Antiretroviral Research Articles

Development and feasibility testing of a time-restricted eating intervention for women living with overweight/obesity and HIV in a resource-limited setting of South Africa

BackgroundHuman Immunodeficiency Virus (HIV) and type 2 diabetes (T2D) are amongst the leading causes of death in South Africa. The preferred first-line anti-retroviral treatment contains dolutegravir (DTG), shown to increase body weight, may compound the already high rates of obesity and associated risk for T2D. South Africa has widespread food insecurity, making traditional dietary strategies difficult to implement. Time-restricted eating (TRE) may be an appropriate intervention in resource-limited communities.MethodsThis article outlines the development and feasibility testing of a TRE intervention to inform the design of a TRE randomised controlled trial in women (20–45 years old) living with overweight/obesity and HIV, receiving DTG-based treatment from a resource-limited community in Cape Town, South Africa. Factors influencing TRE adoption were identified using the Capability, Opportunity, Motivation – Behaviour model and the Theoretical Domains Framework, combining in-depth interviews (IDIs) and focus group discussions. Participants from the IDIs went on to participate in a single arm 4-week TRE pilot trial where feasibility was explored in terms of reach, acceptability, applicability, and implementation integrity. An iterative, thematic analysis approach was employed to analyse the qualitative data.ResultsParticipants included 33 isiXhosa-speaking women (mean age 37.1 years, mean BMI 35.9 kg/m2). Thematic analysis identified psychological capability (knowledge of fasting), social influences (cultural preferences, family support), and reflective motivation (awareness of weight, health impact, motivation for TRE) as key factors influencing adoption of TRE for weight management. In a 4-week TRE pilot trial (n = 12), retention was 100%. Positive outcomes perceived included improved energy, appetite control and weight loss. TRE was perceived as acceptable, easy, and enjoyable. Family support facilitated adherence, while habitual and social eating and drinking practices were barriers. Compliance was high, aided by self-selected eating times, reminders, and weekly calls. Recommendations included the incorporation of dietary education sessions and text messages to provide additional support and reminders.ConclusionsThis study indicates that TRE is a feasible weight management strategy in women living with overweight/obesity and HIV, receiving DTG-based treatment in a resource-limited community. These findings will ensure that the forthcoming TRE randomised controlled trial is adapted and optimised to the local South African context.

Differences in HIV-1 reservoir size, landscape characteristics and decay dynamics in acute and chronic treated HIV-1 Clade C infection.

Background Persisting HIV reservoir viruses in resting CD4 T cells and other cellular subsets are the main barrier to cure efforts. Antiretroviral therapy (ART) intensification by early initiation has been shown to enable post-treatment viral control in some cases but the underlying mechanisms are not fully understood. We hypothesized that ART initiated during the hyperacute phase of infection before peak will affect the size, decay dynamics and landscape characteristics of HIV-1 subtype C viral reservoirs. Methods We studied 35 women at high risk of infection from Durban, South Africa identified with hyperacute HIV infection by twice weekly testing for plasma HIV-1 RNA. Study participants included 11 who started ART at a median of 456 (297-1203) days post onset of viremia (DPOV), and 24 who started ART at a median of 1 (1-3) DPOV. We used peripheral blood mononuclear cells (PBMC) to measure total HIV-1 DNA by ddPCR and to sequence reservoir viral genomes by full length individual proviral sequencing (FLIP-seq) from onset of detection of HIV up to 1 year post treatment initiation. Results Whereas ART in hyperacute infection blunted peak viremia compared to untreated individuals (p<0.0001), there was no difference in total HIV-1 DNA measured contemporaneously (p=0.104). There was a steady decline of total HIV DNA in early treated persons over 1 year of ART (p=0.0004), with no significant change observed in the late treated group. Total HIV-1 DNA after one year of treatment was lower in the early treated compared to the late treated group (p=0.02). Generation of 697 single viral genome sequences revealed a difference in the longitudinal proviral genetic landscape over one year between untreated, late treated, and early treated infection: the relative contribution of intact genomes to the total pool of HIV-1 DNA after 1 year was higher in untreated infection (31%) compared to late treated (14%) and early treated infection (0%). Treatment initiated in both late and early infection resulted in a more rapid decay of intact (13% and 51% per month) versus defective (2% and 35% per month) viral genomes. However, intact genomes were still observed one year post chronic treatment initiation in contrast to early treatment where intact genomes were no longer detectable. Moreover, early ART reduced phylogenetic diversity of intact genomes and limited the seeding and persistence of cytotoxic T lymphocyte immune escape variants in the reservoir. Conclusions Overall, our results show that whereas ART initiated in hyperacute HIV-1 subtype C infection did not impact reservoir seeding, it was nevertheless associated with more rapid decay of intact viral genomes, decreased genetic complexity and immune escape in reservoirs, which could accelerate reservoir clearance when combined with other interventional strategies.

