Sophia Pathai

Accelerated biological ageing in HIV-infected individuals in South Africa: a case–control study

Objectives:Little is known about the impact of HIV infection on biological ageing in sub-Saharan Africa. The study aimed to assess biological ageing in South African HIV-infected adults and HIV-seronegative individuals using two validated biomarkers, telomere length and CDKN2A expression (a mediator of cellular senescence). Design:A case–control study. Methods:Two hundred and thirty-six HIV-infected adults aged at least 30 years and 250 age and sex frequency matched HIV-seronegative individuals were recruited from clinics in township communities in Cape Town. Biological ageing was evaluated by measurement of telomere length and CDKN2A expression in peripheral blood leukocytes. Results:The median ages of the HIV-infected and HIV-seronegative participants were 39 and 40 years, respectively. Among HIV-infected participants, 87.1% were receiving antiretroviral therapy (ART), their median CD4+ cell count was 468 cells/&mgr;l and 84.3% had undetectable viral load. Both biomarkers were validated against chronological age in HIV-seronegative individuals. Telomere length was significantly shorter in HIV-infected individuals than in HIV-seronegative individuals (mean relative T/S ratio ±SE:0.91 ± 0.007 vs. 1.07 ± 0.008, P < 0.0001). CD2NKA expression was higher in HIV-infected participants than in HIV-seronegative individuals (mean expression: 0.45 ± 0.02 vs. 0.36 ± 0.03, P = 0.003). Socioeconomic factors were not associated with biological ageing in HIV-infected participants. However, in participants on ART with undetectable viral load, biomarker levels indicated greater biological ageing in those with lower current CD4+ cell counts. Conclusion:Telomere length and CDKN2A expression were both consistent with increased biological ageing in HIV-infected individuals. Prospective studies of the impact of HIV on biological ageing in sub-Saharan Africa are warranted.

Frailty in HIV-infected adults in South Africa.

Objectives:Some evidence suggests that HIV infection is associated with premature frailty—a syndrome typically viewed as being related to ageing. We determined the prevalence and predictors of frailty in a population of HIV-infected individuals in South Africa. Design:Case-control study of 504 adults more than the age of 30 years, composed of 248 HIV-infected adults and 256 age- and gender-matched, frequency-matched HIV-seronegative individuals. Methods:Frailty was defined by standardized assessment comprised of ≥3 of weight loss, low physical activity, exhaustion, weak grip strength, and slow walking time. Independent predictors of frailty were evaluated using multivariable logistic regression. Results:The mean ages of the HIV-infected and HIV-seronegative groups were 41.1 ± 7.9 years and 42.6 ± 9.6 years, respectively. Of the HIV-infected adults, 87.1% were receiving antiretroviral treatment (median duration, 58 months), their median CD4 count was 468 cells/&mgr;L (interquartile range = 325–607 cells/&mgr;L) and 84.3% had undetectable plasma viral load. HIV-infected adults were more likely to be frail than HIV-seronegative individuals (19.4% vs. 13.3%; P = 0.07), and this association persisted after adjustment for confounding variables [adjusted OR = 2.14; 95% confidence interval (95% CI): 1.16–3.92, P = 0.01]. Among HIV-infected individuals, older age was a strong predictor of frailty, especially among women (women: OR = 2.55 per 10-year age increase; men: OR = 1.29 per 10-year age increase, P-interaction = 0.01). Lower current CD4 count (<500 cells/&mgr;L) was also independently associated with frailty (OR = 2.84; 95% CI: 1.02 –7.92, P = 0.04). Conclusions:HIV infection is associated with premature development of frailty, especially in women. Since higher CD4 counts were associated with lower risk of frailty, earlier initiation of antiretroviral treatment may be protective.

Prevalence of HIV-associated ophthalmic disease among patients enrolling for antiretroviral treatment in India: a cross-sectional study.

