Timing Of Antiretroviral Therapy Research Articles

Population-based prevalence of congenital defects in a routine sentinel site-based surveillance system in the Western Cape, South Africa.

Lack of data on the burden and scope of congenital disorders (CDs) in South Africa undermines resource allocation and limits the ability to detect signals from potentially teratogenic pregnancy exposures. We used routine electronic data in the Western Cape Pregnancy Exposure Registry (PER) to determine the overall and individual prevalence of CD identified on neonatal surface examination at birth in the Western Cape, South Africa, 2016-2022. CD was confirmed by record review. The contribution of late (≤24 months) and antenatal diagnoses was assessed. We compared demographic and obstetric characteristics between women with/without pregnancies affected by CD. Women with a viable pregnancy (>22 weeks gestation; birth weight ≥ 500 g) (n = 32,494) were included. Of 1106 potential CD identified, 56.1% were confirmed on folder review. When internal and minor CD were excluded the prevalence of major CD identified on surface examination at birth was 7.2/1000 births. When missed/late diagnoses on examination (16.8%) and ultrasound (6.8%) were included, the prevalence was 9.2/1000 births: 8.9/1000 livebirths and 21.5/1000 stillbirths. The PER did not detect 21.5% of major CD visible at birth. Older maternal age and diabetes mellitus were associated with an increased prevalence of CD. Women living with/without HIV (or the timing of antiretroviral therapy, before/after conception), hypertension or obesity did not significantly affect prevalence of CD. A surveillance system based on routine data successfully determined the prevalence of major CD identified on surface examination at birth at rates slightly higher than in equivalent studies. Overall rates, modeled at ~2%, are likely underestimated. Strengthening routine neonatal examination and clinical record-keeping could improve CD ascertainment.

Dating reservoir formation invirologically suppressed people living with HIV-1 inRakai, Uganda.

The timing of the establishment of the HIV latent viral reservoir (LVR) is of particular interest, as there is evidence that proviruses are preferentially archived at the time of antiretroviral therapy (ART) initiation. Quantitative viral outgrowth assays (QVOAs) were performed using Peripheral Blood Mononuclear Cells (PBMC) collected from Ugandans living with HIV who were virally suppressed on ART for >1 year, had known seroconversion windows, and at least two archived ART-naïve plasma samples. QVOA outgrowth populations and pre-ART plasma samples were deep sequenced for the pol and gp41 genes. The bayroot program was used to estimate the date that each outgrowth virus was incorporated into the reservoir. Bayroot was also applied to previously published data from a South African cohort. In the Ugandan cohort (n = 11), 87.9 per cent pre-ART and 56.3 per cent viral outgrowth sequences were unique. Integration dates were estimated to be relatively evenly distributed throughout viremia in 9/11 participants. In contrast, sequences from the South African cohort (n = 9) were more commonly estimated to have entered the LVR close to ART initiation, as previously reported. Timing of LVR establishment is variable between populations and potentially viral subtypes, which could limit the effectiveness of interventions that target the LVR only at ART initiation.

TREX1 531C/T Polymorphism and Autoantibodies Associated with the Immune Status of HIV-1-Infected Individuals.

Autoimmune diseases can develop during HIV-1 infection, mainly related to the individual's immune competence. The study investigated the association of the TREX1 531C/T polymorphism and antinuclear antibodies (ANA) in HIV-1 infection and the time of antiretroviral therapy (ART) used. Cross-sectional and longitudinal assessments were carried out in 150 individuals, divided into three groups: ART-naïve, 5 years and 10 years on ART; ART-naïve individuals were evaluated for 2 years after initiation of treatment. The individuals' blood samples were submitted to indirect immunofluorescence tests, real-time PCR and flow cytometry. The TREX1 531C/T polymorphism was associated with higher levels of TCD4+ lymphocytes and IFN-α in individuals with HIV-1. Individuals on ART had a higher frequency of ANA, higher levels of T CD4+ lymphocytes, a higher ratio of T CD4+/CD8+ lymphocytes and higher levels of IFN-α than therapy-naïve individuals (p < 0.05). The TREX1 531C/T polymorphism was associated with better maintenance of the immune status of individuals with HIV-1 and ANA with immune restoration in individuals on ART, indicating the need to identify individuals at risk of developing an autoimmune disease.

