A mechanistic model for long-term immunological outcomes in South African HIV-infected children and adults receiving ART.
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ABSTRACT:
SUBMITTER: Ujeneza EL
PROVIDER: S-EPMC7857728 | biostudies-literature | 2021 Jan
REPOSITORIES: biostudies-literature
Publications
A mechanistic model for long-term immunological outcomes in South African HIV-infected children and adults receiving ART.
Ujeneza Eva Liliane EL Ndifon Wilfred W Sawry Shobna S Fatti Geoffrey G Riou Julien J Davies Mary-Ann MA Nieuwoudt Martin M
eLife 20210114
Long-term effects of the growing population of HIV-treated people in Southern Africa on individuals and the public health sector at large are not yet understood. This study proposes a novel 'ratio' model that relates CD4+ T-cell counts of HIV-infected individuals to the CD4+ count reference values from healthy populations. We use mixed-effects regression to fit the model to data from 1616 children (median age 4.3 years at ART initiation) and 14,542 adults (median age 36 years at ART initiation). ...[more]
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Project description:Background: HIV-infected individuals have increased risk of developing obstructive lung disease (OLD). Studies from developed countries report high viral load, low CD4 counts, and anti-retroviral therapy (ART) to be associated with OLD; but these findings may not be generalizable to populations in resource-limited settings.Methods: We conducted a prospective cohort study of lung function in 730 HIV-infected black South African adults. Pre-bronchodilator spirometry was performed at enrollment and repeated annually for three years. Logistic regression models were used to identify factors associated with OLD, defined as FEV1/FVC<0.70, at enrollment. Excess annual declines in FEV1 and FVC were modelled as the product-term of follow-up time and exposures using random effects regression.Results: Median (IQR) age at enrollment was 36 (32-41) years, 85% were female and 30% ever-smoked with a median (IQR) exposure of 3 (1-6) pack-years. Median (IQR) CD4 count and viral load at enrollment were 372 (261-518) cells/mm3 and 2655 (91-13,548) copies/mL respectively. Overall, 25% were receiving ART at enrollment, 16% of whom reported at least 6 months of ART receipt. OLD was found in 35 (5%) at enrollment. Increasing age (aOR = 2.08 per 10-years [95%CI 1.22-3.57], p = 0.007), current smoking (aOR = 3.55 [95%CI 1.20-10.53], p = 0.02), and CRP (aOR = 1.01 per unit-increase [95%CI 1.00-1.03], p = 0.04) were significantly associated with OLD at enrollment; while increasing CD4 count (aOR = 1.02 per-100 cells/mm3 [95%CI 0.85-1.22], p = 0.82), viral load (aOR = 0.67 per log-increase [95%CI 0.43-1.10], p = 0.12) and receipt of ART (aOR = 0.57 [95%CI 0.18-1.75], p = 0.32) were not. The median (IQR) follow-up time was 18 (12-24) months. Participants with a history of tuberculosis (TB) had a 35 mL (95%CI 2-68, p = 0.03) and 57 mL (95%CI 19-96, p = 0.003) per year excess loss of FEV1 and FVC respectively.Conclusion: Prevalent OLD was associated with older age, current smoking and higher CRP levels, but not CD4 counts and ART, in HIV-infected South African adults. Better understanding of the long-term effects of TB, smoking and inflammation on lung function in HIV-infected populations is urgently needed.
| S-EPMC5597201 | biostudies-literature
Project description:A recently concluded randomized study in Tanzania found that short-term conditional cash and food transfers significantly improved HIV-infected patients’ possession of antiretroviral therapy (ART) and reduced patient loss to follow-up (LTFU) (McCoy, S. I., Njau, P. F., Fahey, C., Kapologwe, N., Kadiyala, S., Jewell, N. P., & Padian, N. S. (2017). Cash vs. food assistance to improve adherence to antiretroviral therapy among HIV-infected adults in Tanzania. AIDS, 31(6), 815–825. doi:10.1097/QAD.0000000000001406 ). We examined whether these transfers had differential effects within population subgroups. In the parent study, 805 individuals were randomized to one of three study arms: standard-of-care (SOC) HIV services, food assistance, or cash transfer. We compared achievement of the medication possession ratio (MPR) ≥ 95% at 6 and 12 months and patient LTFU at 12 months between those receiving the SOC and those receiving food or cash (combined). Using a threshold value of p < 0.20 to signal potential effect measure modifiers (EMM), we compared intervention effects, expressed as risk differences (RD), within subgroups characterized by: sex, age, wealth, and time elapsed between HIV diagnosis and ART initiation. Short-term transfers improved 6 and 12-month MPR ≥ 95% and reduced 12-month LTFU in most subgroups. Study results revealed wealth and time elapsed between HIV diagnosis and ART initiation as potential EMMs, with greater effects for 6-month MPR ≥ 95% in the poorest patients (RD: 32, 95% CI: (9, 55)) compared to those wealthier (RD: 16, 95% CI: (5, 27); p = 0.18) and in newly diagnosed individuals (<90 days elapsed since diagnosis) (RD: 25, 95% CI: (13, 36)) compared to those with ≥90 days (RD: 0.3, 95% CI (−17, 18); p = 0.02), patterns which were sustained at 12 months. Results suggest that food and cash transfers may have stronger beneficial effects on ART adherence in the poorest patients. We also provide preliminary data suggesting that targeting interventions at patients more recently diagnosed with HIV may be worthwhile. Larger and longer-term assessments of transfer programs for the improvement of ART adherence and their potential heterogeneity by sub-population are warranted.