Population dynamics of HIV drug resistance during treatment scale-up in Uganda: a population-based longitudinal study.

Clinical studies have reported rising pre-treatment HIV drug resistance during antiretroviral treatment (ART) scale-up in Africa, but representative data are limited. We estimated population-level drug resistance trends during ART expansion in Uganda. We analyzed data from the population-based open Rakai Community Cohort Study conducted at agrarian, trading, and fishing communities in southern Uganda between 2012 and 2019. Consenting participants aged 15-49 were HIV tested and completed questionnaires. Persons living with HIV (PLHIV) provided samples for viral load quantification and virus deep-sequencing. Sequence data were used to predict resistance. Population prevalence of class-specific resistance and resistance-conferring substitutions were estimated using robust log-Poisson regression. Data from 93,622 participant-visits, including 4,702 deep-sequencing measurements, showed that the prevalence of NNRTI resistance among pre-treatment viremic PLHIV doubled between 2012 and 2017 (PR:1.98, 95%CI:1.34-2.91), rising to 9.61% (7.27-12.7%). The overall population prevalence of pre-treatment viremic NNRTI and NRTI resistance among all participants decreased during the same period, reaching 0.25% (0.18% - 0.33%) and 0.05% (0.02% - 0.10%), respectively ( p- values for trend = 0.00015, 0.002), coincident with increasing treatment coverage and viral suppression. By the final survey, population prevalence of resistance contributed by treatment-experienced PLHIV exceeded that from pre-treatment PLHIV, with NNRTI resistance at 0.54% (0.44%-0.66%) and NRTI resistance at 0.42% (0.33% - 0.53%). Overall, NNRTI and NRTI resistance was predominantly attributable to rtK103N and rtM184V. While 10.52% (7.97%-13.87%) and 9.95% (6.41%-15.43%) of viremic pre-treatment and treatment-experienced PLHIV harbored the inT97A mutation, no major dolutegravir resistance mutations were observed. Despite rising NNRTI resistance among pre-treatment PLHIV, overall population prevalence of pre-treatment resistance decreased due to treatment uptake. Most NNRTI and NRTI resistance is now contributed by treatment-experienced PLHIV. The high prevalence of mutations conferring resistance to components of current first-line ART regimens among PLHIV with viremia is potentially concerning. National Institutes of Health and the Gates Foundation. Evidence before the study: We searched PubMed for studies matching the keywords "hiv" "resistance" "longitudinal" "cohort" "population" published since 2004 (the beginning of antiretroviral therapy (ART) availability in sub-Saharan Africa) and identified 50 studies. We excluded 34 studies not based in sub-Saharan Africa, five studies primarily concerned with infection with other pathogens (e.g. HBV, M. tuberculosis ), two studies concerned with insulin resistance, one sequencing-methods paper, and one paper concerned with host susceptibility to HIV infection. The remaining seven studies were not population-based meaning that the study population was not all persons but e.g. people living with HIV enrolled in care at a given clinic. Population-based cohort are essential for monitoring HIV drug resistance in both treated and untreated individuals, including those people who may go undetected in clinical settings, capturing evolutionary dynamics of resistance in real-world conditions. Added value of this study: We estimated the prevalence of drug resistance over five consecutive survey rounds of a population-based open-cohort study in southern Uganda between 2012 and 2019 during a period of intense treatment scale-up. We show that among the entire population regardless of HIV status, 0.8% and 0.5% of individuals harbor viremic resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) and nucleoside-reverse transcriptase inhibitors (NRTIs), respectively, of which the majority is dual-class NNRTI/NRTI resistance. Despite a two-fold increase in the prevalence of NNRTI resistance among pre-treatment viremic PLHIV, the overall prevalence of pre-treatment viremic resistance in the entire population decreased by more than 50% due to increased treatment initiation and population viral load suppression. The majority of resistance in recent survey rounds was contributed by treatment-experienced PLHIV. Among treatment-experienced viremic PLHIV, we observe a substantial burden of mutations that confer resistance to the NNRTI and NRTI components of dolutegravir and cabotegravir based regimens e.g. rtM184V (34%) rtY181C (15%), rtG190A (12%), rtK65R (12%), and rtK101E (9.5%). The integrase strand transfer inhibitor (INSTI) resistance mutation inT97A was observed in about a tenth of viremic PLHIV.These results provide the first longitudinal population-based estimates of temporal trends in the prevalence of drug resistance during ART program expansion in a high-burden setting. Further, they provide critical insight into the landscape of prevalent drug resistance substitutions circulating in this population.Implications of all the available evidence: Scale-up of HIV treatment has increased the prevalence of drug resistance mutations among viremic people living with HIV in sub-Saharan Africa. The relatively high prevalence of NNRTI resistance has prompted a recent shift to first-line regimens including dolutegravir (an INSTI) in combination with NRTIs. The high prevalence of mutations conferring resistance to components of current first-line regimens in our population warrants continued monitoring of treatment failures and the prevalence of drug resistance in high burden settings.