Timing of antiretroviral therapy in cryptococcal meningitis: What we can (and cannot) learn from observational data.

Timing of antiretroviral therapy in cryptococcal meningitis: What we can (and cannot) learn from observational data.

Type and timing of antiretroviral therapy during pregnancy: Impact on risk of preterm delivery and small-for-gestational age births in Canada, a retrospective cohort study.

To evaluate the impact of type and timing of antiretroviral therapy (ART) on the risk of preterm delivery (PTD) and small-for-gestational age (SGA) birth among pregnant women and people living with HIV in Canada. Data for this retrospective cohort study were analyzed from the Canadian Perinatal HIV Surveillance Program from 1990 to 2020. The association between ART and risk of PTD (<37 weeks) and SGA birth(<10th percentile)was explored using mixed effects logistic regression and time-dependent Cox proportional hazards models. Overall, there were 14.9% (654 of 4379) PTD and 18.5% (732 of 3947) SGA cases. A higher risk of PTD was observed with nonnucleoside reverse transcriptase inhibitor-(adjusted hazard ratio [aHR], 1.73; P=0.019) and boosted protease inhibitor-(aHR,186;P=0.007)based regimenscompared with integrase strand transfer inhibitor (INSTI)-based regimens. ART initiation prior to conception was associated with a lower risk of SGA birthcompared with ART initiation after conception at 1 to 14 weeks (adjusted odds ratio [aOR], 0.69; P=0.024) and > 14 weeks (aOR, 0.70; P=0.005). INSTI-based ART regimens were associated with lower risk of PTD compared with other regimens, and ART initiation before conception was associated with a lower risk of SGAbirth. These findings, with overall safety data, should be considered when providing pregnancy counseling to people living with HIV.

Machine learning with routine electronic medical record data to identify people at high risk of disengagement from HIV care in Tanzania.

Machine learning methods for health care delivery optimization have the potential to improve retention in HIV care, a critical target of global efforts to end the epidemic. However, these methods have not been widely applied to medical record data in low- and middle-income countries. We used an ensemble decision tree approach to predict risk of disengagement from HIV care (missing an appointment by ≥28 days) in Tanzania. Our approach used routine electronic medical records (EMR) from the time of antiretroviral therapy (ART) initiation through 24 months of follow-up for 178 adults (63% female). We compared prediction accuracy when using EMR-based predictors alone and in combination with sociodemographic survey data collected by a research study. Models that included only EMR-based indicators and incorporated changes across past clinical visits achieved a mean accuracy of 75.2% for predicting risk of disengagement in the next 6 months, with a mean sensitivity of 54.7% for targeting the 30% highest-risk individuals. Additionally including survey-based predictors only modestly improved model performance. The most important variables for prediction were time-varying EMR indicators including changes in treatment status, body weight, and WHO clinical stage. Machine learning methods applied to existing EMR data in resource-constrained settings can predict individuals' future risk of disengagement from HIV care, potentially enabling better targeting and efficiency of interventions to promote retention in care.

A role for CD4 + helper cells in HIV control and progression.

It remains unclear why HIV persists in most untreated individuals, and why a small minority of individuals can control the virus, either spontaneously or after an early treatment. Striking differences have been discovered between patient cohorts in CD4 + T-cell avidity but not in CD8 + T-cell avidity. The present work has the aim to explain the diverse outcome of infection and identify the key virological and immunological parameters predicting the outcome. A mathematical model informed by these experiments and taking into account the details of HIV virology is developed. The model predicts an arms race between viral dissemination and the proliferation of HIV-specific CD4 + helper cells leading to one of two states: a low-viremia state (controller) or a high-viremia state (progressor). Helper CD4 + cells with a higher avidity favor virus control. The parameter segregating spontaneous and posttreatment controllers is the infectivity difference between activated and resting CD4 + T cells. The model is shown to have a better connection to experiment than a previous model based on T-cell 'exhaustion'. Using the model informed by patient data, the timing of antiretroviral therapy can be optimized.