| S-EPMC6366443 | biostudies-literature
Project description:BackgroundHigh HIV-1 DNA levels in peripheral blood mononuclear cells (PBMC) were associated with a higher risk of severe morbidity and a faster decline in CD4 count in ART-naive patients. We report the association between HIV-1 DNA and mortality in HIV-infected adults in a trial of early ART in West Africa.MethodsIn the Temprano trial, HIV-infected adults were randomly assigned to start ART immediately or defer ART. After trial termination, HIV-1 DNA was measured in whole blood samples frozen at baseline. We analyzed the association between baseline PBMC HIV-1 DNA and long-term mortality.Findings2019 patients were followed for 9253 patient-years (median 4.9 years). At baseline, the median CD4 count was 462/mm3 [IQR 368-571], the median plasma HIV-1 RNA 4.7 log10 copies/ml [IQR 4.0-5.2], and the median HIV-1 DNA 2.9 log10 copies/million PBMC [IQR 2.5-3.3]. During follow-up, 86 participants died. In univariate analysis, the hazard ratio [HR] of death was 2.67 (95% CI, 1.68-4.22) for patients with HIV-1 DNA ≥3 log10 copies/million PBMC vs. others, and 2.10 (95% CI, 1.38-3.21) for patients with HIV-1 RNA ≥5 log10 copies/ml vs. others. In multivariate Cox regression analysis, HIV-1 DNA levels ≥3 log10 copies/million PBMC were strongly associated mortality (adjusted HR = 2.09, 95% CI 1.24-3.52, p= 0.005) while the association between baseline plasma HIV-1 RNA and mortality was not significant.InterpretationIn these African adults who started ART with high CD4 counts, HIV-1 DNA was a strong independent predictor of death. The HIV reservoir still plays a prognostic role in the early ART era.FundingThis trial was supported by the French National Agency for AIDS and viral hepatitis research (ANRS, Paris, France; Grants ANRS 12136, 12224 and 12253).
| S-EPMC7276518 | biostudies-literature
Project description:RationaleLung disease is a common cause of mortality and morbidity in HIV-infected adolescents, but there is limited information on the spectrum of lung function impairment in adolescents on antiretroviral therapy.ObjectivesTo investigate lung function in HIV-infected adolescents on antiretroviral therapy in the Cape Town Adolescent Antiretroviral Cohort (Cape Town, South Africa).MethodsA total of 515 South African adolescents, aged 9-14 years, stable on antiretroviral therapy for at least 6 months, underwent baseline lung function testing. Measures included spirometry, nitrogen multiple-breath washout, forced oscillation technique, 6-minute walk test, single-breath carbon monoxide diffusion testing, and bronchodilator response testing. A comparator group of 110 age- and ethnicity-matched HIV-uninfected adolescents was also tested.ResultsFor the HIV-infected adolescents (mean [SD] age 12 [1.6] years, 52% male), the median (interquartile range) duration of antiretroviral therapy was 7.6 (4.6-9.2) years. The median (interquartile range) nadir CD4 was 510.5 (274-903) cells/mm3. HIV-infected adolescents had significantly lower FEV1, FVC, FEV1/FVC, diffusing capacity of carbon monoxide, respiratory system compliance, and functional residual capacity than HIV-uninfected adolescents (P < 0.05 for all associations). HIV-infected adolescents had higher airway resistance and lung clearance index than HIV-uninfected adolescents (P < 0.05 for all associations). Although generally small in magnitude, these differences remained significant after adjusting for age, sex, and height. In addition, age, sex, height, and history of past lower respiratory tract infection or pulmonary tuberculosis were associated with reduced lung function.ConclusionsPerinatally infected South African HIV-infected adolescents on antiretroviral therapy have lower lung function than uninfected adolescents. Prior lower respiratory tract infection or pulmonary tuberculosis is associated with lower lung function.