BackgroundThe ocular manifestations of HIV may lead to visual impairment or blindness. In India, patients typically initiate antiretroviral treatment (ART) with low CD4 cell counts when the risk of ocular complications may be high. The objective of this study was to determine the prevalence and types of HIV-associated ocular conditions in patients referred for ART in India.MethodsThis cross-sectional study was undertaken at a large public sector ART centre in Mumbai, India. Data collection including a standardised symptom screen, and an ophthalmic examination were performed on all consecutive patients satisfying the criteria for enrolment into the ART clinic irrespective of the presence or absence of ophthalmic/visual symptoms.ResultsEnrolled patients (n = 149) had a median CD4 cell count of 180 cell/μL (inter-quartile range [IQR], 106-253 cells/μL). The prevalence of HIV-associated ocular disease was 17.5% (95% CI, 11.2-23.6%) in all participants and 23.8% (95% CI: 14.5-33.1) in those with CD4 cell counts <200 cells/μL (n = 84). Only 7.7% of patients with HIV-associated ocular disease reported any eye symptoms in the standardised symptom screen. Objective visual impairment was detected in 20% of those with HIV-associated ocular disease compared to 6% in those without ocular manifestations (p = 0.02). Vitreoretinal disease was the most common manifestation, of which cytomegalovirus retinitis (CMVR) was the most frequent retinal infection (overall prevalence 8.7%, 95% CI: 4.1-13.3%). In a multivariable analysis, HIV-associated ocular disease was independently associated with a CD4 count <100 cells/μL (odds ratio [OR], 6.3, 95% CI: 1.5-25.9) and WHO clinical stages 3 and 4 (OR 9.4, 95% CI: 2.4-37.2). However, symptoms were not independently predictive of ocular disease. Sensitivity of ocular symptom screening was 7.7%, with a positive predictive value of 18% in this population.ConclusionOver a fifth of unselected patients who are eligible for ART in this setting have HIV-related ocular disease of which CMVR is the most common form. Such patients may be at risk of developing ocular immune reconstitution phenomena during ART. Screening for ocular symptoms is not a reliable method to identify those with ocular morbidity and this highlights the need for routine ophthalmic screening prior to commencement of ART.

Differing spectrum of HIV‐associated ophthalmic disease among patients starting antiretroviral therapy in India and South Africa

Differences in the prevalence and spectrum of HIV‐associated ophthalmic disease in Africa and Asia are not well documented. We studied two comparable cohorts of patients initiating antiretroviral therapy in Mumbai, India, and Cape Town, South Africa. The prevalence of HIV‐associated ophthalmic disease was higher in the Indian population (17.5%) than in the South African population (12.1%). This was largely because of vitreo‐retinal opportunistic infections (11.4%vs. 2.6%, respectively), notably cytomegalovirus retinitis. This difference persisted after adjusting for confounding factors (adjusted odds ratio = 11.32, 95% confidence interval: 2.67–48.13), confirming a marked geographical difference in the prevalence of HIV‐associated retinal disease.

Retinal Arterioles Narrow with Increasing Duration of Anti-Retroviral Therapy in HIV Infection: A Novel Estimator of Vascular Risk in HIV?

Objectives HIV infection is associated with an increased risk of age-related morbidity mediated by immune dysfunction, atherosclerosis and inflammation. Changes in retinal vessel calibre may reflect cumulative structural damage arising from these mechanisms. The relationship of retinal vessel calibre with clinical and demographic characteristics was investigated in a population of HIV-infected individuals in South Africa. Methods Case-control study of 491 adults ≥30 years, composed of 242 HIV-infected adults and 249 age- and gender-matched HIV-negative controls. Retinal vessel calibre was measured using computer-assisted techniques to determine mean arteriolar and venular diameters of each eye. Results The median age was 40 years (IQR: 35–48 years). Among HIV-infected adults, 87.1% were receiving highly active antiretroviral therapy (HAART) (median duration, 58 months), their median CD4 count was 468 cells/µL, and 84.3% had undetectable plasma viral load. Unadjusted mean retinal arteriolar diameters were 163.67±17.69 µm in cases and 161.34±17.38 µm in controls (p = 0.15). Unadjusted mean venular diameters were 267.77±18.21 µm in cases and 270.81±18.98 µm in controls (p = 0.07). Age modified the effect of retinal arteriolar and venular diameters in relation to HIV status, with a tendency towards narrower retinal diameters in HIV cases but not in controls. Among cases, retinal arteriolar diameters narrowed with increasing duration of HAART, independently of age (167.83 µm <3 years of HAART vs. 158.89 µm >6 years, p-trend = 0.02), and with a HIV viral load >10,000 copies/mL while on HAART (p = 0.05). HIV-related venular changes were not detected. Conclusions Narrowing of retinal arteriolar diameters is associated with HAART duration and viral load, and may reflect heightened inflammatory and pro-atherogenic states of the systemic vasculature. Measurement of retinal vascular calibre could be an innovative non-invasive method of estimating vascular risk in HIV-infected individuals.

Increased ocular lens density in HIV-infected individuals with low nadir CD4 counts in South Africa: evidence of accelerated aging.

Background:HIV infection is thought to be associated with an increased risk of age-related morbidity and premature aging. Lens density increases with age and may function as a biomarker of aging. The relationship of lens density measurements with clinical and demographic characteristics in HIV-infected individuals in comparison with a matched population of HIV-seronegative individuals was investigated. Methods:Case–control study of 490 adults aged greater than or equal to 30 years composed of 242 HIV-infected adults and 248 age- and sex-matched HIV-seronegative individuals. Lens density was assessed using lens densitometry (Pentacam) imaging. Measurements were divided into quartiles, and comparison of HIV status and HIV-related factors was assessed by multivariate and multinomial logistic regression. Results:The mean age was 41.2 years in HIV-infected adults and 42.3 years in HIV-seronegative individuals (P = 0.14). Of the HIV-infected adults, 88% were receiving antiretroviral therapy (ART) (median duration, 58 months), and within this group, their median CD4 count was 468 cells per microliter and 84% had undetectable viral load. Although adjusted lens densities were similar by HIV serostatus, participants on ART and who had nadir CD4 counts less than 200 cells per microliter had a higher risk of high lens density compared with HIV-seronegative individuals (P trend = 0.04). Lens density was weakly associated with detectable HIV viremia despite ART, but not with current CD4 count. Conclusions:HIV-infected individuals on ART with nadir CD4 counts <200 cells per microliter had increased risk of higher lens density. Lens density may represent a novel biomarker of aging, providing insight into accelerated aging trajectories in HIV infection.