Interventions during Early Infection: Opening a Window for an HIV Cure?

Although combination antiretroviral therapy (ART) has been a landmark achievement for the treatment of human immunodeficiency virus (HIV), an HIV cure has remained elusive. Elimination of latent HIV reservoirs that persist throughout HIV infection is the most challenging barrier to an HIV cure. The progressive HIV infection is marked by the increasing size and diversity of latent HIV reservoirs until an effective immune response is mobilized, which can control but not eliminate HIV infection. The stalemate between HIV replication and the immune response is manifested by the establishment of a viral set point. ART initiation during the early stage limits HIV reservoir development, preserves immune function, improves the quality of life, and may lead to ART-free viral remission in a few people living with HIV (PLWH). However, for the overwhelming majority of PLWH, early ART initiation alone does not cure HIV, and lifelong ART is needed to sustain viral suppression. A critical area of research is focused on determining whether HIV could be functionally cured if additional treatments are provided alongside early ART. Several HIV interventions including Block and Lock, Shock and Kill, broadly neutralizing antibody (bNAb) therapy, adoptive CD8+ T cell therapy, and gene therapy have demonstrated delayed viral rebound and/or viral remission in animal models and/or some PLWH. Whether or not their application during early infection can improve the success of HIV remission is less studied. Herein, we review the current state of clinical and investigative HIV interventions and discuss their potential to improve the likelihood of post-treatment remission if initiated during early infection.

Vaccine responses and hybrid immunity in people living with HIV after SARS-CoV-2 breakthrough infections

The COVID-19 pandemic posed a challenge for people living with HIV (PLWH), particularly immune non-responders (INR) with compromised CD4 T-cell reconstitution following antiretroviral therapy (CD4 count <350 cells per mm3). Their diminished vaccine responses raised concerns about their vulnerability to SARS-CoV-2 breakthrough infections (BTI). Our in-depth study here revealed chronic inflammation in PLWH and a limited anti-Spike IgG response after vaccination in INR. Nevertheless, the imprinting of Spike-specific B cells by vaccination significantly enhanced the humoral responses after BTI. Notably, the magnitude of cellular CD4 response in all PLWH was comparable to that in healthy donors (HD). However, the polyfunctionality and phenotype of Spike-specific CD8 T cells in INR differed from controls. The findings highlight the need for additional boosters with variant vaccines, and for monitoring ART adherence and the durability of both humoral and cellular anti-SARS-CoV-2 immunity in INR.

SMART Designs: Bridging the Gap Between Clinical Trials and Practice in Infectious Diseases.

Traditional Randomized Controlled Trials often fall short in addressing the specific needs of clinical practice due to their one-size-fits-all treatment approaches. Sequential Multiple Assignment Randomized Trials (SMARTs) offer a dynamic and adaptive approach, allowing for multiple randomizations based on patient responses and evolving conditions. SMARTs enable personalized treatment pathways, such as in the trial for antiretroviral therapy (ART) in South Africa, which adjusts treatment based on patient outcomes. Despite these advantages, the use of SMARTs in infectious diseases remains limited. Greater adoption of SMARTs could promote more personalized treatment approaches, improve flexibility in response to public health needs, and enhance the effectiveness of interventions. However, challenges such as recruitment and increased expertise needed for more complex analyses must be addressed. Additionally, combining SMARTs with other adaptive designs could further improve the relevance and outcomes of clinical research.

Analysis of ICAM-1 rs3093030, VCAM-1 rs3783605, and E-Selectin rs1805193 Polymorphisms in African Women Living with HIV and Preeclampsia.

Intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1), and E-selectin are cell adhesion molecules that play a significant role in inflammation and are implicated in the pathophysiology of preeclampsia development and HIV infection. More specifically, the immune expression of ICAM-1, VCAM-1, and E-selectin within cyto- and syncytiotrophoblast cells are dysregulated in preeclampsia, indicating their role in defective placentation. This study investigates the associations of ICAM-1, VCAM-1, and E-selectin gene variants (rs3093030, rs3783605, and rs1805193, respectively) with preeclampsia comorbid with HIV infection in women of African ancestry. It also examines the susceptibility to preeclampsia development and the effect of highly active antiretroviral therapy (HAART). A total of 405 women were enrolled in this study. Out of these women, 204 were preeclamptic and 201 were normotensive. Clinical characteristics were maternal age, weight, blood pressure (systolic and diastolic), and gestational age. Whole blood was collected, DNA was extracted, and genotyping of the ICAM-1 (rs3093030 C>T), VCAM-1(rs3783605 A>G), and E-selectin (rs1805193 A>C) gene polymorphisms was performed. Comparisons were made using the Chi-squared test. Our results demonstrated that preeclamptic women exhibited a higher frequency of analyzed variants, in contrast to those with the duality of preeclampsia and HIV infection. Additionally, the C allele of the ICAM-1 (rs3093030 C>T) and G allele of the VCAM-1 (rs3783605 A>G) genes were found to have a greater role in the co-morbidity and may be considered as a risk factor for preeclampsia development in women of African ancestry. In contrast, the SNP of rs1805193 of the E-selectin gene indicated that A>C was only significantly associated with HIV infection and not with preeclampsia. These findings highlight a strong association of the rs3093030 SNP of the ICAM-1 gene and of the VCAM-1 rs3783605 gene with the development of preeclampsia, indicating their role in the defective trophoblast invasion of preeclampsia. Sub-group analysis further reveals an association of the AA genotype with late-onset preeclampsia, a less severe form of disease indicating differing genetic predispositions between early and late-onset forms.