Timing of Antiretroviral Therapy: Initiation and Birth Outcomes Among Pregnant Women With Human Immunodeficiency Virus in Tanzania

Combination antiretroviral therapy (cART) initiation during pregnancy reduces the risk of perinatal human immunodeficiency virus (HIV) transmission; however, studies have suggested that there may be unintended adverse consequences on birth outcomes for selected cART regimens. We analyzed adverse birth outcomes among a prospective cohort of 1307 pregnant women with HIV in Dar es Salaam who initiated cART during the first or second trimester of a singleton pregnancy. Our primary analysis compared birth outcomes by gestational age at cART initiation among these women initiating cART in pregnancy. Among women who initiated cART in pregnancy, there was no relationship of gestational age at cART initiation with the risk of fetal death or stillbirth. However, women who initiated cART before 20 weeks of gestation compared with after 20 weeks had increased risk of preterm birth (risk ratio [RR], 1.30; 95% confidence interval [CI], 1.03-1.67) but decreased risk of small-for-gestational age birth (RR, 0.71; 95% CI, .55-.93). With increasing use of cART preconception and early in pregnancy, clinicians should be aware of the benefits and potential risks of cART regimens to optimize birth outcomes.

Prevalence of anaemia and its associated factors among HIV-infected adults at the time of ART initiation at Debre Markos Comprehensive Specialized Hospital, Northwest Ethiopia: a retrospective cross-sectional study

ObjectiveThe aim of this study was to assess the prevalence of anaemia and its associated factors at the time of antiretroviral therapy (ART) initiation among HIV-infected adults at Debre Markos...

Observed CD4 counts at entry into HIV care and at antiretroviral therapy prescription by age in the USA, 2004-18: a cohort study.

Adults aged 50 years or older comprise a majority of people with HIV in the USA. Our objective was to describe observed differences by age in CD4 count at entry into HIV care, timing of antiretroviral therapy (ART) prescription, and CD4 count at time of ART prescription before (2004-11) and during (2012-18) the current era of universal treatment. For this descriptive study, we calculated median (IQR) CD4 count at entry into care, days from entry into care to ART prescription, and CD4 count at time of ART prescription among patients enrolled in US-based clinical cohorts of the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD; see appendix). We excluded participants with no CD4 count recorded at entry into care, medical records that suggested previous ART use, or previous AIDS diagnosis. All calculations were stratified by age (≥50 and 18-50 years) and calendar year. Of 35 293 ART-naive adult participants entering care between Jan 1, 2004 and Dec 31, 2018, 5794 (16%) were women and 29 499 (84%) were men; 15817 (45%) were Black, 11566 (33%) were White, 5538 (16%) were Hispanic (any race), 737 (2%) were Asian or Pacific Islander, 152 (0.4%) were Indigenous, and 98 (0.3%) were multiracial. Median age at entry into care was 39 years (IQR 29-49); 8004 (23%) were aged 50 years or older. Of 29 141 participants initially prescribed ART, 7274 (25%) were aged 50 years or older. From 2004 to 2018, median CD4 count at entry into care increased from 228 cells per µL (IQR 80-422) to 295 cells per µL (134-489) among adults aged 50 years and older, and from 297 cells per µL (119-480) to 378 cells per µL (202-564) among adults younger than 50 years. Median days from entry into care to ART prescription declined from 56 (IQR 17-658) to 6 (0-15) among adults older than 50 years, and from 61 (17-509) to 6 (0-16) among adults younger than 50 years. Median CD4 count at time of ART prescription increased from 139 cells per µL (IQR 59-257) to 311 cells per µL (137-504) among adults aged 50 years or older, and from 166 cells per µL (49-287) to 377 cells per µL (198-564) among adults younger than 50 years. Before the release of universal treatment guidelines by the US Department of Health and Human Services in 2012, median time to ART prescription was already falling, leading to increases in median CD4 count at ART prescription for both age groups; both measures continued to improve in the treat-all era. However, median CD4 counts, both at entry into care and at ART prescription, among adults aged 50 years and older were lower than those of adults younger than 50 years throughout the study period. Furthermore, even into the treat-all era, over half of adults aged 50 years and older entered care with CD4 counts of less than 350 cells per µL, potentially because of factors including immunosenescence, delayed HIV diagnosis, and late presentation to care. Given that age-related immunological changes might not be fully avoidable, targeted strategies for increasing HIV risk awareness, routine testing, and immediate linkage to HIV care at diagnosis are particularly essential for this population. US National Institutes of Health grant U01AI069918.