Corneal endothelial cells provide evidence of accelerated cellular senescence associated with HIV infection: a case-control study.

Background Cellular senescence may be a key factor in HIV-related premature biological aging. We assessed features of the corneal endothelium that are known to be associated with biological aging, and cellular senescence markers in HIV-infected adults. Methods Case-control study of 242 HIV-infected adults and 249 matched controls. Using specular microscopy, the corneal endothelium was assessed for features of aging (low endothelial cell density [ECD], high variation in cell size, and low hexagonality index). Data were analysed by multivariable regression. CDKN2A expression (a cell senescence mediator) was measured in peripheral blood leukocytes and 8-hydroxy-2′-deoxyguanosine (8-OHDG; an oxidative DNA damage marker) levels were measured in plasma. Results The median age of both groups was 40 years. Among HIV-infected adults, 88% were receiving antiretroviral therapy (ART); their median CD4 count was 468 cells/µL. HIV infection was associated with increased odds of variation in cell size (OR = 1.67; 95% CI: 1.00–2.78, p = 0.04). Among HIV-infected participants, low ECD was independently associated with current CD4 count <200 cells/µL (OR = 2.77; 95%CI: 1.12–6.81, p = 0.03). In participants on ART with undetectable viral load, CDKN2A expression and 8-OHDG levels were higher in those with accelerated aging, as reflected by lower ECD. Conclusions The corneal endothelium shows features consistent with HIV-related accelerated senescence, especially among those with poor immune recovery.

Assessment of candidate ocular biomarkers of ageing in a South African adult population: Relationship with chronological age and systemic biomarkers

Highlights • Structural parameters of the eye change with increasing chronological age.• Ocular age-related parameters may serve as biomarkers of aging.• Relevant ocular parameters include retinal vessel calibre and lens density.

Retinal Nerve Fibre Layer Thickness and Contrast Sensitivity in HIV-Infected Individuals in South Africa: A Case-Control Study

Background Antiretroviral treatment (ART) has altered the spectrum of HIV-related eye disease, resulting in a lower prevalence of retinal opportunistic infections (OIs). However, abnormalities in visual function have been reported in HIV-infected individuals despite effective viral suppression and the absence of retinal OIs. These changes may be mediated by an HIV-associated ‘neuroretinal disorder’, characterized by changes in the retinal nerve fibre layer (RNFL). HIV infection may also be associated with accelerated biological aging. The aim of this study was to investigate the relationships between contrast sensitivity, RNFL thickness, HIV infection and frailty in South African adults. Methods Case-control study of 225 HIV-infected individuals without retinal OIs and 203 gender/age-matched HIV-seronegative individuals. Peri-papillary RNFL thickness was determined with spectral domain optical coherence tomography in four quadrants. CS was measured using a Pelli-Robson chart. Frailty was assessed using standard criteria. Multivariable linear and logistic regression were used to assess associations between HIV status and RNFL/CS and frailty. Results The median age of both groups was similar (41.2 vs. 41.9 years, p = 0.37). 88% of HIV-infected individuals were receiving ART and their median CD4 count was 468 cells/μl. Adjusted CS score was lower in HIV-infected participants compared to HIV-seronegative individuals (1.76 vs. 1.82, p = 0.002). Independent predictors of poor CS in the HIV-infected group were positive frailty status and current HIV viral load >2 log copies/ml. Lower CS score was also associated with thin temporal RNFL in HIV-infected individuals (p = 0.04). Superior quadrant RNFL thickness was greatest in ART-naïve participants relative to the HIV-uninfected group (p-trend = 0.04). Longer ART duration was associated with thinning of inferior and nasal RNFL quadrants (p-trend = 0.03 and 0.04, respectively). Conclusions Contrast sensitivity is reduced in HIV-infected individuals and functionally associated with frailty and unsuppressed viraemia. This may reflect structural changes in the RNFL that are evident despite the absence of OIs.

Ocular parameters of biological ageing in HIV-infected individuals in South Africa: relationship with chronological age and systemic biomarkers of ageing

Highlights • HIV is associated with age-related morbidity despite antiretroviral treatment.• Ocular age-related parameters may serve as biomarkers of ageing.• Lens density may have a role in the determination of biological age in HIV infection.