Mlambe economic and relationship-strengthening intervention for alcohol use decreases violence and improves relationship quality in couples living with HIV in Malawi

IntroductionA syndemic of unhealthy alcohol use, intimate partner violence (IPV), and economic insecurity threatens to derail progress towards UNAIDS 95-95-95 targets in sub-Saharan Africa. We developed a combined economic and relationship-strengthening intervention called Mlambe to reduce unhealthy alcohol use and increase adherence to antiretroviral therapy for couples in Malawi. This study evaluates the additional impact of Mlambe on IPV and relationship dynamics. MethodsIn a pilot randomized controlled trial, 78 married couples (156 individuals) living with HIV and reporting unhealthy alcohol use based on the AUDIT-C (at least one partner) were recruited from HIV care clinics in Zomba, Malawi. The intervention arm (39 couples) received a 10-month program consisting of incentivized savings accounts with financial literacy education, relationship education, and couples counseling sessions to build relationship skills. The control arm (39 couples) received enhanced usual care (EUC) with brief alcohol counseling. We used linear mixed-effects models to assess the effects of Mlambe on relationship quality (e.g., constructive communication, unity, sexual satisfaction) and IPV (physical, sexual, and emotional) by including fixed effects for treatment arm and a random effect for dyad, and tested whether effects on IPV and relationship quality differed by gender. ResultsAt 10- and 15-month follow-up visits, couples in the Mlambe arm showed greater increases in couple communication, unity, sexual satisfaction, intimacy, and trust (Cohen's d ranged from 0.36 to 0.56; p < 0.05) as compared to EUC. Couples in the Mlambe arm also showed significant decreases in physical and emotional IPV (Cohen's d ranged from 0.33 to 0.49; p < 0.05) as compared to EUC. Subsequent moderation analyses indicated that women reported significantly greater improvements in relationship quality than men, except for sexual satisfaction (p < 0.05), and greater declines in physical IPV than men (p < 0.05). ConclusionsMlambe resulted in significant improvements in relationship quality and decreased IPV in couples, particularly for women who as a group reported lower relationship quality at baseline. Economic and relationship-strengthening interventions have potential to disrupt harmful syndemics of violence, substance use, and poverty among couples living with HIV. Clinical trial numberNCT#04906616.

Adverse perinatal outcomes associated with different classes of antiretroviral drugs in pregnant women living with HIV: a systematic review and meta-analysis.

Women living with HIV (WLHIV) are at increased risk of adverse perinatal outcomes compared to HIV-negative women, despite antiretroviral therapy (ART). There is evidence that the risk of adverse perinatal outcomes may differ according to ART regimen. We aimed to assess the risk of adverse perinatal outcomes among WLHIV receiving different classes of ART, compared to HIV-negative women. Systematic review and meta-analysis. We searched Medline, CINAHL, Global Health and EMBASE for studies published between 1 January 1980 and 14 July 2023. We included studies which assessed the risk of 11 predefined adverse perinatal outcomes among WLHIV receiving non-nucleoside reverse transcriptase inhibitor (NNRTI)-based ART, protease inhibitor (PI)-based ART or integrase strand transfer inhibitor (INSTI)-based ART, compared to HIV-negative women. The perinatal outcomes assessed were preterm birth (PTB), very PTB (VPTB), spontaneous PTB (sPTB), low birthweight (LBW), very LBW (VLBW), term LBW, preterm LBW, small for gestational age (SGA), very SGA (VSGA), stillbirth and neonatal death (NND). Random effects meta-analyses examined the risk of each adverse outcome in WLHIV receiving either NNRTI-based, PI-based or INSTI-based ART, compared with HIV-negative women. Subgroup and sensitivity analyses were conducted based on country income status, study quality, and timing of ART initiation. The protocol is registered with PROSPERO, CRD42021248987. Of 108,720 identified citations, 22 cohort studies including 191,857 women were eligible for analysis. We found that WLHIV receiving NNRTI-based ART (mainly efavirenz or nevirapine) are at increased risk of PTB (risk ratio (RR) 1.40, 95% confidence interval 1.27-1.56), VPTB (1.94, 1.25-3.01), LBW (1.63, 1.30-2.04), SGA (1.53, 1.17-1.99) and VSGA (1.48, 1.16-1.87), compared with HIV-negative women. WLHIV receiving PI-based ART (mainly lopinavir/ritonavir or unspecified) are at increased risk of PTB (1.88, 1.55-2.28), VPTB (2.06, 1.01-4.18), sPTB (16.96, 1.01-284.08), LBW (2.90, 2.41-3.50), VLBW (4.35, 2.67-7.09) and VSGA (2.37, 1.84-3.05), compared with HIV-negative women. WLHIV receiving INSTI-based ART (mainly dolutegravir) are at increased risk of PTB (1.17, 1.06-1.30) and SGA (1.20, 1.08-1.33), compared with HIV-negative women. The risks of adverse perinatal outcomes are higher among WLHIV receiving ART compared with HIV-negative women, irrespective of the class of ART drugs. This underlines the need to further optimise ART in pregnancy and improve perinatal outcomes of WLHIV.

