for hepatitis C virus (HCV) transmission was MSM (98.9%). Most participants were infected with HCV genotype 1 (78.3%). The median baseline HCV RNA level (IQR) was 230 000 (135 000-474 432) IU/mL, and the median CD4+ T-cell count was 574/µL (547-604/µL. Of all cases, 92% received combination antiretroviral therapy, with 91% showing suppressed HIV RNA levels (<200 copies/mL). The median maximum alanine aminotransferase level (IQR) was 445 (402-522) U/L. SC of RAHCV infection occurred in 55 of 464 cases (11.9%). A >2-log decline in HCV RNA levels 4 weeks after diagnosis of RAHCV infection was the strongest predictor of SC (P < .001; sensitivity, 96.4%; specificity, 97.5%; positive predictive value, 84.1%; negative predictive value, 99.5%). SC of RAHCV in HIV-positive MSM is found in only 11.9% of cases and a <2-log drop in HCV RNA level at week 4 after diagnosis should prompt early DAA-based treatment. However, immediate DAA treatment for RAHCV infection may also be favored in patients with ongoing transmission risk behavior.

Mother-to-Child Transmission of HIV Within 24 Months After Delivery in Women Initiating Lifelong Antiretroviral Therapy Pre/Post-Conception or Postnatally; Effects of Adolescent Girl and Young Woman Status and Plasma Viremia Late in Pregnancy

IntroductionMother-to-child-transmission (MTCT) of human immunodeficiency virus (HIV) can occur in pregnancy/in utero (IU), during childbirth/intrapartum (IP), or postpartum (PP) through breastfeeding from an infected mother to her infant. Burden of PP-MTCT and associated risk factors remain poorly described, especially in adolescent girls and young women (AGYW) aged 15–24 years. Furthermore, despite concerns on high postnatal seroconversions, there is paucity of data on the burden of subsequent MTCT rates.MethodsPregnant women ≥20 weeks of gestation were enrolled into the University of Zimbabwe Birth Cohort from four primary health centers in Harare, Zimbabwe. Mother–infant dyads were followed up from delivery, week(s) 1, 6, 10, 14, 24, 36, 48, 72, and 96 after birth. Women who were uninfected at baseline were re-tested for HIV on subsequent visits. Plasma HIV RNA was quantified using reverse transcriptase polymerase chain reaction. Exposed babies were tested for HIV using qualitative/quantitative proviral DNA PCR on dried blood spots. Maternal–infant factors were tested in univariable/multivariable regression analyses for HIV-MTCT predictors.ResultsA total of 600 HIV-uninfected and 608 HIV-infected pregnant women on Tenofovir/Lamivudine/Efavirenz regimen were enrolled from 2016 to 2019. Postnatal HIV incidence was 0.42 cases/100 women-years [95% confidence interval (CI): 0.12–1.1]. Postnatal seroconverters were less likely to have children/pregnancies sharing same father and unaware of their spouses/intimate partner’s HIV status: p = 0.008 and p = 0.02, respectively, compared with non-seroconverters.Overall HIV-MTCT rate was (15/549): 2.7% (CI: 1.3–4.1%); (7/93) 7.5% observed in AGYW against 1.7%; in women aged &amp;gt;24, p = 0.008. PP-MTCT was the predominant 9/15 (60%) route, followed by IP-MTCT 4/15 (26.6%), whereas IU and postnatal MTCT rates each contributed 6.7% of all infant infections. Postnatal MTCT incidence was 12.8 (CI: 0.3–71.4) infant HIV infections/100 child-years of breastfeeding; a rate 14 times higher than PP-MTCT rate in babies born to women HIV-infected pre/post-conception whose babies were HIV DNA PCR–negative at six weeks.Antenatal HIV RNA &amp;gt;1,000 copies/ml was independently associated with MTCT; odds ratio [CI: 9.3 (2.6–43.1)]. Infected infants’ pre–HIV treatment HIV RNA levels correlated positively with maternal viral load; Spearman’s rank correlation. r = 0.6; p = 0.03.DiscussionMothers were 9.3 times more likely to transmit if HIV RNA was &amp;gt;1,000 copies/ml, disproportionately occurring in vulnerable AGYW. Breastfeeding-associated PP-MTCT remains high; therefore, it is imperative that HIV-infected women commence antiretroviral therapy early in pregnancy to suppress HIV RNA until weaning to decrease the risk of MTCT and possibly reduce the severity of disease in infected infants. HIV-uninfected lactating mothers should be continuously counseled on the risks of postnatal seroconversion.www.clinicaltrials.gov, trial registration number: NCT04087239.