Undetectable Anti-HBs Antibodies: Need of a Booster Dose for HIV-1-Infected Individuals.

HBV vaccination effectively prevents HBV transmission and the development of liver cancer. Disease progression and liver-related complications are more common in HIV-1/HBV co-infected than HBV mono-infected individuals. A considerable body of literature, which will be reviewed here, indicates that response to HBV vaccine is suboptimal in HIV-1-infected individuals and that the poor maintenance of protective immunity to HBV vaccines in these individuals is an important medical issue. Several factors affect HBV vaccine response during HIV-1 infection including CD4+ T cell counts, B cell response, vaccine formulation, schedules, and timing of antiretroviral therapy (ART). The initial response to HBV vaccination also plays a critical role in the sustainability of antibody responses in both HIV-1-infected and uninfected vaccinees. Thus, regular follow-up for antibody titer and a booster dose is warranted to prevent HBV transmission in HIV-1 infected people.

Timing of antiretroviral therapy for HIV-infected patients with cytomegalovirus retinitis: study protocol of a multi-center prospective randomized controlled trial

BackgroundCytomegalovirus retinitis (CMVR) is an important opportunistic infection (OI) occurring mainly in patients with acquired immunodeficiency syndrome (AIDS) and has the potential to cause severe visual impairment and blindness among AIDS patients. Subsequent to the adoption and implementation of widespread antiretroviral therapy (ART), the prognosis of AIDS-associated CMVR has been substantially improved. Nevertheless, the equivocal clinical evidence as regards the optimal timing for ART initiation in patients with an established CMVR diagnosis is required. We therefore designed the present study in order to investigate the optimal timing for ART initiation in AIDS/CMVR patients.MethodsThis will be a prospective, randomized controlled trial to be performed at 17 hospitals in mainland China. A total of 300 participants with CMVR will be randomly assigned to an early ART initiation group (ART initiation within 2 weeks after anti-CMV therapy), or a deferred ART initiation group (initiation of ART more than 2 weeks after anti-CMV therapy) at a 1:1 ratio. All participants will receive 48 weeks of follow-up after anti-CMV therapy initiation. Our primary outcome will be the incidence of visual loss (to a visual acuity worse than 20/40 or 20/200) in the two groups during the 48-week follow-up period. Secondary outcomes will include changes in HIV virological suppression and serum CD4+ T-cell counts, the incidence of mortality, retinitis progression (movement of the peripheral border of a CMV lesion ≥ ½ disc diameter, or occurrence of a new CMV lesion), retinal detachment, immune recovery uveitis (IRU), and other OIs and adverse events between the two study groups during the 48 weeks of follow-up.DiscussionThe study aims to investigate the optimal timing for ART initiation in AIDS/CMVR patients. We hope to be able to extract robust clinical evidence for use in optimal AIDS/CMVR management should our trial be successful.Trial registrationThis research was registered as one of the twelve clinical trials under the name of a general project “A study for precision diagnosing and treatment strategies in difficult-to-treat AIDS cases and HIV-infected patients with highly fatal or highly disabling opportunistic infections”, ChiCTR1900021195. Registered on 1 February 2019, http://www.chictr.org.cn/showproj.aspx?proj=35362.

Rate of HIV Seroconversion Among Seronegative Male Partners Living with HIV Positive Women in Addis Ababa, Ethiopia, 2019: A Retrospective Cohort Study

ObjectiveThis study aimed to assess rate of HIV seroconversion and predictors among seronegative male partners living with HIV-positive women in Addis Ababa, Ethiopia, 2019.MethodsInstitutional-based retrospective cohort was used to conduct the study. All eligible 227 sample medical records were used for the study. Kaplan–Meier analysis was used to estimate seroconversion time. Cox proportional-hazard regression was used to identify predictor variables.ResultsIn this study, 227 seronegative male partners living with HIV-positive women were followed for 60 months retrospectively and 38 (16.7%) seroconversion was observed. The overall seroconversion rate was 6.4 (95%CI: 4.64–8.76) per 100 person-year observation. Time of antiretroviral therapy (ART) initiation, CD4 level, condom use, and having history of pregnancy after being diagnosed as discordant were identified significant predictors of seroconversion.ConclusionThe risk of HIV transmission from seropositive partner to seronegative partner in a discordant couple is poorly controlled. Seronegative partners in discordant a couple can be seropositive at any time with influence of predictors unless proper protective measures, counseling, and follow-up are given emphasis.