The prevalence of antiretroviral drug interactions with other drugs used in women living with HIV and its association with HIV drug change and patient compliance

BackgroundDrug-drug interactions (DDIs) between antiretroviral therapy (ART) and commonly used co-medications in HIV patients, especially women, impact treatment efficacy and patient safety.ObjectiveThis study aimed to study the prevalence and types of drug-drug interactions (DDIs) between antiretroviral therapy drugs (ARTs) and comedications among a female population with HIV. Additionally, the study investigates the association of these DDIs with ART medication changes and treatment adherence.MethodsThis cross-sectional study included 632 adult women living with HIV (WLHIV). Data was retrospectively extracted from patient files. Drug.com interaction checker website was used to assess DDIs between ART and non-ART medications. Changes to the ART regimen previously attributed to ART side effects or patient non-adherence were considered drug changes.ResultsA total of 429 WLHIV (mean age: 44.05 ± 9.50) were eligible. The prevalence of DDIs between ART and non-ART medications was 21.4%, with 4.7% minor, 18.4% moderate, and 8.9% major interactions. The highest prevalence of DDI was among cardiovascular medication users (71.7%), followed by central nervous system drugs (69.2%). Changing medications resulted in a decrease in DDIs, with significant reductions in total and minor interactions. Participants without DDIs had better adherence to ART. DDI between ART and non-ART medications was significantly associated with ART drug change, even after accounting for side effects attributed to ARTs, indicating an independent twofold association (OR = 1.99, CI 1.04–3.77). Moreover, further adjustments for HIV viral load and CD4 + cell count did not change the significance of the association (OR = 2.01, CI 1.03–3.92).ConclusionDDIs in WLHIV impact adherence to ART. Altering ART may not be directly related to ART side effects, but rather primarily due to interactions with non-ART medications. Modifying non-ART drug regimens can reduce the likelihood of DDIs.

Incidence and predictors of common opportunistic infections among children living with HIV at Bahir Dar City, Ethiopia

Despite the dramatic decline in the incidence of common opportunistic infections (OIs) after antiretroviral therapy initiation, they remain a significant cause of morbidity and mortality among children with HIV. For better interventions, information regarding the incidence and predictors of common OIs is essential for Children living with HIV. Still, there is a lack of studies in low and middle-income countries, including Ethiopia. Therefore, this study aims to assess the incidence and predictors of common OIs among Children living with HIV on anti-retroviral therapy (ART) at public health institutions in Bahir Dar City, Northwest Ethiopia. The reasons for excluding children not on ART is we want to study the effectiveness of chronic HIV care service, ART drugs and OIs prophylaxis drugs for the prevention of common OIs because it is obvious that the occurrence of OIs in children not on ART and OIs prophylaxis drugs is high. A health institution-based retrospective cohort study was done among 403 Human Immunodeficiency Virus-infected children at public health institutions in Bahir Dar City from 2010 to 2020. Data was entered using Epi-data version 4.6 and analyzed using STATA 14.0. A bivariable Cox-proportional hazards regression model was employed to appreciate the relationship between each explanatory variable with the outcome variable. In the bivariable analysis, variables with a p-value of less than 0.25 were candidates for the multivariable proportional hazard model. The Cox proportional hazards model was used to determine predictors of common opportunistic infections at a 5% significance level. The overall incidence rate of common opportunistic infections was 7.06 with a 95% confidence interval ((CI) 5.78, 9.75) per 100 person-years of observation. Statically significant predictors were World Health Organization (WHO) clinical stage III and IV (adjusted hazard ratio (AHR) = 1.90; (95% CI 1.34, 2.75), having fair/poor adherence to anti-retroviral therapy (ART) (AHR) = 1.80; (95% CI 1.25, 2.94) and hemoglobin level < 10 g/dl (AHR) = 2.00; (95% CI 1.36, 2.89). The overall incidence rate of common OIs among children living with HIV on ART was high. Independent predictors of common OIs among children on ART were advanced-stage of HIV disease, poor ART adherence, and lower hemoglobin level. Therefore, we recommend strongly working on the prevention of advanced stages of HIV disease and improving poor ART adherence to prevent the incidence of OIs among children living with HIV on ART.