Research Progress on the Relationship between the NLRP3 Inflammasome and Immune Reconstitution in HIV-Infected Patients Receiving Antiretroviral Therapy.

Human immunodeficiency virus (HIV) infection is characterized not only by severe immunodeficiency but also by persistent inflammation and immune activation. These characteristics persist in people living with HIV (PLHIV) receiving effective antiretroviral therapy (ART) and are associated with morbidity and mortality in nonacquired immunodeficiency syndrome (AIDS) events. ART can inhibit HIV replication and promote immune reconstitution, which is currently the most effective way to control AIDS. However, despite effective long-term ART and overall suppression of plasma HIV RNA level, PLHIV still shows chronic low-level inflammation. The exact mechanisms that trigger chronic inflammation are unknown. Activation of the inflammasome is essential for the host response to pathogens, and some recent studies have confirmed the role of the inflammasome in the pathogenesis of inflammatory diseases. The NLRP3 inflammasome has been widely studied, which is a pyrin domain-containing protein 3 belonging to the family of nucleotide-binding and oligomerization domain-like receptors (NLRs). Recent studies suggest that inflammasome-mediated pyroptosis is associated with CD4+ T cell loss in the absence of persistent infectious HIV replication. This article reviews the mechanism of the NLRP3 inflammasome and its correlation with immune reconstitution in PLHIV treated with ART.

The relationship of antibodies detected in the Western Blot test with clinical and immunological stages in HIV-infected patients

Background/Aim: The laboratory diagnosis of human immunodeficiency virus (HIV) infection is based on detection of anti-HIV antibodies in an initial ELISA (enzyme-linked immunosorbent assay) test and its confirmation with the Western Blot (WB) procedure. Even though the specificity of WB is high for the detection of antibodies against various viral proteins, there are important differences in the timing of the appearance of antibody bands and intensities in different stages of HIV infection. The aim of this study was to evaluate antibodies detected in WB testing and the relationship to clinical and immunological stages in HIV-infected patients. Methods: Newly diagnosed 78 patients with HIV/AIDS (Acquired Immunodeficiency Syndrome) in our outpatient department between April 2009 and September 2012 were included in the study as a retrospective cohort. Age, gender, complaints, clinical signs, CD4+ T lymphocyte counts and HIV RNA level at diagnosis were collected retrospectively from medical records. WB band patterns obtained from the reference laboratory of the Istanbul Public Health Center were examined retrospectively. Results: Of the 78 HIV/AIDS cases, 68 (87.2%) were male. Mean age was 38.87(13.09) years (range, 17-83 years). Median CD4+ T lymphocyte count at diagnosis was 410.2 /mm³ (range, 3-1114). Mean HIV RNA level at diagnosis was 592.894 copies/ml. Rare band profiles were seen in 29.4% (23/78). According to World Health Organization (WHO) clinical staging, 59 (75.6%) patients were at stage I, 4 at stage II, 10 at stage III and 5 at stage IV. Gp120, gp160 and gp41, known as envelope glycoproteins in WB band antibodies, were seen in all patients. There was determined to be a decrease in the p17, p51, p55 and p39 bands in WB tests of the advanced grade (Grade IV) of HIV infection. Conclusions: Reduction of p17, p51, p55, p39 antibodies in advanced stages were related with the progression of HIV infection. This shows that WB test is an important parameter not only in the diagnosis of HIV infection, but also in the follow-up of clinical progression in the absence of these antibodies.