| S-EPMC5427744 | biostudies-literature
Project description:OBJECTIVES:The risk of kidney dysfunction on the WHO recommended first line regimens containing tenofovir disoproxil fumarate (TDF) without protease inhibitors (PI) remains unclear in Asian patients, especially those with low body weight. METHODS:Using data collected in a multicenter clinical trial in Thailand and proportional hazard regression models, we compared the risk of a >25% estimated glomerular filtration rate (eGFR) reduction in HIV naïve patients initiating TDF or zidovudine (AZT) containing non-PI regimen. RESULTS:Of 640 patients included in the analysis, 461 (72%) received a TDF-containing regimen for a median 6.7 years and 179 (28%) an AZT-containing regimen for 6.5 years. The risk of a >25% eGFR reduction was not associated with treatment (HR 1.11, 95% CI 0.84-1.47, P?=?0.46). In multivariate analysis, the risk of >25% eGFR reduction form baseline was associated with body weight at baseline (HR 2.12, 95% CI 1.48-3.02 for <48?kg patients and HR 1.64, 95% CI 1.20-2.25 for 48-59.9?kg patients, compared to those with >60?kg, P < 0.001) and hypertension (HR 4.03, 95% CI 2.0-8.0, P < 0.001). The effect of baseline weight on >25% eGFR reduction did not significantly vary with treatment (P?=?0.27). CONCLUSIONS:The risk of eGFR reduction was not higher on TDF- versus AZT-based non-PI regimens. Although the risk of eGFR reduction was greater for patients of lower body weight, this risk was not significantly increased by TDF.
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Project description:ObjectivesTo assess the burden of sexually transmitted infections (STIs) among HIV-positive South Africans in the period prior to antiretroviral therapy (ART) initiation compared with the period once on ART.MethodsWe linked the clinic records of 1465 patients currently on ART to the electronic database which records all visits to city clinics. We used a mixed effects Poisson model to assess the relative rates of occurrence of treatment seeking for an STI in the periods prior to initiation of ART and while on ART.ResultsWe accumulated 4214 person-years of follow-up, divided nearly equally between the pre-ART and on-ART periods. The rate of treatment seeking for new STIs was 5.50 (95% CI 5.43 to 5.78) per 100 person-years, and individuals had on average a sevenfold higher rate of seeking treatment for STIs in the period prior to initiating ART (9.57 per 100 person-years) compared with the period once on ART (5.5 per 100 person-years) (adjusted rate ratio (RR) 7.01, 95% CI 4.64 to 10.59). Being male (RR 1.73, 95% CI 1.18 to 2.55) or younger (age <25) (RR 2.67, 95% CI 1.53 to 4.65) was associated with higher incidence of clinic visits for STI treatment, while advanced stage of HIV disease (WHO stage 4) (RR 0.33, 95% CI 0.15 to 0.69) was associated with lower incidence.ConclusionsThe period prior to the initiation of ART is a critical period where increased attention should be focused on the detection and treatment of STIs. A successful effort to treat STIs in this period will likely reduce further HIV transmission and fits within a test-and-treat approach.
| S-EPMC4233167 | biostudies-literature
Project description:Neurocognitive impairment (NCI) is one of the most common complications of HIV infection, and has serious medical and functional consequences. South Africa has 7 million people living with HIV (PLHIV) with up to three-quarters of antiretroviral therapy (ART)-naïve individuals having NCI. South Africa's health system struggles to meet the care needs of its millions of PLHIV; screening for NCI is typically neglected due to limited clinical staff trained to administer, score, and interpret neuropsychological tests, as well as long test batteries and limited screening tools for South African populations. Without accurate, clinically useful, and relatively brief NCI screening tests that can be administered by all levels of clinical staff, critical opportunities to provide psychoeducation, behavioral planning, additional ART adherence support, and adjuvant therapies for NCI (when they become available) are missed. To address these challenges and gap in care, we developed an mHealth app screening tool, NeuroScreen, to detect NCI that can be administered by all levels of clinical staff, including lay health workers.The purpose of this study was to examine sensitivity and specificity of an adapted version of NeuroScreen to detect NCI (as determined by a gold standard neuropsychological test battery administered by a trained research psychometrist) among HIV-infected South Africans when administered by a lay health worker.A total of 102 HIV-infected black South African adults who had initiated ART at least 12 months prior were administered NeuroScreen and a gold standard neuropsychological test battery in the participants' choice of language (ie, English or isiXhosa). Three composite z scores were calculated for NeuroScreen: (1) sum of all individual test scores, (2) sum of all individual test scores and error scores from four tests, and (3) sum of four tests (abbreviated version). Global deficit scores were calculated for the gold standard battery where a score of 0.5 or greater indicated the presence of NCI.The mean age of participants was 33.31 (SD 7.46) years, most (59.8%, 61/102) had at least 12 years of education, and 81.4% (83/102) of the sample was female. Gold standard test battery results indicated that 26.5% (27/102) of the sample had NCI. Sensitivity and specificity of age-, education-, and sex-adjusted NeuroScreen scores were 81.48% and 74.67% for composite score 1, 81.48% and 81.33% for composite score 2, and 92.59% and 70.67% for composite score 3, respectively.NeuroScreen, a highly automated, easy-to-use, tablet-based screening test to detect NCI among English- and isiXhosa-speaking South African HIV patients demonstrated robust sensitivity and specificity to detect NCI when administered by lay health workers. NeuroScreen could help make screening for NCI more feasible. However, additional research is needed with larger samples and normative test performance data are needed.