Association of ART regimen and adherence to viral suppression: an observational study of a clinical population of people with HIV

Adherence to antiretroviral therapy (ART) is essential for the effective management of HIV, which includes keeping the HIV viral load undetectable. This study aimed to determine whether certain ART medications are more “forgiving” of poor adherence in achieving viral suppression. We identified subgroups of ART medication usage and determined the extent to which ART adherence is associated with viral suppression across those subgroups. Data came from claims and clinical records (2017–2019) of 3,552 HIV-positive adult members of a Medicaid managed care plan. Pharmacy fill data were examined to characterize ART medications using latent class analysis (LCA), which captures the complexity of real-world ART usage (i.e., multiple medications, ART switching). LCA yielded five ART medication patterns over three years, mostly characterized by recent medications and formulations of ART, though they varied in number of tablets and in medication class. Mixed effects logistic regression models were estimated to determine whether odds of viral suppression differed by ART adherence level. After adjusting for covariates, those with at least 90% adherence (i.e., 90 to < 95%) did not significantly differ from those with 95% adherence or greater in terms of viral suppression, which corroborates existing clinical recommendations. These findings can inform provider-patient communication for people with HIV, especially those who have difficulty maintaining adherence. This includes those experiencing unstable housing, mental health conditions, or substance use.

Risk of tuberculosis after achieving HIV virological suppression on antiretroviral therapy: a Danish nationwide prospective cohort study.

In countries with low tuberculosis (TB) burden, the risk of TB in people with HIV (PWH) once HIV virological suppression is achieved is not fully understood. In a nationwide cohort, we included all adult PWH from the Danish HIV Cohort initiating antiretroviral therapy (ART) (1995-2017) without prior TB disease. We used Kaplan-Meier estimation and Poisson regression to calculate TB incidence rate (IR) after six months of ART, along with associated risk factors and mortality rates (MR). Among 6,849 PWH initiating ART (median follow-up 7.4 years), 84 developed TB (IR 1.4/1000 person-year [PY]), 54 of them beyond six months of ART initiation, IR 0.97/1000 PY (95%CI:1.17-1.79): 1.95 (95%CI:1.34-2.76) in non-Danish born, 0.36 (95%CI:0.21-0.62) in Danish-born without injection drug use (IDU), and 2.95 (95%CI:1.53-5.66) in Danish-born with IDU. Danish-born with suppressed viremia, and no IDU or known TB exposures had the lowest risk (IR 0.05/1000 PY).In the adjusted analysis, being non-Danish born (aIRR 4.27[95%CI:2.36-7.72]), IDU (aIRR 4.95[95%CI:2.55-9.62]), and previous AIDS-defining events (aIRR 2.05[95%CI:1.06-3.94]) raised TB risk, while suppressed HIV-RNA (aIRR 0.58[95%CI:0.34-0.99]) reduced it. The overall MR for HIV/TB co-infected post- ART was high, at 48.9/1000 PY (95%CI:30.4-78.7). The TB risk remains elevated in PWH beyond six months of ART initiation, especially among migrants, IDU, those without suppressed HIV-RNA, and individuals exposed to high TB endemic areas or with social risk determinants of health. Conversely, PWH without these risk factors have a TB risk similar to the general population and would not require targeted TB screening strategies.

Comparison of At-Home Versus In-Clinic Receipt of Long-Acting Injectable Cabotegravir/Rilpivirine.

The need for frequent travel to a clinic could impair access to injectable antiretroviral therapy for persons living with human immunodeficiency virus type 1 (HIV-1) infection. We hypothesized that allowing persons receiving treatment with long-acting injectable cabotegravir plus rilpivirine (LA CAB/RPV) to receive and store the medication in their own refrigerator prior to in-home administration by a healthcare provider would be as safe and effective as receiving treatment in a clinic. Persons prescribed LA CAB/RPV in the Infectious Diseases clinic at the Medical University of South Carolina were offered enrollment in this non-randomized, observational study between August 2021 and December 2022. After in-clinic receipt of the initial LA CAB/RPV injection, participants chose to receive each subsequent injection over the following 12-months either in clinic or at home. The 33 enrolled participants were primarily Black (64%), male (73%), and had a median age of 46. Three participants stopped LA CAB/RPV and transitioned to oral antiretroviral therapy due to allergy (n = 1), loss of virologic suppression (n = 1), and visit adherence (n = 1) concerns. A comparable number of participants received treatment primarily in clinic (n = 18) relative to at home (n = 15). Injection site pain/soreness was common (52% of injections) but did not differ between groups. There were no differences in safety or efficacy between groups and both groups reported high treatment satisfaction. All participants were virologically suppressed and retained in care at the end of the study. At-home administration of LA CAB/RPV by a healthcare provider was comparably safe, effective, and associated with high participant satisfaction relative to in-clinic administration.