13 Isolated exercise-induced pulmonary hypertension is associated with clinical worsening and poor immunological control in HIV patients

Abstract Aims Exercise-induced pulmonary hypertension (Ex-PH) may represent the earliest sign of pulmonary arterial hypertension (PAH) in human immunodeficiency virus (HIV) patients. We investigated its association with clinical and immunological status, virologic control, and response to antiviral therapy. Methods and results In 32 consecutive HIV patients with either low (n = 29) or intermediate probability (n = 3) of PH at rest, we evaluated the association of isolated Ex-PH with: time to HIV diagnosis; CD4+ T-cell count; clinical progression to acquired immunodeficiency syndrome (AIDS); development of resistance to antiretroviral therapy (ART); HIV RNA levels; time to beginning of ART; current use of protease inhibitors; combination of ART with boosters (ritonavir or cobicistat); immuno-virologic response to ART; and ART discontinuation. Isolated Ex-PH at stress echocardiography (ESE) was defined as absence of PH at rest and systolic pulmonary arterial pressure (sPAP) &amp;gt;45 mmHg or a &amp;gt; 20 mmHg increase during low-intensity exercise cardiac output (&amp;lt;10 l/min). In our cohort, 22% (n = 7) of the enrolled population developed Ex-PH which was inversely related to CD4+ T-cell count (P = 0.047), time to HIV diagnosis (P = 0.014) and time to onset of ART (P = 0.041). Patients with Ex-PH had a worse functional class than patients without Ex-PH (P &amp;lt; 0.001). Ex-PH and AIDS showed a trend (P = 0.093) to a direct relationship. AIDS patients had a higher pulmonary vascular resistance compared to patients without Ex-PH (P = 0.020) at rest echocardiography. Conclusions The presence of isolated Ex-PH associates with a worse clinical status and poor immunological control in HIV patients. Assessment of Ex-PH by ESE may help identify subgroups of HIV patients with a propensity to develop subclinical impairment of pulmonary circulation following poor control of HIV infection.

Isolated exercise-induced pulmonary hypertension is associated with clinical worsening and poorer immunological control in hiv patients

Abstract Background and aim Exercise-induced pulmonary hypertension (Ex-PH), due to impaired pulmonary vascular and right ventricular (RV) contractile reserve on effort, may represent the earliest sign of pulmonary arterial hypertension (PAH), which may develop in Human immunodeficiency virus (HIV) patients with poor disease control. We investigated its association with clinical determinants of immunological status, virological control, and response to antiviral therapy in HIV patients at risk for PAH. Methods In 31 consecutive HIV patients with either low (n=29) or intermediate probability (n=3) of PH at rest, we evaluated the association of isolated ExPH with: time to HIV diagnosis, CD4+ T cell count, clinical progression to AIDS, development of resistance to antiretroviral therapy (ART), HIV RNA levels (copies/mL), time to onset of ART, current use of protease inhibitors, combination of ART with boosters (ritonavir e cobicistat), virological response to ART, ART discontinuation. Isolated ExPH at stress echocardiography (ESE) was defined as absence of PH at rest and systolic pulmonary arterial pressure (sPAP) &amp;gt;45 mmHg or a raise of &amp;gt;20 mmHg during low-intensity exercise (while not exceeding a cardiac output of 10 l/min). Results 20% of the enrolled population developed ExPH. ExPH was inversely associated with CD4+ T cell count (p=0.047), time to HIV diagnosis (p=0.014) and time to onset of ART (p=0.041) compared to patients without ExPH. Patients with ExPH had greater worsening of functional class than patients without ExPH (p&amp;lt;0.001). ExPH and AIDS showed a non-statistically significant trend of direct association (p=0.093). However, AIDS patients had an increase in pulmonary vascular reserve index (PVRI) compared to patients without ExPH (p=0.020) at rest echocardiography. We also observed an inverse correlation between the time to onset of ART with right atrium area (r=−0.411, p=0.022) and indexed right atrial volume (r=−0.102, p=0.009). Conclusions Isolated ExPH associates with clinical worsening and poorer immunological control in HIV patients. The assessment of ExPH by ESE may help identify subgroups of HIV patients with a propensity to develop subclinical impairment of pulmonary circulation following poor control of HIV infection. Funding Acknowledgement Type of funding sources: None.