| S-EPMC5775487 | biostudies-literature
Project description:Peripheral CD4+ T-cell levels are not fully restored in a significant proportion of HIV+ individuals displaying long-term viral suppression on c-ART. These immunological nonresponders (INRs) have a higher risk of developing AIDS and non-AIDS events and a lower life expectancy than the general population, but the underlying mechanisms are not fully understood. We used an in vitro system to analyze the T- and B-cell potential of CD34+ hematopoietic progenitor cells. Comparisons of INRs with matched HIV+ patients with high CD4+ T-cell counts (immune responders (IRs)) revealed an impairment of the generation of T-cell progenitors, but not of B-cell progenitors, in INRs. This impairment resulted in the presence of smaller numbers of recent thymic emigrants (RTE) in the blood and lower peripheral CD4+ T-cell counts. We investigated the molecular pathways involved in lymphopoiesis, focusing particularly on T-cell fate specification (Notch pathway), survival (IL7R-IL7 axis) and death (Fas, P2X7, CD39/CD73). P2X7 expression was abnormally strong and there was no CD73 mRNA in the CD34+ cells of INRs, highlighting a role for the ATP pathway. This was confirmed by the demonstration that in vitro inhibition of the P2X7-mediated pathway restored the T-cell potential of CD34+ cells from INRs. Moreover, transcriptomic analysis revealed major differences in cell survival and death pathways between CD34+ cells from INRs and those from IRs. These findings pave the way for the use of complementary immunotherapies, such as P2X7 antagonists, to restore T-cell lymphopoiesis in INRs.
| S-EPMC4833302 | biostudies-literature
Project description:Older HIV-infected adults have a higher risk of neurocognitive impairment, but the underlying mechanisms are poorly understood. Here, we investigated the associations between levels of HIV DNA in peripheral blood, soluble markers of inflammation and cellular trafficking in blood and cerebrospinal fluid (CSF) and neurocognitive functioning among 18 younger (22-40 years) and 26 older (50-71 years) HIV-infected subjects, who were administered a comprehensive neurocognitive battery. Older HIV-infected individuals presented higher levels of inflammation in CSF and blood compared to younger individuals, but no difference was observed in HIV DNA levels. Among older participants, higher HIV DNA levels were significantly associated with more severe neurocognitive impairment (p = 0.005), particularly in the Executive Functions domain (p = 0.004). No association was observed between HIV DNA and neurocognition among younger individuals. Despite significantly increased inflammation observed in the older group, none of the inflammatory markers were associated with neurocognitive impairment among older HIV+ individuals (p > 0.05). Our study supports the involvement of peripheral HIV DNA reservoir in the pathogenesis of neurocognitive disorder during suppressive ART. Correlates of neurocognitive impairment might differ between younger and older adults, suggesting that future treatment and prevention strategies for HIV-associated neurocognitive disorders likely need to be tailored based on age.
| S-EPMC4658529 | biostudies-literature
Project description:UNLABELLED:We measured plasma human immunodeficiency virus type 1 (HIV-1) RNA levels by means of single-copy assay in 334 participants receiving virologically suppressive antiretroviral therapy (ART). A residual viremia load of ?1 copy/mL after 4 years of ART was predicted by a higher pre-ART HIV-1 RNA level, higher CD8(+) T-cell count during treatment, and a lower ratio of CD4+ T cells to CD8+ T cells during treatment but not by initial ART regimen. In a longitudinal subset of 64 individuals, continued decay of the plasma HIV-1 RNA level was observed, with an average annual decrease of 6% and an estimated half-life of 11.5 years. In contrast to prior reports, the persistent viremia level continues to slowly decline during years 4-12 of suppressive ART. CLINICAL TRIALS REGISTRATION:NCT00001137.
| S-EPMC4721905 | biostudies-literature