The Optimal Timing of Antiretroviral Therapy Initiation in HIV-Infected Patients with Cryptococcal Meningitis: A Multicenter Prospective Randomized Controlled Trial.

The optimal timing of antiretroviral therapy (ART) initiation in human immunodeficiency virus (HIV)-infected patients with cryptococcal meningitis (HIV/CM) is controversial. We designed a clinical trial to inves-tigate the optimal timing for ART initiation in HIV/CM patients. This will be a multicenter, prospective, and randomized clinical trial. Each enrolled patient will be randomized into either the early ART arm or the deferred ART arm. We will compare the mortality and incident rates of immune reconstitution inflammatory syndrome between the two arms. We hope to elucidate the optimal timing for ART initiation in HIV/CM patients.

Multidrug-Resistant Tuberculosis in Patients with Human Immunodeficiency Virus. Management Considerations within High-resourced Settings.

The management of multidrug-resistant tuberculosis (MDR TB) is notably complex among patients with human immunodeficiency virus (HIV). TB treatment recommendations typically include very little information specific to HIV and MDR TB, which often is derived from clinical trials conducted in low-resource settings. Mortality rates among patients with HIV and MDR TB remain high. We reviewed the published literature and recommendations to synthesize possible patient management approaches demonstrated to improve treatment outcomes in high-resourced countries for patients with MDR TB and HIV. Approaches to diagnostic testing, impact and timing of antiretroviral therapy on mortality, anti-MDR TB and antiretroviral drug interactions, and the potential role for short-course MDR TB therapy are examined. The combination of antiretroviral therapy with expanded TB drug therapy, along with the management of immune reconstitution inflammatory syndrome, other potential HIV-associated opportunistic diseases, and drug toxicities, necessitate an integrated multidisciplinary patient care approach using public health case management and provider expertise in drug-resistant TB and HIV management.

Timing of Antiretroviral Therapy and Systemic Inflammation in Sub-Saharan Africa: Results From the META Longitudinal Cohort Study

Chronic inflammation predicts complications in persons with human immunodeficiency virus infection. We compared D-dimer, soluble CD14, and interleukin 6 levels before and 12 months after antiretroviral therapy (ART) initiation, among individuals starting ART during earlier-stage (CD4 T-cell count >350/µL) or late-stage disease (CD4 T-cell count <200/µL). Female sex, older age, viral load, and late-stage disease were associated with pre-ART biomarkers (n = 661; P < .05). However, there were no differences in biomarkers by disease stage after 12 months of ART (n = 438; P > .05), owing to loss from observation and greater declines in biomarkers in late-stage initiators (P < .001). Earlier initiation of ART is associated with decreased inflammation, but levels seem to converge between earlier and later initiators surviving to 12 months.

Treatment of HIV among tuberculosis patients: A replication study of timing of antiretroviral therapy for HIV-1-associated tuberculosis

Co-diagnosis of HIV and tuberculosis presents a treatment dilemma. Starting both treatments at the same time can cause a flood of immune response called immune reconstitution inflammatory syndrome (IRIS) which can be lethal. But, how long to delay HIV treatment is less understood. In 2011, based on the conclusions of three separate studies, WHO recommended starting HIV treatment earlier for those with later HIV disease progression. This paper conducts a replication study of one of the three studies, by Havlir and colleagues. Using their publicly available data, we were able to replicate most of the results presented in the original paper. In our measurement and estimation analyses we use different estimation techniques to assess the robustness of the results. We find that adjusting for loss to follow-up does not affect the main results of the paper. However, an ANCOVA estimation and an instrumental variable model weaken the main result of the paper of better outcomes with early HIV treatment only for those who are sicker, reducing significance from the 5% to the 10% level. A change-point analysis also detects no changes in effect by timing of HIV treatment initiation or different thresholds of CD4 count for the primary outcome. This result suggests that the choice of start time for HIV treatment initiation should be based on other factors including potential drug interactions, overlapping side effects, a high pill burden and severity of illness rather than CD4 threshold and preset timeframes. While we caution against overgeneralizing, the result of this replication is aligned with more recent studies that show no evidence that early initiation of HIV treatment reduces mortality for any patients.