Sex Differences in Human Immunodeficiency Virus Persistence and Reservoir Size During Aging.

Sex differences in human immunodeficiency virus (HIV) reservoir dynamics remain underexplored. Longitudinal samples from virally suppressed midlife women (n = 59, median age 45 years) and age-matched men (n = 31) were analyzed retrospectively. At each time point, we measured sex hormones (by means of enzyme-linked immunosorbent assay) and cellular HIV DNA and RNA (by means of digital droplet polymerase chain reaction). Number of inducible HIV RNA+ cells, which provides an upper estimate of the replication-competent reservoir, was quantified longitudinally in a different subset of 14 women, across well-defined reproductive stages. Mixed-effects models included normalized reservoir outcomes and sex, time since antiretroviral therapy (ART) initiation, and the sex-by-time interaction as predictors. At ART initiation, women and men had median (interquartile range [IQR]) CD4+ T-cell counts of 204/μL (83-306/μL) versus 238/μL (120-284/μL), respectively; median ages of 45 (42-48) versus 47 (43-51) years; and median follow-up times of 79.2/μL (60.5-121.1/μL) versus 66.2/μL (43.2-80.6/μL) months. We observed a significant decline of total HIV DNA over time in both men and women (P < .01). However, the rates of change differed significantly between the sexes (P < .01), with women having a significantly slower rate of decline than men, more pronounced with age. By contrast, the levels of inducible HIV RNA increased incrementally over time in women during reproductive aging (P < .01). In contrast to men, in whom the HIV reservoir steadily declines with aging, the HIV reservoir in women is more dynamic. Total HIV DNA (including intact and defective genomes) declines more slowly in women than in men, while the inducible HIV RNA+ reservoir, which is highly enriched in replication-competent virus, increases in women after menopause.

Safety, pharmacokinetics and antiviral activity of PGT121, a broadly neutralizing monoclonal antibody against HIV-1: a randomized, placebo-controlled, phase 1 clinical trial

Human immunodeficiency virus (HIV)-1-specific broadly neutralizing monoclonal antibodies are currently under development to treat and prevent HIV-1 infection. We performed a single-center, randomized, double-blind, dose-escalation, placebo-controlled trial of a single administration of the HIV-1 V3-glycan-specific antibody PGT121 at 3, 10 and 30 mg kg–1 in HIV-uninfected adults and HIV-infected adults on antiretroviral therapy (ART), as well as a multicenter, open-label trial of one infusion of PGT121 at 30 mg kg–1 in viremic HIV-infected adults not on ART (no. NCT02960581). The primary endpoints were safety and tolerability, pharmacokinetics (PK) and antiviral activity in viremic HIV-infected adults not on ART. The secondary endpoints were changes in anti-PGT121 antibody titers and CD4+ T-cell count, and development of HIV-1 sequence variations associated with PGT121 resistance. Among 48 participants enrolled, no treatment-related serious adverse events, potential immune-mediated diseases or Grade 3 or higher adverse events were reported. The most common reactions among PGT121 recipients were intravenous/injection site tenderness, pain and headache. Absolute and relative CD4+ T-cell counts did not change following PGT121 infusion in HIV-infected participants. Neutralizing anti-drug antibodies were not elicited. PGT121 reduced plasma HIV RNA levels by a median of 1.77 log in viremic participants, with a viral load nadir at a median of 8.5 days. Two individuals with low baseline viral loads experienced ART-free viral suppression for ≥168 days following antibody infusion, and rebound viruses in these individuals demonstrated full or partial PGT121 sensitivity. The trial met the prespecified endpoints. These data suggest that further investigation of the potential of antibody-based therapeutic strategies for long-term suppression of HIV is warranted, including in individuals off ART and with low viral load.