Adherence to antiretroviral therapy among HIV patients at a hospital in Tacna, Peru

ObjectiveThis study aims to provide an overview of antiretroviral therapy adherence and its related factors within a hospital in southern Peru. Materials and methodsWe conducted an analytical cross-sectional study spanning from April to October 2022. This study involved a review of medical records and the administration of a survey to individuals living with Human Immunodeficiency Virus. Adherence to antiretroviral treatment was assessed using the CEAT-HIV (Questionnaire for the Evaluation of Antiretroviral Treatment Adherence), and was categorized as high, adequate, insufficient, or low. The statistical analysis included the calculation of crude and adjusted prevalence ratios (PRs). ResultsOur study comprised 300 participants, with a median age of 30 years, predominantly male (78.3 %). Among these individuals, 83 % exhibited low or insufficient adherence to antiretroviral treatment according to the CEAT-VIH scale. Notably, patients with a viral load >50,000 copies/ml scored higher on the CEAT-VIH scale than those with a viral load <400 (adjusted PR: 2.78, 95 % CI: 1.21 to 6.40). Furthermore, a higher level of education and a viral load below 400 copies/ml were associated to higher scores in the treatment compliance dimension of the CEAT-VIH scale. ConclusionEight out of ten evaluated patients exhibited low or insufficient adherence. While lower adherence was correlated with lower education, the connection between viral load and adherence remains inconclusive.

Mpox in People With Human Immunodeficiency Virus: Predictors of Diagnosis, Outcomes, and Vaccine Effectiveness in a Multisite Cohort.

Since its global reemergence in 2022, monkeypox (mpox) has demonstrated increased incidence and severity among people with human immunodeficiency virus (HIV [PWH]). Predictors of mpox diagnosis, vaccination, and outcomes among PWH are limited. We included PWH with primary care visits after 1 January 2022 at 9 US sites participating in the Centers for AIDS Research Network of Integrated Clinic Systems Network. We identified mpox diagnosed between 1 June 2022 and 31 May 2023, through a combination of polymerase chain reaction result, diagnosis code, and/or tecovirimat receipt. We examined validated clinical diagnoses, laboratory results, vaccine data, and patient reported outcomes. We evaluated relative risks (RR) of mpox diagnosis, hospitalization, tecovirimat treatment, and vaccine receipt. Among 19 777 PWH in care, 413 mpox cases (all male sex at birth) occurred (2.2 cases/100 person-years). Age <40 years, geographic region, Hispanic/Latine ethnicity, lack of antiretroviral therapy, detectable HIV viral load, and recent bacterial sexually transmitted infection predicted mpox diagnosis. PWH with CD4 200-349 cells/mm3 were most likely to be hospitalized (adjusted RR, 3.20; 95% confidence interval: 1.44-7.09) compared to CD4 ≥500, but half as likely as those with CD4 <200 to receive tecovirimat. Overall, smallpox/mpox vaccine effectiveness of ≥1 vaccine was 71% (adjusted RR, 0.29; 95% confidence interval: .14-.47) at preventing mpox, and 86% or better with CD4 ≥350 or HIV viral suppression. Non-Hispanic Black PWH were less likely to be vaccinated than other racial/ethnic identities. PWH not on antiretroviral therapy or with unsuppressed HIV were more likely to be diagnosed with, and hospitalized for, mpox. Mpox/smallpox vaccine effectiveness was high, inclusive of those with low CD4 count and HIV viremia.

Breastfeeding, Antiretroviral Therapy, HIV Transmission, and the HIV Reservoir.

Breastfeeding, Antiretroviral Therapy, HIV Transmission, and the HIV Reservoir.