Bayesian Modelling on Incidence of Pregnancy among HIV/AIDS Patient Women at Adare Hospital, Hawassa, Ethiopia

HIV/AIDS is the most serious diseases human kind has ever faced and a public problem, particularly, for women of childbearing age. For HIV infected women, the prospects of getting pregnant and having an HIV negative baby could be significantly improved with the increasing of the availability of Antiretroviral Therapy (ART). Even though, ART treatment has shown significant effect of clinical importance to reduce the risk of mother to child transmission of HIV but, HIV infected Women remain poorly understood or they fear to be pregnant and having HIV negative child. To the authors’ knowledge, no study examined incidence of pregnancy among women on ART follow-up in Ethiopia. In response, we conducted a study to explore the incidence and potential predictors of pregnancy. The objective of this study was to investigate the incidence of pregnancy among HIV/AIDS patient women under ART follow-up. A retrospective cohort study was conducted based on secondary data that reviews or visits medical chart of HIV/ADIS patient women aged 15-49 years under ART follow-up from April 2008 to February 2015. Out of 720 total patient women, a sample of size 328 was selected by using simple random sampling technique. Bayesian estimation were used for binary logistic regression model to identify the significant factors of incidence of pregnancy. The Gibbs sampler algorithm was implemented by WinBUGS software to solve approximate properties of the marginal posterior distributions for each parameter in Bayesian estimation. The results of this study revealed 21.3% of women got pregnancy during the follow-up. From Bayesian logistic regression analysis, significant predictors of incidence of pregnancy were: WHO clinical stage, marital status, contraception use, number of child alive before ART follow-up, CD4 cell count, time of Antiretroviral Therapy (ART) follow-up, educational level, spouse's HIV status, occupation and age (at p=0.05). In this study, when age of the women increased, the probability of becoming pregnant was decreased and advanced WHO clinical stage were associated with decreased incidence of pregnancy. Time on ART was a strong predictor of becoming pregnant: longer time on ART was associated with increased probability of becoming pregnant. Educational level of women was positively related with incidence of pregnancy that is, women who had college and above educational level was more likely to become pregnant. When CD4 count increased, incidence of pregnancy also increased and married women had more chance to become pregnant. The predictors identified in this study can be used to care for those HIV/AIDS patient women who want to have baby.

Ophthalmologic manifestations of elderly patients with human immunodeficiency virus infection

Objectives: Identify and describe ocular changes in elderly with HIV or aids through ophthalmological examination. Evaluate the association between ocular alterations and the level of TCD4 lymphocytes, time of antiretroviral therapy, demographic characteristics and age range. Methods: Case series of 40 elderly patients with HIV infection. The study was carried out at the ophthalmology and immunology outpatient clinics of the Gaffrée and Guinle University Hospital (HUGG) from january 2017 to june 2018. The patients were attended at the ophthalmology clinic [...]

Antibody and TLR7 agonist delay viral rebound in SHIV-infected monkeys.

The latent viral reservoir is the critical barrier for the development of an HIV-1 cure. Previous studies have shown that potent HIV-1 Env-specific broadly neutralizing antibodies (bNAbs) administered at the time of antiretroviral therapy (ART) discontinuation can exert direct antiviral effects, but whether bNAbs can target the viral reservoir during ART suppression remains unknown. Here we show that the V3 glycan-dependent bNAb PGT121 together with the TLR7 agonist vesatolimod (GS-9620) administered during ART suppression delayed viral rebound following ART discontinuation in SHIV-SF162P3-infected rhesus monkeys that initiated ART during early acute infection. Moreover, the subset of PGT121+GS-9620 treated monkeys that did not show viral rebound following ART discontinuation also did not reveal virus by highly sensitive adoptive transfer and CD8 depletion studies. These data demonstrate the potential of bNAb administration together with innate immune stimulation as a possible strategy to target the viral reservoir.