Single cell spatial profiling of FFPE splenic tissue from a humanized mouse model of HIV infection

BackgroundLatency remains a major obstacle to finding a cure for HIV despite the availability of antiretroviral therapy. Due to virus dormancy, limited biomarkers are available to identify latent HIV-infected cells. Profiling of individual HIV-infected cells is needed to explore potential latency biomarkers and to study the mechanisms of persistence that maintain the HIV reservoir.MethodsSingle cell spatial transcriptomic characterization using the CosMx Spatial Molecular Imager platform was conducted to analyze HIV-infected cells in formalin-fixed paraffin-embedded sections of splenic tissue surgically obtained from an HIV-infected humanized mouse model. Regulation of over a thousand human genes was quantified in both viremic and aviremic specimens. In addition, in situ hybridization and immunohistochemistry were performed in parallel to identify HIV viral RNA- and p24-containing cells, respectively. Finally, initial findings from CosMx gene profiling were confirmed by isolating RNA from CD4 + T cells obtained from a person living with HIV on antiretroviral therapy following either PMA/Ionomycin or DMSO treatment. RNA was quantified using qPCR for a panel of targeted human host genes.ResultsSupervised cell typing revealed that most of the HIV-infected cells in the mouse spleen sections were differentiated CD4 + T cells. A significantly higher number of infected cells, 2781 (1.61%) in comparison to 112 (0.06%), and total HIV transcripts per infected cell were observed in viremic samples compared to aviremic samples, respectively, which was consistent with the data obtained from ISH and IHC. Notably, the expression of 55 genes was different in infected cells within tissue from aviremic animals compared to viremic. In particular, both spleen tyrosine kinase (SYK) and CXCL17, were expressed approximately 100-fold higher. This data was further evaluated against bulk RNA isolated from HIV-infected human primary CD4 + T cells. A nearly 6-fold higher expression of SYK mRNA was observed in DMSO-treated CD4 + T cells compared to those stimulated with PMA/Ionomycin.ConclusionThis study found that the CosMx SMI platform is valuable for assessing HIV infection and providing insights into host biomarkers associated with HIV reservoirs. Higher relative expression of the SYK gene in aviremic-infected cells from the humanized mouse HIV model was consistent with levels found in CD4 + T cells of aviremic donors.

HPV-associated cancers among people living with HIV: nationwide population-based retrospective cohort study 2004–21 in Estonia

Abstract Cancers represent the primary cause of mortality among people living with HIV (PLWH). However, comprehensive nationwide data regarding cancer incidence remains limited. Our objective was to evaluate the incidence rates of cancers, particularly those associated with human papillomavirus (HPV), within a nationwide study cohort. Using data from the Estonian Health Insurance Fund and the National Cancer Registry from 2004 to 2021, we calculated standardized incidence ratios (SIRs) for various cancer types among PLWH to compare to the general population with special emphases on HPV-associated cancers. A total of 7011 individuals (65.7% men) diagnosed with HIV were identified. HPV-associated cancers accounted for 21.4% of all incident cancer cases among PLWH. SIRs for HPV-associated cancers were 3.7 [95% confidence interval (CI) 2.2–6.2] among men living with HIV (MLWH) and 5.7 (95% CI 4.0–7.9) among women living with HIV (WLWH). In MLWH, the highest SIRs were for penile 12.5 (95% CI 4.0–38.7), followed by oropharyngeal 3.6 (95% CI 1.7–7.6) and anal–rectal cancers 2.7 (95% CI 1.1–6.4) in comparison to the general population. In WLWH, an increased incidence of cervical (SIR = 5.8, 95% CI 3.9–8.5), oropharyngeal (SIR = 6.1, 95% CI 1.5–24.3), and anal–rectal (SIR = 3.6, 95% CI 1.2–11.2) cancers was observed. A significantly increased risk of AIDS-defining and non-AIDS-defining cancers is reported. We demonstrate a substantially heightened risk of HPV-associated cancers among PLWH compared to the general population, underscoring the imperative for intensified screening and scaled-up vaccination along with improvement in adherence to antiretroviral therapy.

Ritonavir's Evolving Role: A Journey from Antiretroviral Therapy to Broader Medical Applications.

Ritonavir is a protease inhibitor initially developed for HIV treatment that is now used as a pharmacokinetic booster for other antiretrovirals due to it being a cytochrome P450 3A4 enzyme and P-glycoprotein inhibitor. Consequently, ritonavir is of special interest for repurposing in other diseases. It had an important role in battling the COVID-19 pandemic as a part of the developed drug Paxlovid® in association with nirmatrelvir and has shown effects in hepatitis and other pathogenic diseases. Ritonavir has also shown promising results in overcoming drug resistance and enhancing the efficacy of existing chemotherapeutic agents in oncology. Evidence of cancer repurposing potential was demonstrated in cancers such as ovarian, prostate, lung, myeloma, breast, and bladder cancer, with several mechanisms of action presented. In vitro studies indicate that ritonavir alone can inhibit key pathways involved in cancer cell survival and proliferation, causing apoptosis, cell cycle arrest, endoplasmic reticulum stress, and metabolic stress due to the inhibition of molecules like heat shock protein 90 and cyclin-dependent kinases. Ritonavir also causes resistant cells to become sensitized to anticancer drugs like gemcitabine or docetaxel. These findings indicate that repurposing ritonavir, either on its own or in combination with other medications, could be a promising approach for treating various diseases. This is particularly relevant in cancer therapy, where ritonavir repurposing is the central focus of this review.